PKS762refs.MYD ~?yEgan, M. F. Goldberg, T. E. Kolachana, B. S. Callicott, J. H. Mazzanti, C. M. Straub, R. E. Goldman, D. Weinberger, D. R.2001\Effect of COMT Val(108/158) Met genotype on frontal lobe function and risk for schizophrenia 6917-6922OProceedings of the National Academy of Sciences of the United States of America9812JunAbnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Va(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activity Met allele predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups(n = 11-16) assayed with functional MRI, Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology. and by this mechanism slightly increases risk for schizophrenia.://000169151500070 Times Cited: 512ISI:000169151500070NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Psychiat, Richmond, VA 23298 USA. Egan, MF, NIMH, Clin Brain Disorders Branch, Bldg 10,Ctr Dr, Bethesda, MD 20892 USA.?aHariri, A. Mattay, V. Tessitore, A. Kolachana, B. Fera, F. Goldman, D. Egan, M. Weinberger, D. R.2002OSerotonin transporter genetic variation and the response of the human amygdala.400-403Science297$~?QHariri, A. R. Mattay, V. S. Tessitore, A. Fera, F. Smith, W. G. Weinberger, D. R.2002>Dextroamphetamine modulates the response of the human amygdala 1036-1040Neuropsychopharmacology276Dec(Amphetamine, a potent monoaminergic agonist, has pronounced effects on emotional behavior in humans, including the generation of fear and anxiety. Recent animal studies have demonstrated the importance of monoamines, especially dopamine, in modulating the response of the amygdala, a key brain region involved in the perception of fearful and threatening stimuli, and the generation of appropriate physiological and behavioral responses. We have explored the possibility that the anxiogenic effect of amphetamine in humans reflects the drug's influence on the activity of the amygdala. In a double-blind placebo controlled study, fMRI revealed that dextroamphetamine potentiated the response of the amygdala during the perceptual processing of angry and fearful facial expressions. Our results provide the first evidence of a specific neural substrate for the anxiogenic effects of amphetamine and are consistent with animal models of dopaminergic activation of the amygdala. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.://000179156900015 Times Cited: 23ISI:000179156900015NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Room 3C108, Bethesda, MD 20892 USA.(~?DHariri, A. R. Tessitore, A. Mattay, V. S. Fera, F. Weinberger, D. R.2002LThe amygdala response to emotional stimuli: A comparison of faces and scenes317-323 Neuroimage171SepPAs a central fear processor of the brain, the amygdala initiates a cascade of critical physiological and behavioral responses. Neuroimaging studies have shown that the human amygdala responds not only to fearful and angry facial expressions but also to fearful and threatening scenes such as attacks, explosions, and mutilations. Given the relative importance of facial expressions in adaptive social behavior, we hypothesized that the human amygdala would exhibit a stronger response to angry and fearful facial expressions in comparison to other fearful and threatening stimuli. Twelve subjects completed two tasks while undergoing fMRI: matching angry or fearful facial expressions, and matching scenes depicting fearful or threatening situations derived from the International Affective Picture System (IAPS). While there was an amygdala response to both facial expressions and IAPS stimuli, direct comparison revealed that the amygdala response to facial expressions was significantly greater than that to IAPS stimuli. Autonomic reactivity, measured by skin conductance responses, was also greater to facial expressions. These results suggest that the human amygdala shows a stronger response to affective facial expressions than to scenes, a bias that should be considered in the design of experimental paradigms interested in probing amygdala function.://000178102000023 Times Cited: 63ISI:000178102000023NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA.~?OLangheim, F. J. P. Callicott, J. H. Mattay, V. S. Duyn, J. H. Weinberger, D. R.20027Cortical systems associated with covert music rehearsal901-908 Neuroimage164AugMusical representation and overt music production are necessarily complex cognitive phenomena. While overt musical performance may be observed and studied, the act of performance itself necessarily skews results toward the importance of primary sensorimotor and auditory cortices. However, imagined musical performance (IMP) represents a complex behavioral task involving components suited to exploring the physiological underpinnings of musical cognition in music performance without the sensorimotor and auditory confounds of overt performance. We mapped the blood oxygenation level-dependent fMRI activation response associated with IMP in experienced musicians independent of the piece imagined. IMP consistently activated supplementary motor and premotor areas, right superior parietal lobule, right inferior frontal gyrus, bilateral mid-frontal gyri, and bilateral lateral cerebellum in contrast with rest, in a manner distinct from fingertapping versus rest and passive listening to the same piece versus rest. These data implicate an associative network independent of primary sensorimotor and auditory activity, likely representing the cortical elements most intimately linked to music production.://000177444900005 Times Cited: 13ISI:000177444900005NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NINDS, Lab Funct & Mol Imaging, IRP, NIH, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA.?rMattay, V. Tessitore, A. Callicott, J. H. Bertolino, A. Goldberg, T. E. Chase, T. N. Hyde, T. M. Weinberger, D. R.2002S Dopaminergic modulation of cortical function in patients with Parkinson's disease.156-164 Ann Neurol512~?]Mattay, V. S. Fera, F. Tessitore, A. Hariri, A. R. Das, S. Callicott, J. H. Weinberger, D. R.2002LNeurophysiological correlates of age-related changes in human motor function630-635 Neurology584FebBackground: There are well-defined and characteristic age-related deficits in motor abilities that may reflect structural and chemical changes in the aging brain. Objective: To delineate age-related changes in the physiology of brain systems subserving simple motor behavior. Methods: Ten strongly right-handed young (<35 years of age) and 12 strongly right-handed elderly (>50 years of age) subjects with no evidence of cognitive or motor deficits participated in the study. Whole-brain functional imaging was performed on a 1.5-T MRI scanner using a spiral pulse sequence while the subjects performed a visually paced "button-press" motor task with their dominant right hand alternating with a rest state. Results: Although the groups did not differ in accuracy, there was an increase in reaction time in the elderly subjects (mean score +/- SD, young subjects = 547 +/- 97 ins, elderly subjects = 794 280 ms, p < 0.03). There was a greater extent of activation in the contralateral sensorimotor cortex, lateral premotor area, supplementary motor area, and ipsilateral cerebellum in the elderly subjects relative to the young subjects (p < 0.001). Additional areas of activation, absent in the young subjects, were seen in the ipsilateral sensorimotor cortex, putamen (left > right), and contralateral cerebellum of the elderly subjects. Conclusions: The results of this study show that elderly subjects recruit additional cortical and subcortical areas even for the performance of a simple motor task. These changes may represent compensatory mechanisms invoked by the aging brain, such as reorganization and redistribution of functional networks to compensate for age-related structural and neurochemical changes.://000174012600022 Times Cited: 46ISI:000174012600022NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Mattay, VS, Bldg 10,Ctr Dr,Rm 4S-235, Bethesda, MD 20982 USA.~?ZSt Lawrence, K. S. Ye, F. Q. Lewis, B. K. Weinberger, D. R. Frank, J. A. McLaughlin, A. C.2002wEffects of indomethacin on cerebral blood flow at rest and during hypercapnia: An arterial spin tagging study in humans628-635%Journal of Magnetic Resonance Imaging156JunPurpose: To investigate using an arterial spin tagging (AST) approach the effect of indomethacin on the cerebral blood flow (CBF) response to hypercapnia. Materials and Methods: Subjects inhaled a gas mixture containing 6% CO2 for two 5-minute periods, which were separated by a 10-minute interval, in which subjects inhaled room air. In six subjects, indomethacin (i.v., 0.2 mg/ kg) was infused in the normocapnic interval between the two hypercapnic periods. Results: Indomethacin reduced normocapnic gray matter CBF by 36 +/- 5% and reduced the CBF increase during hypercapnia from 43 +/- 9% to 16 +/- 5% in gray matter (P < 0.001) and from 48 +/- 11% to 35 +/- 9% in white matter (P < 0.025). Conclusion: The results demonstrate that an AST approach can measure the effects of indomethacin on global CBF increases during hypercapnia and suggest that an AST approach could be used to investigate pharmacological effects on focal CBF increases during functional activation.://000175918300002 Times Cited: 4ISI:000175918300002NIH, Lab Diagnost Radiol Res, Clin Ctr, Bethesda, MD 20892 USA. St Lawrence, KS, NIH, Lab Diagnost Radiol Res, Clin Ctr, Bldg 10 Rm B1N 256 10 Ctr Dr MSC 1074, Bethesda, MD 20892 USA.~? jTessitore, A. Hariri, A. R. Fera, F. Smith, W. G. Chase, T. N. Hyde, T. M. Weinberger, D. R. Mattay, V. S.2002UDopamine modulates the response of the human amygdala: A study in Parkinson's disease 9099-9103Journal of Neuroscience2220OctVIn addition to classic motor signs and symptoms, Parkinson's disease (PD) is characterized by neuropsychological and emotional deficits, including a blunted emotional response. In the present study, we explored both the neural basis of abnormal emotional behavior in PD and the physiological effects of dopaminergic therapy on the response of the amygdala, a central structure in emotion processing. PD patients and matched normal controls (NCs) were studied with blood oxygenation level-dependent functional magnetic resonance imaging during a paradigm that involved perceptual processing of fearful stimuli. PD patients were studied twice, once during a relatively hypodopaminergic state (i.e., greater than or equal to12 hr after their last dose of dopamimetic treatment) and again during a dopamine-replete state. The imaging data revealed a robust bilateral amygdala response in NCs that was absent in PD patients during the hypodopaminergic state. Dopamine repletion partially restored this response in PD patients. Our results demonstrate an abnormal amygdala response in PD that may underlie the emotional deficits accompanying the disease. Furthermore, consistent with findings in experimental animal paradigms, our results provide in vivo evidence of the role of dopamine in modulating the response of the amygdala to sensory information in human subjects.://000178686600035 Times Cited: 28ISI:000178686600035NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Mattay, VS, NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Room 3C108, Bethesda, MD 20892 USA. ~? Weinberger, D. R. McClure, R. K.2002zNeurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry - What is happening in the schizophrenic brain?553-558Archives of General Psychiatry596JunIn an era of dramatic discoveries in neuroscience and genetics, it is likely that many popular theories and formulations about mental illness will need to be revised, if not discarded. The "neurodevelopmental hypothesis" is one of the popular theories about the origins of schizophrenia, which posits that abnormalities of early brain development increase risk for the subsequent emergence of the clinical syndrome.(1-3) An early piece of evidence in support of this hypothesis was the apparent lack of progression of cerebral ventricular enlargement observed with computed tomography during illness.(4-9) An important assumption of the neuro developmental hypothesis is that the putative primary pathologic condition of the brain is a reflection of abnormalities of early development. The neuro developmental hypothesis thus assumes that developmental neuropathologic conditions should arrest early in life and not continue to progress. The computed tomography results showing no apparent progression seemed consistent with this assumption. However, a recent series of magnetic resonance imaging (MRI) studies has called into question this assumption, by revealing changes in measurements of brain structures over short periods in patients who have been ill for varying durations and at various stages of life. These recent studies'(10-14) have generated enthusiasm for a "neurodegenerative hypothesis," harkening back to proposals of Kraepelin and other neuropathologists during the first quarter of the 20th century that there is destruction of neural tissue associated with psychosis. In fact, results of MRI measurements have been cited as support for a much broader conceptual revolution in psychiatry, a "neurotoxicity hypothesis" for many psychiatric illnesses, including affective disorders(15,16) and anxiety and stress disorders(17-19) and even jet lag.(20) This recent trend has been bolstered by basic discoveries about the adaptability of neuronal connections(21) and the viability and reproducibility of neurons in the adult brain (eg, apoptosis and neurogenesis).(22,23) These developments have led some to opine that the neurodegenerative hypothesis of schizophrenia may have been unjustly overshadowed by the ascendancy of the neuro developmental hypothesis.(24)://000176055400010 Times Cited: 62ISI:000176055400010NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Bldg 10,Room 3C-101,MSc 1255, Bethesda, MD 20892 USA. %~? eCallicott, J. H. Egan, M. F. Mattay, V. S. Bertolino, A. Bone, A. D. Verchinksi, B. Weinberger, D. R.2003zAbnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia709-719American Journal of Psychiatry1604AprObjective: The identification of neurobiological intermediate phenotypes may hasten the search for susceptibility genes in complex psychiatric disorders such as schizophrenia. Earlier family studies have suggested that deficits in executive cognition and working memory may be related to genetic susceptibility for schizophrenia, but the biological basis for this behavioral phenotype has not been identified. Method: The authors used functional magnetic resonance imaging (fMRI) during performance of the N-back working memory task to assess working memory-related cortical physiology in nonschizophrenic, cognitively intact siblings of patients with schizophrenia. They compared 23 unaffected siblings of schizophrenic patients to 18 matched comparison subjects. As a planned replication, they studied another 25 unaffected siblings and 15 comparison subjects. Results: In both cohorts, there were no group differences in working memory performance. Nevertheless, both groups of siblings showed an exaggerated physiological response in the right dorsolateral prefrontal cortex that was qualitatively similar to results of earlier fMRI studies of patients with schizophrenia. Conclusions: These fMRI data provide direct evidence of a primary physiological abnormality in dorsolateral prefrontal cortex function in individuals at greater genetic risk for schizophrenia, even in the absence of a manifest cognitive abnormality. This exaggerated fMRI response implicates inefficient processing of memory information at the level of intrinsic prefrontal circuitry, similar to earlier findings in patients with schizophrenia. These data predict that inheritance of alleles that contribute to inefficient prefrontal information processing will increase risk for schizophrenia.://000182096300019 Times Cited: 57ISI:000182096300019NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Clin Brain Disorders Branch, IRP, NIH, Bldg 10,Ctr Dr,Rm 4D-20 MSC1389, Bethesda, MD 20892 USA. 1~? ZCallicott, J. H. Mattay, V. S. Verchinski, B. A. Marenco, S. Egan, M. F. Weinberger, D. R.2003TComplexity of prefrontal cortical dysfunction in schizophrenia: More than up or down 2209-2215American Journal of Psychiatry16012Dec5Objective: Numerous neuroimaging studies have examined the function of the dorsolateral prefrontal cortex in schizophrenia; although abnormalities usually are identified, it is unclear why some studies find too little activation and others too much. The authors' goal was to explore this phenomenon. Method: They used the N-back working memory task and functional magnetic resonance imaging at 3 T to examine a group of 14 patients with schizophrenia and a matched comparison group of 14 healthy subjects. Results: Patients' performance was significantly worse on the two-back working memory task than that of healthy subjects. However, there were areas within the dorsolateral prefrontal cortex of the patients that were more active and areas that were less active than those of the healthy subjects. When the groups were subdivided on the basis of performance on the working memory task into healthy subjects and patients with high or low performance, locales of greater prefrontal activation and locales of less activation were found in the high-performing patients but only locales of underactivation were found in the low-performing patients. Conclusions: These findings suggest that patients with schizophrenia whose performance on the N-back working memory task is similar to that of healthy comparison subjects use greater prefrontal resources but achieve lower accuracy (i.e., inefficiency) and that other patients with schizophrenia fail to sustain the prefrontal network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in schizophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex.://000186881900021 Times Cited: 56ISI:000186881900021NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Rm 4D-20,MSC 1389, Bethesda, MD 20892 USA.~? Egan, M. F. Kojima, M. Callicott, J. H. Goldberg, T. E. Kolachana, B. S. Bertolino, A. Zaitsev, E. Gold, B. Goldman, D. Dean, M. Lu, B. Weinberger, D. R.2003uThe BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function257-269Cell1122JanBrain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF://000181191600014 Times Cited: 284ISI:000181191600014NICHHD, Sect Neural Dev & Plast, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20857 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Natl Inst AIST, Cell Dynam Res Grp, Osaka 5638577, Japan. Japan Sci & Technol Corp, CREST, Kawaguchi 3320012, Japan. Lu, B, NICHHD, Sect Neural Dev & Plast, NIH, DHHS, Bldg 49-6A67, Bethesda, MD 20892 USA.&~?kHariri, A. R. Goldberg, T. E. Mattay, V. S. Kolachana, B. S. Callicott, J. H. Egan, M. F. Weinberger, D. R.2003Brain-derived neurotrophic factor val(66)met polymorphism affects human memory-related hippocampal activity and predicts memory performance 6690-6694Journal of Neuroscience2317JulBDNF plays a critical role in activity-dependent neuroplasticity underlying learning and memory in the hippocampus. A frequent single nucleotide polymorphism in the targeting region of the human BDNF gene (val (66)met) has been associated with abnormal intracellular trafficking and regulated secretion of BDNF in cultured hippocampal neurons transfected with the met allele. In addition, the met allele has been associated with abnormal hippocampal neuronal function as well as impaired episodic memory in human subjects, but a direct effect of BDNF alleles on hippocampal processing of memory has not been demonstrated. We studied the relationship of the BDNF val (66)met genotype and hippocampal activity during episodic memory processing using blood oxygenation level-dependent functional magnetic resonance imaging and a declarative memory task in healthy individuals. Met carriers exhibited relatively diminished hippocampal engagement in comparison with val homozygotes during both encoding and retrieval processes. Remarkably, the interaction between the BDNF val (66)met genotype and the hippocampal response during encoding accounted for 25% of the total variation in recognition memory performance. These data implicate a specific genetic mechanism for substantial normal variation in human declarative memory and suggest that the basic effects of BDNF signaling on hippocampal function in experimental animals are important in humans.://000184469200003 Times Cited: 90ISI:000184469200003NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,US Dept HHS, 10 Ctr Dr,Room 4S235, Bethesda, MD 20892 USA.~?DHariri, A. R. Mattay, V. S. Tessitore, A. Fera, F. Weinberger, D. R.2003BNeocortical modulation of the amygdala response to fearful stimuli494-501Biological Psychiatry536Mar{Background: The cortical circuitry involved in conscious cognitive processes and the subcortical circuitry involved in fear responses have been extensively studied with neuroimaging, but their interactions remain largely unexplored. A recent functional magnetic resonance imaging (fMRI) study demonstrated that the engagement of the right prefrontal cortex during the cognitive evaluation of angry and fearful facial expressions is associated with an attenuation of the response of the amygdala to these same stimuli, providing evidence for a functional neural network for emotional regulation. Methods: In the current study, we have explored the generalizability of this functional network by using threatening and fearful non-face stimuli derived from the International Affective Picture System (IAPS), as well as the influence of this network on peripheral autonomic responses. Results: Similar to the earlier findings with facial expressions, blood oxygen level dependent fMRI revealed that whereas perceptual processing of IAPS stimuli was associated with a bilateral amygdala response, cognitive evaluation of these same stimuli was associated with attenuation of this amygdala response and a correlated increase in response of the right prefrontal cortex and the anterior cingulate cortex. Moreover, this pattern was reflected in changes in skin conductance. Conclusions: The current results further implicate the importance of neocortical regions, including the prefrontal and anterior cingulate cortices, in regulating emotional responses mediated by the amygdala through conscious evaluation and appraisal. (C) 2003 Society of Biological Psychiatry.://000181569900004 Times Cited: 90ISI:000181569900004NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Hariri, AR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 10 Ctr Dr,Rm 3C108, Bethesda, MD 20892 USA.~?Hariri, A. R. Weinberger, D. R.2003Imaging genomics259-270British Medical Bulletin65;The recent completion of a working draft of the human genome sequence promises to provide unprecedented opportunities to explore the genetic basis of individual differences in complex behaviours and vulnerability to neuropsychiatric illness. Functional neuroimaging, because of its unique ability to assay information processing at the level of brain within individuals, provides a powerful approach to such functional genomics. Recent fMRI studies have established important physiological links between functional genetic polymorphisms and robust differences in information processing within distinct brain regions and circuits that have been linked to the manifestation of various disease states such as Alzheimer's disease, schizophrenia and anxiety disorders. Importantly, all of these biological relationships have been revealed in relatively small samples of healthy volunteers and in the absence of observable differences at the level of behaviour, underscoring the power of a direct assay of brain physiology like fMRI in exploring the functional impact of genetic variation.://000182080300019 Times Cited: 47ISI:000182080300019NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, 10 Ctr Dr,Room 4S235, Bethesda, MD 20892 USA.~?>Heinz, A. Romero, B. Gallinat, J. Juckel, G. Weinberger, D. R.2003JMolecular brain imaging and the neurobiology and genetics of schizophrenia S152-S157Pharmacopsychiatry36NovIt has been hypothesized that schizophrenia is related to dysfunction in temporolimbic-prefrontal neuronal networks, which is acquired early in an individual's development. After puberty, relatively reduced prefrontal control of striatal dopaminergic neurotransmission may lead to unmodulated striatal dopamine (DA) activity, and the positive symptoms of acute psychosis. Brain imaging studies support the notion of prefrontal dysfunction in schizophrenia and correlated upregulation of presynaptic striatal DA activity. Recent molecular brain imaging studies have combined genetic assessments with a multimodal neuroimaging approach to further refine our understanding of the pathophysiologic architecture of the disorder. We review the literature on functional brain imaging in schizophrenia and discuss genotype effects on core psychotic symptoms. A promising research strategy is the identification of genetic and environmental factors that contribute to intermediate phenotypes such as working memory deficits in schizophrenia. Molecular brain imaging can help to unravel the complex interactions between genes and environment and its association with neuronal network dysfunction in schizophrenia.://000188081200002 Times Cited: 6 Suppl. 3ISI:000188081200002Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, D-10117 Berlin, Germany. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Heinz, A, Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, CCM, Schumannstr 20-21, D-10117 Berlin, Germany. andreas.heinz@charite.de~?Mattay, V. S. Goldberg, T. E. Fera, F. Hariri, A. R. Tessitore, A. Egan, M. F. Kolachana, B. Callicott, J. H. Weinberger, D. R.2003pCatechol O-methyltransferase val(158)-met genotype and individual variation in the brain response to amphetamine 6186-6191OProceedings of the National Academy of Sciences of the United States of America10010May\Monamines subserve many critical roles in the brain, and monoaminergic drugs such as amphetamine have a long history in the treatment of neuropsychiatric disorders and also as a substance of abuse. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes. We explored the effect of a functional polymorphism (val(158)-Met) in the catechol O-methyltransferase gene, which has been shown to modulate prefrontal dopamine animals and prefrontal cortical function in humans, on the modulatory actions of amphetamine on the prefrontal cortex. Amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine, at all levels of task difficulty. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. These data illustrate an application of functional neuroimaging in pharmacogenomics and extend basic evidence of an inverted-"U" functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appear to beat increased risk for an adverse response to amphetamine.://000182939400110 Times Cited: 125ISI:000182939400110NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20982 USA. Weinberger, DR, NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20982 USA.~?IScamvougeras, A. Kigar, D. L. Jones, D. Weinberger, D. R. Witelson, S. F.2003eSize of the human corpus callosum is genetically determined: an MRI study in mono and dizygotic twins91-94Neuroscience Letters3382FebThe factors determining the large variation seen in human corpus callosum (CC) morphology are as yet unknown. In this study heritability of CC size was assessed by comparing the concordance of CC midsagittal area in 14 monozygotic and 12 dizygotic twin pairs with a mean age of 27 years, using magnetic resonance imaging and various methods of calculating trait heritability. Heritability was high regardless of method of assessment. The application of a structural equation model resulted in the estimate that 94% of the variance in CC midsagittal size is attributable to the genome. This indicates that under normal conditions and before the effects of normal aging, there is very modest influence of the environment on CC morphology. The results suggest that correlates of CC size, such as the pattern of cerebral lateralization, cognitive abilities and neuropsychiatric dysfunction may be associated with the genetic determinants of CC morphology. (C) 2002 Published by Elsevier Science Ireland Ltd.://000181014300001 Times Cited: 6ISI:000181014300001McMaster Univ, Albert Einstein Irving Zucker Chair Neurosci, Dept Psychiat & Behav Neurosci, Hamilton, ON L8N 3Z5, Canada. Univ British Columbia, Dept Psychiat, Neuropsychiat Unit, Vancouver, BC, Canada. NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Witelson, SF, McMaster Univ, Albert Einstein Irving Zucker Chair Neurosci, Dept Psychiat & Behav Neurosci, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada.~?^Scarabino, T. Bertolino, A. Burroni, M. Popolizio, T. Duyn, J. Weinberger, D. R. Salvolini, U.2003wWhite matter lesions in phenylketonuria: Evaluation with magnetic resonance Imaging and magnetic resonance spectroscopy251-261Rivista Di Neuroradiologia162Apr.Phenylketonuria (PKU) is a congenital metabolic autosomic recessive disease, caused by a deficit in the liver of phenyl-alanine hydroxylase, the enzyme responsible for conversion of phenyl-alanine (PHE) into tyrosine. Reduction of this enzymatic activity is responsible for increased phenyl-alanine in blood and tissues and, above all, in brain. Accumulation of PHE causes neural damage which produces a typical clinical picture with mental retardation, psychiatric symptoms and epilepsy. It is now possible to diagnose this disease early (with neonatal screening), before irreversible clinical symptoms reflecting central nervous system injury appear. Early diagnosis allows timely onset of therapy (the only possible) consisting of a special diet with reduced intake of PHE (integrated with a mix of aminoacids) whose objective is to keep levels of PHE low in the blood (3-6 mg/dl). Magnetic Resonance Imaging (MRI) is the elective diagnostic tool to evaluate in vivo the involvement of the brain in PKU. Previous MRI morphological studies in patients with PKU have reported various focal symmetrical lesions in periventricular white matter (especially parieto-occipital) of patients with PKU with PHE blood values higher than 10 mg/dl. These lesions, whose importance is not yet clear, seem to represent a reversible structural alteration of myelin, since they regress if blood PHE decreases. Proton magnetic resonance spectroscopy (H-1-MRS) can measure in vivo brain metabolites which could help determine the nature of white matter lesions. In particular, changes in NAA (a marker of neuronal integrity) or mI (a potential astrocytic marker) could point to possible neurochemical dysfunction, whereas Cho levels may parallel the degree of the tissue myelination. The purpose of the present study was to evaluate morphologically and biochemically the regional specificity of white matter lesions with structural MRI and with H-1-MRSI. The study included 12 patients with PKU ten to 42 years of age. All patients underwent structural MRI scans while eight of them were also studied with H-1-MRSI. Structural MRI lesions in white matter were analyzed both qualitatively (signal intensity) and quantitatively (location and extension). H-1-MRSI metabolites were measured as the ratio of the area under each peak: NAA/Cr, NAA/Cho, Cho/Cr. Analysis of location and extension of the lesion on structural MRI data showed limited involvement of parieto-occipital white matter in three cases (with isointense or vaguely hypointense lesions in T1, and moderately hyperintense lesions in T2); medium involvement in six cases (with fairly hypointense or isointense lesions in T1, fairly or moderately hyperintense lesions in T2); serious involvement in three cases (with isointense or fairly hypointense lesions in T1, and fairly hyperintense lesions in T2). As for H-1-MRSI data, ANOVA showed a significant reduction of NAA/Cho and increase in Cho/Cr in white matter lesions, but no change in NAA/Cr. No correlation was found between clinical parameters and morphological or spectroscopic data. In conclusion, our morphological MRI data confirmed the presence of multiple signal alterations, focal and symmetrical, in deep periventricular white matter (especially posterior), with occasional involvement of subcortical white matter. However, these lesions do not seem to be strongly predictive of clinical outcome. H-1-MRSI data suggest increased Cho levels in white matter lesions. Since Cho is thought to reflect membrane turnover, these data may support the demyelinating nature of lesions, consistent with earlier post mortem studies.://000184842000003 Times Cited: 0ISI:000184842000003_Casa Sollievo Sofferenza Sci Inst, Dept Neuroradiol, San Giovanni Rotondo, Italy. Univ Bari, Dept Neurol & Psychiat Sci, Psychiat Neurosci Grp, Bari, Italy. Gen Hosp, Dept Neuropsychiat, Fano, Italy. NIH, Lab Diagnost Radiol Res, Bethesda, MD USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD USA. Univ Ancona, Dept Neuroradiol, Ancona, Italy.b~?FWinterer, G. Coppola, R. Egan, M. F. Goldberg, T. E. Weinberger, D. R.2003WFunctional and effective frontotemporal connectivity and genetic risk for schizophrenia 1181-1192Biological Psychiatry5411DecBackground: Functional neuroimaging and electrophysiologic studies have found disturbed frontotemporal interaction in schizophrenia. We sought to determine whether abnormalities of frontotemporal connectivity are trait markers of genetic risk for schizophrenia. Methods: We investigated 64 schizophrenia patients, 79 of their clinically unaffected siblings, and 88 unrelated normal controls with an auditory oddball electroencephalogram (EEG) evoked potential paradigm. We measured: 1) frontotemporal event-related EEG-coherence (i.e. a measure of functional connectivity); and 2) we performed structural equation modeling of the effective connectivity between the frontal P300 and temporoparietal P300-amplitude. Results: Schizophrenic patients and their siblings showed a reduction of frontotemporal coherence. At peak activation during the P300 time-window, a negative ("inhibitory") frontotemporal path coefficient was found in normal controls, whereas a positive coefficient was seen in schizophrenic patients with siblings being intermediate. Intra-class correlations between sib-pairs and relative risk estimates of the applied connectivity measures were non-significant. Topographic correlation matrix analyses suggested that the altered functional and effective frontotemporal connectivity indirectly reflect regional abnormalities of increased activation variance. Conclusions: Impaired interaction of the frontotemporal macro-circuit indirectly reflects genetically determined abnormalities of frontal and temporoparietal microcircuits. The reasons why frontotemporal connectivity appears to be a poor predictor of genetic risk for schizophrenia are discussed.://000186792300007 Times Cited: 23ISI:000186792300007NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Winterer, G, Univ Mainz, Psychiat Klin & Poliklin, Untere Zahlbacher Str 8, D-55131 Mainz, Germany. :~?Bertolino, A. Blasi, G. Caforio, G. Latorre, V. De Candia, M. Rubino, V. Callicott, J. H. Mattay, V. S. Bellomo, A. Scarabino, T. Weinberger, D. R. Nardini, M.2004yFunctional lateralization of the sensorimotor cortex in patients with schizophrenia: Effects of treatment with olanzapine190-197Biological Psychiatry563AugBackground: Earlier cross-sectional studies with functional magnetic resonance imaging (fMRI) in treated patients with schizophrenia have reported abnormalities of cortical motor processing, including reduced lateralization of primary sensory motor cortex. The objective of the present longitudinal study was to evaluate whether such cortical abnormalities represent state or trait phenomena of the disorder. Methods: Seventeen acutely ill, previously untreated patients were studied after 4 weeks and after 8 weeks of olanzapine therapy. Seventeen matched healthy subjects served as control subjects. All subjects underwent two fMRI scans 4 weeks apart during a visually paced motor task using a simple periodic block design. Functional magnetic resonance imaging data were analyzed in Statistical Parametric Mapping (SPM99). Region of interest analyses were used to determine a laterality quotient (an index of lateralization) of motor cortical regions. Results: The fMRI data indicated that patients bad reduced activation of the primary sensory motor cortex at 4 weeks but not at 8 weeks; however, the laterality quotient in the primary sensory motor cortex was reduced in patients at both time points. Conclusions: These results suggest that some cortical abnormalities during motor processing represent state phenomena, whereas reduced functional lateralization of the primary sensory motor complex presents an enduring trait of schizophrenia.://000222878800009 Times Cited: 9ISI:000222878800009Univ Bari, Dipartimento Sci Neurol & Psichiat, Grp Neurosci Psichiat, Sez Clin Malattie Mentali, I-70124 Bari, Italy. Univ Foggia, Dept Psychiat, Foggia, Italy. Inst Ricovero & Cura Carattere Sci, Dept Neuroradiol, San Giovanni Rotondo, Foggia, Italy. NIMH, Clin Brain Disorders Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Bertolino, A, Univ Bari, Dipartimento Sci Neurol & Psichiat, Grp Neurosci Psichiat, Sez Clin Malattie Mentali, Piazza Giulio Cesare 9, I-70124 Bari, Italy. ~?Egan, M. F. Straub, R. E. Goldberg, T. E. Yakub, I. Callicott, J. H. Hariri, A. R. Mattay, V. S. Bertolino, A. Hyde, T. M. Shannon-Weickert, C. Akil, M. Crook, J. Vakkalanka, R. K. Balkissoon, R. Gibbs, R. A. Kleinman, J. E. Weinberger, D. R.2004UVariation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia 12604-12609OProceedings of the National Academy of Sciences of the United States of America10134AugGRM3, a metabotropic glutamate receptor-modulating synaptic glutamate, is a promising schizophrenia candidate gene. in a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001). Within this haplotype, the A allele of single-nucleotide polymorphism (SNP) 4 (hCV11245618) in intron 2 was slightly overtransmitted to probands (P = 0.02). We studied the effects of this SNP on neurobiological traits related to risk for schizophrenia and glutamate neurotransmission. The SNP4 A allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. The physiological basis of this effect was assessed with functional MRI, which showed relatively deleterious activation patterns in both cortical regions in control subjects homozygous for the SNP4 A allele. We next looked at SNP4's effects on two indirect measures of prefrontal glutamate neurotransmission. Prefrontal N-acetylaspartate, an in vivo MRI measure related to synaptic activity and closely correlated with tissue glutamate, was lower in SNP4 AA homozygotes. In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate. Effects of SNP4 on prefrontal GRM3 mRNA and protein levels were marginal. Resequencing revealed no missense or splice-site SNIPS, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription. These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia.://000223596200039 Times Cited: 34ISI:000223596200039NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Univ Bari, Clin Psichiatr 2, I-70121 Bari, Italy. ES Cell Int Pte Ltd, Melbourne, Vic 8008, Australia. Weinberger, DR, NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 45-227,MSC 1384, Bethesda, MD 20892 USA. weinberd@intra.nimh.nih.gov~?OKnutson, B. Bjork, J. M. Fong, G. W. Hommer, D. Mattay, V. S. Weinberger, D. R.20040Amphetamine modulates human incentive processing261-269Neuron432JulResearch suggests that psychostimulants can physiologically alter dopamine kinetics in the ventral striatum (VS) and psychologically enhance mood and attention. Using event-related functional magnetic resonance imaging (fMRI), we conducted a within-subject, double-blind, placebo (PLAC)-controlled study of the effects of oral dextroamphetamine (AMPH, 0.25 mg/kg) treatment on brain activity and affect during incentive processing. In two counterbalanced scanning sessions 60-180 min after ingesting AMPH or PLAC, 8 healthy volunteers played a game involving anticipation and receipt of monetary gains and losses. Group and volume of interest analyses suggested that by enhancing tonic over phasic activation, AMPH treatment "equalized" levels of VS activity and positive arousal during anticipation of both gain and loss. These findings suggest that therapeutic effects of amphetamine on incentive processing may involve reducing the difference between anticipation of gains and losses.://000222905400014 Times Cited: 11ISI:000222905400014Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. NIAAA, Clin Studies Lab, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. Knutson, B, Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. knutson@psych.stanford.edu5?Pezawas, L. Verchinksi, B. Mattay, V. Callicott, J. H. Kolachana, B. Straub, R. E. Egan, M. Meyer-Lindenberg, A. Weinberger, D. R.2004i The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. 10099-10102Journal of Neuroscience2545 ~?Bertolino, A. Arciero, G. Rubino, V. Latorre, V. De Candia, M. Mazzola, V. Blasi, G. Caforio, G. Hariri, A. Kolachana, B. Nardini, M. Weinberger, D. R. Scarabino, T.2005xVariation of human amygdala response during threatening stimuli as a function of 5'HTTLPR genotype and personality style 1517-1525Biological Psychiatry5712JunBackground: In the brain, processing of fearful stimuli engages the amygdala, and the variability of its activity is associated with genetic factors as well as with emotional salience. The objective of this study was to explore the relevance of personality style for variability of amygdala response. Methods. We studied two groups (n = 14 in each group) of healthy subjects categorized by contrasting cognitive styles with which they attribute salience to fearful stimuli: so-called phobic prone subjects who exaggerate potential environmental threat versus so-called eating disorders prone subjects who tend to be much, less centered around fear. The two groups underwent functional magnetic resonance imaging (fMRI) at 3T during performance of a perceptual task of threatening stimuli and they were also matched for the genotype of the 5'variable number tandem repeat (VNTR) polymorphism in the serotonin transporter Results. The fMRI results indicated that phobic prone results indicated that phobic prone subjects selectively recruit the amygdala to a larger extent than eating disorders prone subjects. Activity in the amygdala was also independently predicted by personality style and genotype of the serotonin transporter. Moreover, brain activity during a working memory task did not differentiate the two groups. Conclusions. The results of the present study suggest that aspects of personality style are rooted in biological responses of the fear circuitry associated with processing of environmental information.://000230007700007 Times Cited: 9ISI:000230007700007PUniv Bari, Dipartimento Sci Neurol & Psichiatriche, Sect Mental Disorders, I-70124 Bari, Italy. Univ Bari, Psychiat Neurosci Grp, I-70124 Bari, Italy. Ist Psicoterapia & Postrazionalista, Rome, Italy. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. IRCCS Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, Italy. Univ Pittsburgh, Sch Med, Dept Psychiat, Dev Imaging Genom Program, Pittsburgh, PA USA. Bertolino, A, Univ Bari, Dipartimento Sci Neurol & Psichiatriche, Sect Mental Disorders, Piazza Giulio Cesare,9, I-70124 Bari, Italy. bertolia@psichiat.uniba.it9~?Blasi, G. Mattay, V. S. Bertolino, A. Elvevag, B. Callicott, J. H. Das, S. Kolachana, B. S. Egan, M. F. Goldberg, T. E. Weinberger, D. R.2005REffect of catechol-O-methyltransferase val(158)met genotype on attentional control 5038-5045Journal of Neuroscience2520MayThe cingulate cortex is richly innervated by dopaminergic projections and plays a critical role in attentional control ( AC). Evidence indicates that dopamine enhances the neurophysiological signal-to-noise ratio and that dopaminergic tone in the frontal cortex is critically dependent on catechol-O-methyltransferase ( COMT). A functional polymorphism ( val(158)met) in the COMT gene accounts for some of the individual variability in executive function mediated by the dorsolateral prefrontal cortex. We explored the effect of this genetic polymorphism on cingulate engagement during a novel AC task. We found that the COMT val(158)met polymorphism also affects the function of the cingulate during AC. Individuals homozygous for the high-activity valine ("val") allele show greater activity and poorer performance than val/methionine ("met") heterozygotes, who in turn show greater activity and poorer performance than individuals homozygous for the low-activity met allele, and these effects are most evident at the highest demand for AC. These results indicate that met allele load and presumably enhanced dopaminergic tone improve the "efficiency" of local circuit processing within the cingulate cortex and thereby its function during AC.://000229203600016 Times Cited: 18ISI:000229203600016NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv,Gene Cognit & Psychosis Pr, Bethesda, MD 20892 USA. Univ Bari, Dept Neurol & Psychiat Sci, Neurosci Psychiat Grp, I-70124 Bari, Italy. Ist Ricovero & Cura Carattere Sci Casa Sollievo S, Dept Neuroradiol, I-71013 San Giovanni Rotondo, Italy. Weinberger, DR, NIMH, Clin Brain Disorders Branch, NIH, Dept Hlth & Human Serv,Gene Cognit & Psychosis Pr, Bldg 10,Ctr Dr,Room 4S-235, Bethesda, MD 20892 USA. weinberd@mail.nih.gov?Callicott, J. H. Straub, R. E. Pezawas, L. Egan, M. Mattay, V. Hariri, A. Verchinksi, B. Meyer-Lindenberg, A. Balkissoon, R. Kolachana, B. Goldberg, T. E. Weinberger, D. R.2005cVariation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. 8627-8632OProceedings of the National Academy of Sciences of the United States of America102244?Fera, F. Weickert, T. Goldberg, T. E. Tessitore, A. Hariri, A. Das, S. Lee, S. Zoltick, B. Meeter, M. Myers, C. E. Gluck, M. A. Weinberger, D. R. Mattay, V.2005MNeural mechanisms underlying probabilistic category learning in normal aging. 11340-11348Journal of Neuroscience2549?ZHariri, A. Drabant, E. M. Munoz, K. E. Kolachana, B. Mattay, V. Egan, M. Weinberger, D. R.2005WA susceptibility gene for affective disorders and the response of the human amygdala. 142-152Arch Gen Psychiatry622C?Pezawas, L. Meyer-Lindenberg, A. Drabant, E. M. Verchinksi, B. Munoz, K. E. Kolachana, B. Egan, M. Mattay, V. Hariri, A. Weinberger, D. R.2005y 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. 828-834Nature Neuroscience86 ~? YTessitore, A. Hariri, A. R. Fera, F. Smith, W. G. Das, S. Weinberger, D. R. Mattay, V. S.2005`Functional changes in the activity of brain regions underlying emotion processing in the elderly9-18 Psychiatry Research-Neuroimaging1391MayAging is associated with a decline in both cognitive and motor abilities that reflects deterioration of underlying brain circuitry. While age-related alterations have also been described in brain regions underlying emotional behavior (e.g., the amygdala), the functional consequence of such changes is less clear. To this end, we used blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) to explore age-related changes in brain regions underlying emotion processing. Twelve young (age < 30 years) and 14 elderly subjects (age > 60 years) were studied with BOLD fMRI during a paradigm that involved perceptual processing of fearful and threatening stimuli. Consistent with previous reports, direct group comparisons revealed relatively increased BOLD fMRI responses in prefrontal cortical regions, including Broca's area, and relatively decreased responses in the amygdala and posterior fusiform gyri in elderly subjects. Importantly, additional analyses using an elderly-specific brain template for spatial normalization of the elderly BOLD fMRI data confirmed these divergent regional response patterns. While there was no difference between groups in accuracy on the task, elderly subjects were significantly slower (delayed reaction times) in performing the task. Our current data suggest that elderly subjects engage a more distributed neocortical network during the perceptual processing of emotional facial expressions. In light of recent converging data froth two other studies, our observed effects may reflect age-related compensatory responses and/or alternative strategies in processing emotions, as the elderly appear to engage cognitive/linguistic systems in the context of reduced sensory and/or limbic responses. (c) Published by Elsevier Ireland Ltd.://000230603600002 Times Cited: 2ISI:000230603600002NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Univ Naples 2, Dept Neurosci, Div Neurol 2, I-80138 Naples, Italy. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. CNR, Inst Neurol Sci, Lab Neuroimaging, I-87050 Cosenza, Italy. Mattay, VS, NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. vsm@helix.nih.gov~?!Bertolino, A. Caforio, G. Petruzzella, V. Latorre, V. Rubino, V. Dimalta, S. Torraco, A. Blasi, G. Quartesan, R. Mattay, V. S. Callicott, J. H. Weinberger, D. R. Scarabino, T.2006pPrefrontal dysfunction in schizophrenia controlling for COMT Val(158)Met genotype and working memory performance221-226 Psychiatry Research-Neuroimaging1472-3OctEarlier studies with functional imaging in schizophrenia have demonstrated dysfunction of the dorsolateral prefrontal cortex during working memory. Controlling for behavioral performance and for catechol-O-methyltransferase (COMT) Val(158)Met genotype, we here demonstrate in a functional magnetic resonance imaging paradigm that patients recruit greater neuronal resources in prefrontal cortex during working memory, suggesting that this phenotype is a core functional trait of the disease. We also replicated earlier findings that the Val allele of the COMT polymorphism is associated with greater engagement of the prefrontal cortex. (c) 2006 Elsevier Ireland Ltd. All rights reserved.://000241326800013 Times Cited: 0ISI:0002413268000131Univ Bari, Dipartimento Sci Neurol & Psichiatr, Sect Mental Disorders, Psychiat Neurosci Grp, I-70124 Bari, Italy. Univ Bari, Dept Med Biochem & Mol Biol, I-70124 Bari, Italy. Univ Perugia, Dept Clin & Expt Med, I-06100 Perugia, Italy. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. IRCCS Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, FG, Italy. Bertolino, A, Univ Bari, Dipartimento Sci Neurol & Psichiatr, Sect Mental Disorders, Psychiat Neurosci Grp, Piazz Giulio Cesare 9, I-70124 Bari, Italy. bertolia@psichiat.uniba.itk~?"Bertolino, A. Rubino, V. Sarnbataro, F. Blasi, G. Latorre, V. Fazio, L. Caforio, G. Petruzzella, V. Kolachana, B. Hariri, A. Meyer-Lindenberg, A. Nardini, M. Weinberger, D. R. Scarabino, T.2006`Prefrontal-hippocampal coupling during memory processing is modulated by COMT Val158met genotype 1250-1258Biological Psychiatry6011DecBackground: Studies in humans and in animals have demonstrated that a network of brain regions is involved in performance of declarative and recognition memory tasks. This network includes the hippocampal formation (HF) as well as the ventrolateral prefrontal cortex (VLPFC). Studies in animals have suggested that the relationship between these brain regions is strongly modulated by dopamine. Methods. Using fMRI in healthy humans matched for a series of demographic and genetic variables, we studied the effect of the COMT val158met polymorphism on function of HF and VLPFC as well as on their functional coupling during recognition memory. Results: The COMT Val allele was associated with: relatively poorer performance at retrieval; reduced recruitment of neuronal resources in HF and increased recruitment in VLPFC during both encoding and retrieval; and unfavorable functional coupling between these two regions at retrieval. Moreover, functional coupling during retrieval was predictive of behavioral accuracy. Conclusions: These results shed new light on individual differences in responsivity and connectivity between HE and VLPFC related to genetic modulation of dopamine, a mechanism accounting at least in pan for individual differences in recognition memory performance.://000242278700011 Times Cited: 1ISI:000242278700011Univ Bari, Psychiat Neurosci Grp, Sect Mental Disorders, Dept Psychiat & Neurol Sci, Bari, Italy. NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Univ Bari, Dept Med Biochem & Med Biol, Bari, Italy. IRCCSS Casa Sollievo Sofferenza, Dept Neuroradiol, San Giovanni Rotondo, Italy. Bertolino, A, Univ Bari, Dipartimento Sci Neurol & Psichiat, Piazza Giulio Cesare 9, I-70124 Bari, Italy. bertolia@psichiat.uniba.it ~?#Blasi, G. Goldberg, T. E. Weickert, T. Das, S. Kohn, P. Zoltick, B. Bertolino, A. Callicott, J. H. Weinberger, D. R. Mattay, V. S.2006XBrain regions underlying response inhibition and interference monitoring and suppression 1658-1664 European Journal of Neuroscience236MarMResponse inhibition and interference monitoring and suppression are two important aspects of cognitive control. Previous functional imaging studies have suggested a common network of brain regions underlying these cognitive processes; the dorsolateral prefrontal cortex (DLPFC), the ventrolateral prefrontal cortex (VLPFC), the dorsal cingulate (dACC), and the parietal cortex (PC). The relative contribution of these regions to these cognitive subprocesses, however, has not been determined. Based on previous findings supporting a role for dACC in the monitoring of conflicting information within a stimulus, we hypothesized greater activity in this cortical region during interference monitoring and suppression relative to response inhibition. On the other hand, as response inhibition is characterized by differential cognitive processes such as control implementation, top down modulation of the response, expectancy, and inhibition of behavioural response, we hypothesized increased activity in the other cortical nodes of the cognitive control network relative to interference monitoring and suppression. To this end, we conducted an event-related functional magnetic resonance imaging (fMRI) study in 57 healthy volunteers using a task preferentially involving either interference monitoring and suppression or response inhibition. Accuracy for response inhibition was lower than for interference monitoring and suppression. Imaging data showed activation in DLPFC, dACC, VLPFC, PC for both conditions. Comparisons between the two conditions indicated greater activation bilaterally in DLPFC, VLPFC and PC during response inhibition, and greater activation in the dACC during interference monitoring and suppression. These results extend previous findings by suggesting regional functional specialization within a cortical network supporting cognitive control.://000236176000027 Times Cited: 0ISI:000236176000027@NIMH, CBDB, GCAP, NIH,Dept Hlth & Human Serv, Bethesda, MD 20982 USA. Univ Bari, Psychiat Neurosci Grp, Dept Neurol & Psychiat Sci, Bari, Italy. IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy. Mattay, VS, NIMH, CBDB, GCAP, NIH,Dept Hlth & Human Serv, Bldg 10,Ctr Dr, Bethesda, MD 20982 USA. vsm@mail.nih.gov!?$oDrabant, E. M. Hariri, A. Meyer-Lindenberg, A. Munoz, K. E. Mattay, V. Kolachana, B. Egan, M. Weinberger, D. R.2006sCatechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. 1396-1406Arch Gen Psychiatry63 ~?%}Goldberg, T. E. Straub, R. E. Callicott, J. H. Hariri, A. Mattay, V. S. Bigelow, L. Coppola, R. Egan, M. F. Weinberger, D. R.2006EThe G72/G30 gene complex and cognitive abnormalities in schizophrenia 2022-2032Neuropsychopharmacology319SepA recently discovered gene complex, G72/G30 (hereafter G72, but now termed DAOA), was found to be associated with schizophrenia and with bipolar disorder, possibly because of an indirect effect on NMDA neurotransmission. In principle, if G72 increases risk for psychosis by this mechanism, it might impact with greater penetrance those cortically based cognitive and neurophysiological functions associated with NMDA signaling. We performed two independent family-based association studies (one sample contained more than 200 families and the other more than 65) of multiple SNPs in the G72 region and of multiple SNPs in the gene for (D)amino acid oxidase (DAAO), which may be modulated by G72. We examined the relationship between select cognitive measures in attention, working memory, and episodic memory and a restricted set of G72 SNPs in over 600 normal controls, schizophrenic patients, and their nonpsychotic siblings using mixed model ANOVAs. We also determined genotype effects on neurophysiology measures in normal controls using the fMRI BOLD response obtained during activation procedures involving either episodic memory or working memory. There were no significant single G72 SNP associations and clinical diagnosis in either sample, though one approached significance (p = 0.06). Diagnosis by genotype interaction effects for G72 SNP 10 were significant for cognitive variables assessing working memory and attention (p = 0.05), and at the trend level for episodic memory, such that in the schizophrenia group an exaggerated allele load effect in the predicted directions was observed. In the fMRI paradigms, a strong effect of G72 SNP 10 genotype was observed on BOLD activation in the hippocampus during the episodic memory paradigm. Tests of association with DAAO were consistently nonsignificant. We present evidence that SNP variations in the G72 gene region increase risk of cognitive impairment in schizophrenia. SNP variations were not strongly associated with clinical diagnosis in family-based analyses.://000239920400019 Times Cited: 0ISI:000239920400019NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD USA. Goldberg, TE, Hillside Hosp, Div Psychiat Res, 75 59 263rd St, Glen Oaks, NY 11004 USA. tgoldber@nshs.edu~?&`Marenco, S. Rawlings, R. Rohde, G. K. Barnett, A. S. Hone, R. A. Pierpaoli, C. Weinberger, D. R.2006FRegional distribution of measurement error in diffusion tensor imaging69-78 Psychiatry Research-Neuroimaging1471JunnThe characterization of measurement error is critical in assessing the significance of diffusion tensor imaging (DTI) findings in longitudinal and cohort studies of psychiatric disorders. We studied 20 healthy volunteers, each one scanned twice (average interval between scans of 51 +/- 46.8 days) with a single shot echo planar DTI technique. Intersession variability for fractional anisotropy (FA) and Trace (D) was represented as absolute variation (standard deviation within subjects: SDw), percent coefficient of variation (CV) and intraclass correlation coefficient (ICC). The values from the two sessions were compared for statistical significance with repeated measures analysis of variance or a non-parametric equivalent of a paired t-test. The results showed good reproducibility for both FA and Trace (CVs below 10% and ICCs at or above 0.70 in most regions of interest) and evidence of systematic global changes in Trace between scans. The regional distribution of reproducibility described here has implications for the interpretation of regional findings and for rigorous preprocessing. The regional distribution of reproducibility measures was different for SDw, CV and ICC. Each one of these measures reveals complementary information that needs to be taken into consideration when performing statistical operations on groups of DT images. Published by Elsevier Ireland Ltd.://000239973800006 Times Cited: 0ISI:000239973800006aNIMH, CBDB, Genes Cognit & Psychosis Program, IRP, Bethesda, MD 20892 USA. NIAAA, Sect Brain Electrophysiol & Imaging, LCS, IRP, Bethesda, MD USA. NICHD, Sect Tissue Biophys & Biomimet, LIMB, IRP, Bethesda, MD USA. Marenco, S, NIMH, CBDB, Genes Cognit & Psychosis Program, IRP, 10 Ctr Dr,Bldg 10,Room 4S235, Bethesda, MD 20892 USA. marencos@mail.nih.gov ~?'Mattay, V. S. Fera, F. Tessitore, A. Hariri, A. R. Berman, K. F. Das, S. Meyer-Lindenberg, A. Goldberg, T. E. Callicott, J. H. Weinberger, D. R.2006ONeurophysiological correlates of age-related changes in working memory capacity32-37Neuroscience Letters3921-2JanCognitive abilities such as working memory (WM) capacity decrease with age. To determine the neurophysiological, correlates of age-related reduction in working memory capacity, we studied 10 young subjects (<35 years of age; mean age = 29) and twelve older subjects (>55 years of age; mean age = 59) with whole brain blood oxygenation-level dependent (BOLD) fMRI on a 1.5 T GE MR scanner using a SPIRAL FLASH pulse sequence (TE = 24 ms, TR = 56 ms, FA = 60 degrees, voxel dimensions = 3.75 mm(3)). Subjects performed a modified version of the "n" back working memory task at different levels of increasing working memory load (I-Back, 2-Back and 3-Back). Older subjects performed as well as the younger subjects at 1-Back (p = 0.4), but performed worse than the younger subjects at 2-Back (p < 0.01) and 3-Back (p = 0.06). Older subjects had significantly longer reaction time (RT) than younger subjects (p < 0.04) at all levels of task difficulty. Image analysis using SPM 99 revealed a similar distribution of cortical activity between younger and older subjects at all task levels. However, an analysis of variance revealed a significant group x task interaction in the prefrontal cortex bilaterally; within working memory capacity, as in I-Back when the older subjects performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher working memory loads, however, when they performed worse then the younger subjects, the older subjects showed relatively reduced activity in these prefrontal regions. These data suggest that, within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed past a threshold beyond which physiological compensation cannot be made and, a decline in performance occurs. (C) 2005 Elsevier Ireland Ltd. All rights reserved.://000234268400007 Times Cited: 3ISI:000234268400007NIMH, Clin Brain Disorders Branch, Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Mattay, VS, Bldg 10,Ctr Dr,Rm 3C-108, Bethesda, MD 20982 USA. vsm@mail.nih.gov?(VMcClure, R. K. Phillips, I. Jazayerli, R. Barnett, A. S. Coppola, R. Weinberger, D. R.2006^Regional change in brain morphometry in schizophrenia associated with antipsychotic treatment.121-132Biological Research148V~?)Meyer-Lindenberg, A. Buckholtz, J. W. Kolachana, B. Hariri, A. R. Pezawas, L. Blasi, G. Wabnitz, A. Honea, R. Verchinski, B. Callicott, J. H. Egan, M. Mattay, V. Weinberger, D. R.2006HNeural mechanisms of genetic risk for impulsivity and violence in humans 6269-6274OProceedings of the National Academy of Sciences of the United States of America10316AprNeurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.://000236999000039 Times Cited: 6ISI:000236999000039US Dept HHS, Unit Syst Neurosci Psychiat, NIMH, NIH, Bethesda, MD 20892 USA. US Dept HHS, Neuroimaging Core Facil, NIMH, NIH, Bethesda, MD 20892 USA. US Dept HHS, Clin Brain Disorders Branch, NIMH, Genes Cognit & Psychosis Program,NIH, Bethesda, MD 20892 USA. Meyer-Lindenberg, A, US Dept HHS, Unit Syst Neurosci Psychiat, NIMH, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.gov7~?*Meyer-Lindenberg, A. Nichols, T. Callicott, J. H. Ding, J. Kolachana, B. Buckholtz, J. Mattay, V. S. Egan, M. Weinberger, D. R.2006CImpact of complex genetic variation in COMT on human brain function867-877Molecular Psychiatry119Sep:Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a workingmemory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 30 region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.://000240043100010 Times Cited: 3ISI:000240043100010NIMH, Neuroimaging Core Facil, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Unit Syst Neurosci Psychiat, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, DHHS,Cognit & Psychosis Program, Bethesda, MD 20892 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Meyer-Lindenberg, A, NIMH, Neuroimaging Core Facil, NIH, DHHS, 10-3C103,9000 Rockville Pike, Bethesda, MD 20892 USA. andreasml@nih.gov !~?+vTan, H. Y. Sust, S. Buckholtz, J. W. Mattay, V. S. Meyer-Lindenberg, A. Egan, M. F. Weinberger, D. R. Callicott, J. H.2006RDysfunctional prefrontal regional specialization and compensation in schizophrenia 1969-1977American Journal of Psychiatry16311NovObjective: It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits. Method: Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects. Results: High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high-and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex. Conclusions: The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition.://000241669900021 Times Cited: 0ISI:000241669900021 NIMH, Unit Funct MRI, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. Callicott, JH, NIMH, Unit Funct MRI, Clin Brain Disorders Branch, Intramural Res Program, 10 Ctr Dr,Rm 4C-216,MSC 1364, Bethesda, MD 20892 USA. callicottj@mail.nih.gov~?,vWinterer, G. Musso, F. Beckmann, C. Mattay, V. Egan, M. F. Jones, D. W. Callicott, J. H. Coppola, R. Weinberger, D. R.2006<Instability of prefrontal signal processing in schizophrenia 1960-1968American Journal of Psychiatry16311Nov Objective: Prefrontal dysfunction is considered a fundamental characteristic of schizophrenia. Recent electrophysiological evidence points to a major instability of signal processing in prefrontal cortical microcircuits because of reduced phase-synchronization (i.e., an increased stimulusrelated variability [noise] of single-trial responses in the spatial and time domain). The authors used functional magnetic resonance imaging (fMRI) during a visual two-choice reaction task in order to measure, with higher topographic accuracy, signal stability in patients with schizophrenia and its relationship to more traditional measures of activation. Method: Twelve clinically stable inpatients with schizophrenia and 16 matched comparison subjects were evaluated. Event-related blood-oxygen-level-dependent responses were subjected to an analysis of residual noise variance and to independent data dimension independent component analysis in the medial prefrontal cortex. Results: In patients with schizophrenia, the authors found increased residual noise variance of the blood-oxygen-level-dependent response that predicted the level of prefrontal activation in these subjects. In the left hemisphere, residual noise variance strongly correlated with psychotic symptoms. Independent component analysis revealed a "fractionized" and unfocussed pattern of activation in patients. Conclusions: These findings suggest that unstable cortical signal processing underlies classic abnormal cortical activation patterns as well as psychosis in schizophrenia.://000241669900020 Times Cited: 0ISI:000241669900020dNIH, Genes Cognit & Psychosis Program, NIMH, Bethesda, MD 20892 USA. Univ Mainz, Dept Psychiat, Lab Mol Neuroimaging & Electrophysiol, D-6500 Mainz, Germany. Oxford Ctr Funct Magnet Resonance Imaging Brain, Oxford, England. Weinberger, DR, NIH, Genes Cognit & Psychosis Program, NIMH, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. weinberd@intra.nimh.nih.gov ^~?-oWinterer, G. Musso, F. Vucurevic, G. Stoeter, P. Konrad, A. Seker, B. Gallinat, J. Dahmen, N. Weinberger, D. R.2006SCOMT genotype predicts BOLD signal and noise characteristics in prefrontal circuits 1722-1732 Neuroimage324OctObjective: Prefrontal dopamine (DA) is catabolized by the COMT (catechol-O-methyltransferase) enzyme. Literature suggests that the Val/Met single nucleotide polymorphism (SNP) in the COMT gene predicts executive cognition in humans with Val carriers showing poorer performance due to less available synaptic DA. Recent fMRI studies are thought to agree with these studies having demonstrated prefrontal hyperactivation during n-back and attention-requiring tasks. This was interpreted as "less efficient" processing due to impaired signal-to-noise ratio (SNR) of neuronal activity. However, electrophysiological studies of neuronal SNR in primates and humans imply that prefrontal cortex should show a diminished prefrontal BOLD response in Val carriers. In the present study, we addressed the question of whether the prefrontal SNR of the BOLD response is decreased in Val carriers using a visual oddball task and an approach to analysis of fMRI data that maximizes noise characterization. Methods: We investigated N=17 homozygous Met carriers compared with N=24 Val carriers matched for age, sex, education, IQ, reaction time (variability) and head motion. Event-related fMRI was conducted presenting 160 visual stimuli (40 targets, checkerboard reversal). Subjects had to respond as quickly as possible to targets by button press. In the fMRI GLM [y(t)=beta* x(t)+c+e(t)] analysis, voxel-by-voxel 'activation' [y(t)] as well as residual noise variance [e(t)=sigma(2)] were calculated using a conservative full-width half maximum (FWHM=6 mm). Results: As compared to Val carriers, we observed a stronger and more extended BOLD responses in homozygous Met carriers in left supplementary motor area (SMA) extending to ACC and dorsolateral prefrontal cortex. Vice versa, increased levels of noise were seen in Val carriers surrounding the peak activation maximum. Discussion: In line with our expectations from prior electrophysiological studies, we observed a diminished BOLD response and increased noise in Val carriers. This suggests that the DA stabilizes cortical microcircuits by sharpening the signal and suppressing surrounding noise. (c) 2006 Elsevier Inc. All rights reserved.://000240969200018 Times Cited: 0ISI:000240969200018Univ Dusseldorf, Dept Psychiat, D-40629 Dusseldorf, Germany. Univ Mainz, Inst Neuroradiol, D-6500 Mainz, Germany. Univ Mainz, Dept Psychiat, D-6500 Mainz, Germany. Charite Berlin, Berlin, Germany. NIMH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. Winterer, G, Univ Dusseldorf, Dept Psychiat, Bergische Landstr 2, D-40629 Dusseldorf, Germany. georg.winterer@uni-duesseldorf.de?.nAltamura, M. Elvevag, B. Blasi, G. Bertolino, A. Callicott, J. H. Weinberger, D. R. Mattay, V. Goldberg, T. E.2007SDissociating the effects of Sternberg working memory demands in prefrontal cortex. 103-114Psychiatry Research1542.?/Apud, J.A. Mattay, V. Chen, J. Kolachana, B. Callicott, J. H. Rasetti, R. Alce, G. Iudicello, J.E. Akbar, N. Egan, M. Goldberg, T. E. Weinberger, D. R.2007ZTolcapone improves cognition and cortical information processing in normal human subjects. 1011-1020Neuropharmacology32*?0{Blasi, G. Goldberg, T. E. Elvevag, B. Rasetti, R. Bertolino, A. Cohen, J. Alce, G. Zoltick, B. Weinberger, D. R. Mattay, V.2007eDifferentiating allocation of resources and conflict detection within attentional control processing.594-602 European Journal of Neuroscience25Y?1Buckholtz, J. Meyer-Lindenberg, A. Honea, R. Straub, R. E. Pezawas, L. Egan, M. Vakkalanka, R. K. Kolachana, B. Verchinksi, B. Sust, S. Mattay, V. Weinberger, D. R. Callicott, J. H.2007]Allelic variation in RGS4 impacts functional and structural connectivity in the human brain. 1584-1593Journal of Neuroscience277>F?2Buckholtz, J. Callicott, J. H. Kolachana, B. Hariri, A. Goldberg, T. E. Genderson, M. Egan, M. Mattay, V. Weinberger, D. R. Meyer-Lindenberg, A.in press{Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personalityMolecular PsychiatryF?3rBuckholtz, J. Sust, S. Tan, H. Y. Mattay, V. Straub, R. E. Meyer-Lindenberg, A. Weinberger, D. R. Callicott, J. H.in press<fMRI evidence for functional epistasis between COMT and RGS4Molecular PsychiatryMF?4Honea, R. Meyer-Lindenberg, A. Hobbs, K. B. Pezawas, L. Mattay, V. Egan, M. Verchinksi, B. Passingham, R. E. Weinberger, D. R. Callicott, J. H.in pressIs gray matter volume an intermediate phenotype for schizophrenia? A VBM study of patients with schizophrenia and their healthy siblings.Biological Psychiatry?F?5Straub, R. E. Lipksa, B. K. Egan, M. Goldberg, T. E. Callicott, J. H. Mayhew, M. B. Vakkalanka, R. K. Kolachana, B. Kleinman, J. E. Weinberger, D. R.in presswAllelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expressionMolecular PsychiatryMF?6vTan, H. Y. Chen, Q. Sust, S. Buckholtz, J. Egan, M. Mattay, V. Meyer-Lindenberg, A. Weinberger, D. R. Callicott, J. H.in pressiEvidence of biologic epistasis between COMT and GRM3 on human prefrontal function during working memory. OProceedings of the National Academy of Sciences of the United States of AmericaF?7MWinterer, G. Carver, F. W. Musso, F. Mattay, V. Weinberger, D. R. Coppola, R.in pressnComplex relationship between BOLD signal and synchronization/desynchronization of human brain MEG oscillationsHuman Brain MappingQ* it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology. and by this mechanism slightly increases risk for schizophrenia.://000169151500070 Times Cited: 512ISI:000169151500070NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Psychiat,k ?c/Harezlak, J. Ryan, L. M. Giedd, J. N. Lange, N.2005[Individual and population penalized regression splines for accelerated longitudinal designs 1037-1048 Biometrics614^http://www.scopus.com/scopus/inward/record.url?eid=2-s2.0-32644444942&partnerID=40&rel=R6.5.0 CCited By (since 1996): 1 Export Date: 19 August 2007 Source: ScopusTNle predicted enhanced cognitive performance. We then examined the effect of COMT genotype on prefrontal physiology during a working memory task in three separate subgroups(n = 11-16) assayed with functional MRI, Met allele load consistently predicted a more efficient physiological response in prefrontal cortex. Finally, in a family-based association analysis of 104 trios, we found a significant increase in transmission of the Val allele to the schizophrenic offspring. These data suggest that the COMT Val allele<Qrtical physiology. In 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance (P = 0.001) in frequency of perseverative errors. Consistent with other evidence that dopamine enhances prefrontal neuronal function, the load of the low-activityT of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. We examined the relationship of a common functional polymorphism (Va(108/158) Met) in the catechol-O-methyltransferase (COMT) gene, which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefU01\Effect of COMT Val(108/158) Met genotype on frontal lobe function and risk for schizophrenia 6917-6922OProceedings of the National Academy of Sciences of the United States of America9812JunAbnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular m~?9DJiang, Y. Haxby, J. V. Martin, A. Ungerleider, L. G. Parasuraman, R.2000JComplementary neural mechanisms for tracking items in human working memory643-646Science2875453JanRecognition of a specific visual target among equally familiar distracters requires neural mechanisms for tracking items in working memory. Event-related functional magnetic resonance imaging revealed evidence for two such mechanisms: (i) Enhanced neural responses, primarily in the frontal cortex, were associated with the target and were maintained across repetitions of the target. (ii) Reduced responses, primarily in the extrastriate visual cortex, were associated with stimulus repetition, regardless of whether the stimulus was a target or a distracter, These complementary neural mechanisms track the status of familiar items in working memory, allowing for the efficient recognition of a currently relevant object and rejection of irrelevant distracters.://000084989400045 Times Cited: 60ISI:000084989400045NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Catholic Univ Amer, Cognit Sci Lab, Washington, DC 20064 USA. Jiang, Y, NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA.~?:+Kastner, S. De Weerd, P. Ungerleider, L. G.2000FTexture segregation in the human visual cortex: A functional MRI study 2453-2457Journal of Neurophysiology834Apr*Texture segregation in the human visual cortex: a functional MRI study. J. Neurophysiol. 83: 2453-2457, 2000. The segregation of visual scenes based on contour information is a fundamental process of early vision. Contours can be defined by simple cues, such as luminance, as well as by more complex cues, such as texture. Single-cell recording studies in monkeys suggest that the neural processing of complex contours starts as early as primary visual cortex. Additionally, lesion studies in monkeys indicate an important contribution of higher order areas to these processes. Using functional MRI, we have investigated the level at which neural correlates of texture segregation can be found in the human visual cortex. Activity evoked by line textures, with and without texture-defined boundaries, was compared in five healthy subjects. Areas V1, V2/VP, V4, TEO, and V3A were activated by both kinds of line textures as compared with blank presentations. Textures with boundaries forming a checkerboard pattern, relative to uniform textures, evoked significantly more activity in areas V4, TEO, less reliably in V3A, but not in V1 or V2/VP. These results provide evidence that higher order areas with large receptive fields play an important role in the segregation of visual scenes based on texture-defined boundaries.://000086598900057 Times Cited: 37ISI:000086598900057NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Arizona, Coll Social & Behav Sci, Dept Psychol, Tucson, AZ 85721 USA. Kastner, S, NIMH, Lab Brain & Cognit, NIH, Bldg 49,Rm 1B80, Bethesda, MD 20892 USA. 4~?;UKastner, S. De Weerd, P. Pinsk, M. A. Elizondo, M. I. Desimone, R. Ungerleider, L. G.2001dModulation of sensory suppression: Implications for receptive field sizes in the human visual cortex 1398-1411Journal of Neurophysiology863Sep Neurophysiological studies in monkeys show that when multiple visual stimuli appear simultaneously in the visual field, they are not processed independently, but rather interact in a mutually suppressive way. This suggests that multiple stimuli compete for neural representation. Consistent with this notion, we have previously found in humans that functional magnetic resonance imaging (fMRI) signals in V1 and ventral extrastriate areas V2, V4, and TEO are smaller for simultaneously presented (i.e., competing) stimuli than for the same stimuli presented sequentially (i.e., not competing). Here we report that suppressive interactions between stimuli are also present in dorsal extrastriate areas V3A and MT, and we compare these interactions to those in areas V1 through TEO. To exclude the possibility that the differences in responses to simultaneously and sequentially presented stimuli were due to differences in the number of transient onsets, we tested for suppressive interactions in area V4, in an experiment that held constant the number of transient onsets. We found that the fMRI response to a stimulus in the upper visual field was suppressed by the presence of nearby stimuli in the lower visual field. Further, we excluded the possibility that the greater fMRI responses to sequential compared with simultaneous presentations were due to exogeneous attentional. cueing by having our subjects count T's or L's at fixation, an attentionally demanding task. Behavioral testing demonstrated that neither condition interfered with performance of the T/L task. Our previous findings suggested that suppressive interactions among nearby stimuli in areas V1 through TEO were scaled to the receptive field (RF) sizes of neurons in those areas. Here we tested this idea by parametrically varying the spatial separation among stimuli in the display. Display sizes ranged from 2 x 2 degrees to 7 X 7 degrees and were centered at 5.5 degrees eccentricity. Based on the effects of display size on the magnitude of suppressive interactions, we estimated that RF sizes at an eccentricity of 5.5 degrees were <2 in V1, 2-4 degrees in V2, 4-6 degrees in V4, larger than 7 degrees (but still confined to a quadrant) in TEO, and larger than 6 degrees (confined to a quadrant) in V3A. These estimates of RF sizes in human visual cortex are strikingly similar to those measured in physiological mapping studies in the homologous visual areas in monkeys.://000171024400031 Times Cited: 44ISI:000171024400031APrinceton Univ, Ctr Study Brain Mind & Behav, Dept Psychol, Princeton, NJ 08544 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. Univ Arizona, Dept Psychol, Coll Social & Behav Sci, Tucson, AZ 85721 USA. Kastner, S, Princeton Univ, Ctr Study Brain Mind & Behav, Dept Psychol, Green Hall, Princeton, NJ 08544 USA.?<LDoyon, J. Song, A. W. Karni, A. Lalonde, F. Adams, M. M. Ungerleider, L. G.2002TExperience-dependent changes in cerebellar contributions to motor sequence learning. 1017-1022OProceedings of the National Academy of Sciences of the United States of America99~?=)Ishai, A. Haxby, J. V. Ungerleider, L. G.2002PVisual imagery of famous faces: Effects of memory and attention revealed by fMRI 1729-1741 Neuroimage174Dec\Complex pictorial information can be represented and retrieved from memory as mental visual images. Functional brain imaging studies have shown that visual perception and visual imagery share common neural substrates. The type of memory (short- or long-term) that mediates the generation of mental images, however, has not been addressed previously. The purpose of this study was to investigate the neural correlates underlying imagery generated from short- and long-term memory (STM and LTM). We used famous faces to localize the visual response during perception and to compare the responses during visual imagery generated from STM (subjects memorized specific pictures of celebrities before the imagery task) and imagery from LTM (subjects imagined famous faces without seeing specific pictures during the experimental session). We found that visual perception of famous faces activated the inferior occipital gyri, lateral fusiform gyri, the superior temporal sulcus, and the amygdala. Small subsets of these face-selective regions were activated during imagery. Additionally, visual imagery of famous faces activated a network of regions composed of bilateral calcarine, hippocampus, precuneus, intraparietal sulcus (IPS), and the inferior frontal gyrus (IFG). In all these regions, imagery generated from STM evoked more activation than imagery from LTM. Regardless of memory type, focusing attention on features of the imagined faces (e.g., eyes, lips, or nose) resulted in increased activation in the right IPS and right IFG. Our results suggest differential effects of memory and attention during the generation faces.://000179969800007 Times Cited: 42ISI:000179969800007wNIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Ishai, A, NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA.~?>=Pessoa, L. Gutierrez, E. Bandettini, P. A. Ungerleider, L. G.2002TNeural correlates of visual working memory: fMRl amplitude predicts task performance975-987Neuron355Aug~We used fMRI to investigate how moment-to-moment neural activity contributes to success or failure on individual trials of a visual working memory (WM) task. We found that different nodes of a distributed cortical network were activated to a greater extent for correct compared to incorrect trials during stimulus encoding, memory maintenance during delays, and at test. A logistic regression analysis revealed that the fMRI signal amplitude during the delay interval in a network of frontoparietal regions predicted successful performance on a trial-by-trial basis. Differential delay activity occurred even for only those trials in which BOLD activity during encoding was strong, demonstrating that it was not a simple consequence of effective versus ineffective encoding. Our results indicate that accurate memory depends on strong sustained signals that span the delay interval of WM tasks.://000177779800018 Times Cited: 41ISI:000177779800018xNIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Pessoa, L, NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA.~??)Pessoa, L. Kastner, S. Ungerleider, L. G.2002FAttentional control of the processing of neutral and emotional stimuli31-45Cognitive Brain Research151DecA typical scene contains many different objects that compete for neural representation due to the limited processing capacity of the visual system. At the neural level, competition among multiple stimuli is evidenced by the mutual suppression of their visually evoked responses and occurs most strongly at the level of the receptive field. The competition among multiple objects can be biased by both bottom-up sensory-driven mechanisms and top-down influences, such as selective attention. Functional brain imaging studies reveal that biasing signals due to selective attention can modulate neural activity in visual cortex not only in the presence but also in the absence of visual stimulation. Although the competition among stimuli for representation is ultimately resolved within visual cortex, the source of top-down biasing signals likely derives from a distributed network of areas in frontal and parietal cortex. Competition suggests that once attentional resources are depleted, no further processing is possible, Yet, existing data suggest that emotional stimuli activate brain regions,automatically,' largely immune from attentional control. We tested the alternative possibility, namely, that the neural processing of stimuli with emotional content is not automatic and instead requires some degree of attention. Our results revealed that, contrary to the prevailing view, all brain regions responding differentially to emotional faces, including the amygdala, did so only when sufficient attentional resources were available to process the faces. Thus, similar to the processing of other stimulus categories, the processing of facial expression is under top-down control, Published by Elsevier Science B.V.://000179798900003 Times Cited: 35ISI:000179798900003NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Princeton Univ, Dept Psychol, Ctr Study Brain Mind & Behav, Princeton, NJ 08544 USA. Pessoa, L, NIMH, Lab Brain & Cognit, 49 Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. ~?@7Pessoa, L. McKenna, M. Gutierrez, E. Ungerleider, L. G.20027Neural processing of emotional faces requires attention 11458-11463OProceedings of the National Academy of Sciences of the United States of America9917AugCAttention gates the processing of stimuli relatively early in visual cortex. Yet, existing data suggest that emotional stimuli activate brain regions automatically, largely immune from attentional control. To resolve this puzzle, we used functional magnetic resonance imaging to first measure activation in regions that responded differentially to faces with emotional expressions (fearful and happy) compared with neutral faces. We then measured the modulation of these responses by attention, using a competing task with a high attentional load. Contrary to the prevailing view, all brain regions responding differentially to emotional faces, including the amygdala, did so only when sufficient attentional resources were available to process the faces. Thus, the processing of facial expression appears to be under top-down control.://000177606900091 Times Cited: 136ISI:000177606900091NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Pessoa, L, NIMH, Lab Brain & Cognit, Bldg 10,Room 4C104, Bethesda, MD 20892 USA.~?A&Ungerleider, L. G. Doyon, J. Karni, A.20024Imaging brain plasticity during motor skill learning553-564#Neurobiology of Learning and Memory783NovThe search for the neural substrates mediating the incremental acquisition of skilled motor behaviors has been the focus of a large body of animal and human studies in the past decade. Much less is known, however, with regard to the dynamic neural changes that occur in the motor system during the different phases of learning. In this paper, we review recent findings, mainly from our own work using fMRI, which suggest that: (i) the learning of sequential finger movements produces a slowly evolving reorganization within primary motor cortex (M I) over the course of weeks and (ii) this change in M1 follows more dynamic, rapid changes in the cerebellum, striatum, and other motor-related cortical areas over the course of days. We also briefly review neurophysiological and psychophysical evidence for the consolidation of motor skills, and we propose a working hypothesis of its underlying neural substrate in motor sequence learning. (C) 2002 Elsevier Science (USA).://000179527900007 Times Cited: 61ISI:0001795279000072NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. Univ Haifa, Fac Sci, IL-31999 Haifa, Israel. Univ Haifa, Fac Educ, IL-31999 Haifa, Israel. Ungerleider, LG, NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr,Bldg 10,Room 4C104, Bethesda, MD 20892 USA.?B)Pessoa, L. Kastner, S. Ungerleider, L. G.2003]Neuroimaging studies of attention: from modulation of sensory processing to top-down control. 3990-3998Journal of Neuroscience23~?CPessoa, L. Ungerleider, L. G.2003MNeuroimaging studies of attention and the processing of emotion-laden stimuli171-182Roots of Visual Awareness144Because the processing capacity of the visual system is limited, selective attention to one part of the visual field comes at the cost of neglecting other parts. In this paper, we review evidence from single-cell studies in monkeys and functional magnetic resonance imaging (fMRI) studies in humans for neural competition and how competition is biased by, attention. We Suggest that, at the neural level, an important consequence of attention is to enhance the influence of behaviorally relevant stimuli at the expense of irrelevant ones, providing a mechanism for the filtering of distracting information in Cluttered visual scenes. Psychophysical evidence suggests that processing outside the focus of attention is attenuated and may be even eliminated under some conditions. A major exception to the critical role of attention may be in the neural processing of emotion-laden stimuli, which are reported to be processed automatically, namely. without attention. Contrary to this prevailing view, in a recent study we found that all brain regions responding differentially to faces with emotional content, including the amygdala, did so only when sufficient resources were available to process those faces. After reviewing our findings, we discuss their implications, in particular (1) how emotional stimuli can bias competition for processing resources; (2) the source of the biasing signal for emotional stimuli: (3) how Visual information reaches the amygdala; and finally (4) the relationship between attention and awareness.://000187421400012 Progress in Brain ResearchTimes Cited: 0ISI:000187421400012NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Pessoa, L, NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, 49 Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA.?D@Heekeren, H. R. Marrett, S. Bandettini, P. A. Ungerleider, L. G.2004FA general mechanism for perceptual decision-making in the human brain.859-562Nature431431o~?E4Ishai, A. Pessoa, L. Bikle, P. C. Ungerleider, L. G.20047Repetition suppression of faces is modulated by emotion 9827-9832OProceedings of the National Academy of Sciences of the United States of America10126JunzSingle-unit recordings and functional brain imaging studies have shown reduced neural responses to repeated stimuli in the visual cortex. By using event-related functional MRI, we compared the activation evoked by repetitions of neutral and fearful faces,which were either task relevant (targets) or irrelevant (distracters). We found that within the inferior occipital gyri, lateral fusiform gyri, superior temporal sulci, amygdala, and the inferior frontal gyri/insula, targets evoked stronger responses than distracters and their repetition was associated with significantly reduced responses. Repetition suppression, as manifested by the difference in response amplitude between the first and third repetitions of a target, was stronger for fearful than neutral faces. Distracter faces, regardless of their repetition or valence, evoked negligible activation, indicating top-down attenuation of behaviorally irrelevant stimuli. Our findings demonstrate a three-way interaction between emotional valence, repetition, and task relevance and suggest that repetition suppression is influenced by high-level cognitive processes in the human brain.://000222405600056 Times Cited: 22ISI:000222405600056Natl Inst Mental Hlth, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Ishai, A, Univ Zurich, Brain Res Inst, Winterthurerstr 190, CH-8057 Zurich, Switzerland. ishai@hifo.unizh.ch B~?FPessoa, L. Ungerleider, L. G.2004SNeural correlates of change detection and change blindness in a working memory task511-520Cerebral Cortex145May|Detecting changes in an ever-changing environment is highly advantageous, and this ability may be critical for survival. In the present study, we investigated the neural substrates of change detection in the context of a visual working memory task. Subjects maintained a sample visual stimulus in short-term memory for 6 s, and were asked to indicate whether a subsequent, test stimulus matched or did not match the original sample. To study change detection largely uncontaminated by attentional state, we compared correct change and correct no-change trials at test. Our results revealed that correctly detecting a change was associated with activation of a network comprising parietal and frontal brain regions, as well as activation of the pulvinar, cerebellum, and inferior temporal gyrus. Moreover, incorrectly reporting a change when none occurred led to a very similar pattern of activations. Finally, few regions were differentially activated by trials in which a change occurred but subjects failed to detect it (change blindness). Thus, brain activation was correlated with a subject's report of a change, instead of correlated with the physical change per se. We propose that frontal and parietal regions, possibly assisted by the cerebellum and the pulvinar, might be involved in controlling the deployment of attention to the location of a change, thereby allowing further processing of the visual stimulus. Visual processing areas, such as the inferior temporal gyrus, may be the recipients of top-down feedback from fronto-parietal regions that control the reactive deployment of attention, and thus exhibit increased activation when a change is reported (irrespective of whether it occurred or not). Whereas reporting that a change occurred, be it correctly or incorrectly, was associated with strong activation in fronto-parietal sites, change blindness appears to involve very limited territories.://000220895500006 Times Cited: 9ISI:000220895500006Brown Univ, Dept Psychol, Providence, RI 02912 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Pessoa, L, Brown Univ, Dept Psychol, 89 Waterman St, Providence, RI 02912 USA. pessoa@brown.edu~?GQVan Boven, R. W. Ingeholm, J. E. Beauchamp, M. S. Bikle, P. C. Ungerleider, L. G.20057Tactile form and location processing in the human brain 12601-12605OProceedings of the National Academy of Sciences of the United States of America10235AugTo elucidate the neural basis of the recognition of tactile form and location, we used functional MRI while subjects discriminated gratings delivered to the fingertip of either the right or left hand. Subjects were required to selectively attend to either grating orientation or grating location under identical stimulus conditions. Independent of the hand that was stimulated, grating orientation discrimination selectively activated the left intraparietal sulcus, whereas grating location discrimination selectively activated the right temporoparietal junction. Hence, hemispheric dominance appears to be an organizing principle for cortical processing of tactile form and location.://000231675900057 Times Cited: 3ISI:000231675900057NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Ungerleider, LG, NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. ungerlel@mail.nih.gov ~?HLHeekeren, H. R. Marrett, S. Ruff, D. A. Bandettini, P. A. Ungerleider, L. G.2006zInvolvement of human left dorsolateral prefrontal cortex in perceptual decision making is independent of response modality 10023-10028OProceedings of the National Academy of Sciences of the United States of America10326JunPerceptual decision making typically entails the processing of sensory signals, the formation of a decision, and the planning and execution of a motor response. Although recent studies in monkeys and humans have revealed possible neural mechanisms for perceptual decision making, much less is known about how the decision is subsequently transformed into a motor action and whether or not the decision is represented at an abstract level, i.e., independently of the specific motor response. To address this issue, we used functional MRI to monitor changes in brain activity while human subjects discriminated the direction of motion in random-dot visual stimuli that varied in coherence and responded with either button presses or saccadic eye movements. We hypothesized that areas representing decision variables should respond more to high- than to low-coherence stimuli independent of the motor system used to express a decision. Four areas were found that fulfilled this condition: left posterior dorsolateral prefrontal cortex (DLPFC), left posterior cingulate cortex, left inferior parietal lobule, and left fusifom/parahippocampal gyrus. We previously found that, when subjects made categorical decisions about degraded face and house stimuli, left posterior DLPFC showed a greater response to high- relative to low-coherence stimuli. Furthermore, the left posterior DLPFC appears to perform a comparison of signals from sensory processing areas during perceptual decision making. These data suggest that the involvement of left posterior DLPFC in perceptual decision making transcends both task and response specificity, thereby enabling a flexible link among sensory evidence, decision, and action.://000238872900050 Times Cited: 1ISI:000238872900050NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Max Planck Inst Human Dev, D-14195 Berlin, Germany. Max Planck Inst Human Cognit & Brain Sci, D-04103 Leipzig, Germany. Charite Univ Med Berlin, Berlin Neuroimaging Ctr, D-10117 Berlin, Germany. NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. Ungerleider, LG, NIMH, Lab Brain & Cognit, NIH, 10 Ctr Dr MSC 1366,Bldg 10,Room 4C104, Bethesda, MD 20892 USA. ungerlel@mail.nih.gov~?I)Ishai, A. Bikle, P. C. Ungerleider, L. G.20060Temporal dynamics of face repetition suppression289-295Brain Research Bulletin704-6Oct3Single-unit recordings and functional brain imaging studies have shown reduced neural responses to repeated stimuli in the visual cortex. Using MEG, we compared responses evoked by repetitions of neutral faces to those evoked by fearful faces, which were either task relevant (targets) or irrelevant (distracters). Faces evoked a bi-phasic response in extrastriate cortex, peaking at 160-185 ms and at 220-250 ms, with stronger responses to neutral faces at the earlier interval and stronger responses to fearful faces at the later interval. At both latencies, repetitions of neutral and fearful targets resulted in reduced amplitude of the MEG signal. Additionally, we found that the context in which targets were presented affected their processing: fearful distracters increased the responses evoked by both neutral and fearful targets. Our data indicate that valence enhancement and context effects can be detected in extrastriate visual cortex within 250 ms and that these processes likely reflect feedback from other regions. (c) 2006 Elsevier Inc. All rights reserved.://000241546500004 Times Cited: 0ISI:000241546500004Univ Zurich, Inst Neuroradiol, CH-8057 Zurich, Switzerland. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Ishai, A, Univ Zurich, Inst Neuroradiol, Winterhurerstr 190, CH-8057 Zurich, Switzerland. ishai@hifo.unizh.ch~?J3Pessoa, L. Japee, S. Sturman, D. Ungerleider, L. G.2006STarget visibility and visual awareness modulate amygdala responses to fearful faces366-375Cerebral Cortex163MarThe goals of the present study were twofold. First, we wished to investigate the neural correlates of aware and unaware emotional face perception after characterizing each subject's behavioral performance via signal detection theory methods. Second, we wished to investigate the extent to which amygdala responses to fearful faces depend on the physical characteristics of the stimulus independently of the percept. We show that amygdala responses depend on visual awareness. Under conditions in which subjects were not aware of fearful faces flashed for 33 ms, no differential activation was observed in the amygdala. On the other hand, differential activation was observed for 67 ms fearful targets that the subjects could reliably detect. When trials were divided into hits, misses, correct rejects, and false alarms, we show that target visibility is an important factor in determining amygdala responses to fearful faces. Taken together, our results further challenge the view that amygdala responses occur automatically.://000235277500008 Times Cited: 2ISI:000235277500008Brown Univ, Dept Psychol, Providence, RI 02912 USA. NIMH, Lab Brain & Cognit, Bethesda, MD USA. Pessoa, L, Brown Univ, Dept Psychol, 89 Waterman St, Providence, RI 02912 USA. pessoa@brown.edu ~?KXGaillard, W. D. Hertz-Pannier, L. Mott, S. H. Barnett, A. S. LeBihan, D. Theodore, W. H.2000[Functional anatomy of cognitive development - fMRI of verbal fluency in children and adults180-185 Neurology541JanObjective: To identify age-dependent activation patterns of verbal fluency with functional MRT (fMRI), Background: Few fMRI language studies have been performed in children, and none provide comparison data to adult studies. Normative data are important for interpretation of similar studies in patients with epilepsy. Methods: A total of 10 normal children (5 boys, 5 girls; mean age, 10.7 years; range, 8.1 to 13.1 years) and 10 normal adults (5 men, 5 women; mean age, 28.7 years; range, 19.3 to 48 years) were studied on a 1.5-T Sigma MRI scanner using BOLD echo planar imaging of the frontal lobes with a verbal fluency paradigm, covert word generation to letters. Studies were analyzed with a cross-correlation algorithm (r = 0.7). A region-of-interest analysis was used to determine the extent, magnitude, and laterality of brain activation. Results: Children and adults activated similar regions, predominantly in left inferior frontal cortex (Broca's area) and left, middle frontal gyrus (dorsolateral prefrontal cortex). Children had, on average, 60% greater extent of activation than adults, with a trend for greater magnitude of activation. Children also had significantly more right hemisphere and inferior frontal gyrus activation than adults. Conclusions. In a test of verbal fluency, children tended to activate cortex more widely than adults, but activation patterns for fluency appear to be established by middle childhood. Thus, functional MRI using verbal fluency paradigms may be applied to pediatric patient populations for determining language dominance in anterior brain regions. The greater activation found in children, including the right inferior frontal gyrus, may reflect developmental plasticity for the ongoing organization of neural networks, which underlie language capacity.://000084727900031 Times Cited: 106ISI:0000847279000319Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. NINDS, Neuroimaging Branch, NIH, Bethesda, MD 20892 USA. Gaillard, WD, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA.4~?LGaillard, W. D. Theodore, W. H.20004Mapping language in epilepsy with functional imaging390-400Neuroscientist65Oct Surgery is an important therapeutic alternative for patients with uncontrolled epilepsy. Preoperative identification of brain regions important for language is important to reduce the risk of functional impairment after surgery, The Wada test suffers from several technical and clinical disadvantages and provides hemispheric data at best. More invasive methods such as intraoperative or chronic subdural cortical mapping have more limited application. New approaches using neuroimaging methods offer the opportunity to localize, as well as lateralize, language. In addition, normal volunteers can be studied with the same techniques, providing comparative and control data. Although most normal studies have been reported as group data, it is important for individual scans to be available for comparison with patient studies to understand the normal range of interindividual variability. Two techniques, PET with O-15-water-PET and fMRI, have been used. Both detect signal changes associated with increased regional blood flow during neuronal activity. Usually, scans performed during a language task are compared with those obtained during control conditions. It is important to choose activation tasks carefully, to make sure one is imaging activation associated with the particular process of interest. PET has advantages, including a fully diffusible tracer, standardized analytic methods, a more comfortable environment, and less sensitivity to movement artifact. On the other hand, it involves a cyclotron-produced tracer, radiation exposure, and is more difficult to repeat. FMRI over represents the effects of large vascular structures and is very sensitive to movement but uses widely available equipment and has no limitation on the number of studies. For both studies, it is important to understand the potential effects of such factors as attention, fatigue, and familiarity with the material. Several studies comparing O-15-water-PET and fMRI to the Wada test found that the former are at least as accurate for language lateralization. In addition, we compared O-15-water-PET to direct subdural electrode cortical stimulation and found that regions showing increased cerebral blood flow during naming tasks co-registered with subdural electrodes that disrupted language during electrical stimulation. In this and other studies, PET detected more regions than electrical stimulation techniques. The whole brain cannot be covered with electrodes, but some areas participating in a task may not be crucial for it. FMRI is particularly useful for children. We compared cortical activation patterns in normal children, adolescents, and adults. The activation patterns, and laterality of language dominance, in children 8 years and above, were similar to adults, although some differences could reflect maturation and evolving focality of cognitive processes. In children with epilepsy, fMRI successfully identified language laterality and provided data on intrahemispheric localization. Studies also showed the effects of the epileptic focus on normal activation patterns for several tasks. Neuroimaging functional mapping is an important tool, still in the process of development and evolution. Although potentially of great clinical and scientific value, it should be used and interpreted cautiously.://000089436300020 Times Cited: 2ISI:000089436300020bNIH, Clin Epilepsy Sect, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA.~?M[Spanaki, M. V. Kopylev, L. Liow, K. DeCarli, C. Fazilat, S. Gaillard, W. D. Theodore, W. H.2000`Relationship of seizure frequency to hippocampus volume and metabolism in temporal lobe epilepsy 1227-1229 Epilepsia419SepNPurpose: To examine the relationship between frequency of complex partial (CPS) and secondarily generalized tonic-clonic seizures (sGTCS) on hippocampal volume (HV) temporal lobe metabolism. Methods: We performed volumetric magnetic resonance imaging (MRI) and positron emission tomography with (18)fluorodeoxyglucose ((18)FDG-PET) in 32 patients with epilepsy. Temporal lobe foci were localized by ictal video-EEG. Results: We did not find any association between CPS frequency or lifetime number of sGTCS and HV or metabolism ipsilateral to electroencephalographic focus. Conclusion: The progress of metabolic or pathologic abnormalities of temporal lobe epilepsy may not be altered by adequate seizure control. The presence of an epileptic focus might be associated with progressive neuronal injury even in clinically well-controlled patients.://000089128200019 Times Cited: 10ISI:000089128200019 NINDS, Clin Epilepsy Sect, ERB, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Theodore, WH, NINDS, Clin Epilepsy Sect, ERB, Bldg 10,Room 5N-250,10 Ctr Dr,MSC 1408, Bethesda, MD 20892 USA.u~?NATheodore, W. H. Gaillard, W. D. De Carli, C. Bhatia, S. Hatta, J.2001IHippocampal volume and glucose metabolism in temporal lobe epileptic foci130-132 Epilepsia421JanPurpose: Reports conflict on the relation of glucose metabolism to hippocampal volume in temporal lobe foci. Previous studies usually have used side-side ratios rather than regional metabolic rates. Methods: We measured hippocampal volume and glucose metabolism in 37 patients with temporal epileptogenic zones identified by ictal video-EEG telemetry. Metabolic rates were normalized to global brain mean. Results: Both 18-fluoro-2-deoxyglucose-PET and volumetric MRI lateralized the epileptic focus determined by ictal video-EEG. There were significant correlations between left-right metabolic asymmetry and hippocampal formation volume left-right ratios. Comparisons between normalized metabolism and hippocampal formation volume, ignoring the side of the epileptic focus, showed significant relations between left hippocampal volume and left inferior lateral temporal metabolism, right hippocampus and right inferior mesial temporal, and left hippocampus and left inferior mesial temporal metabolism. In contrast, when normalized metabolism was compared with hippocampal volume in the epileptic focus, no relation was found. Conclusions. Our study suggests that the relation between hippocampal volume and glucose metabolism breaks down in epileptic foci and that hypometabolism is not dependent on neuronal loss. It is consistent with data suggesting that hypometabolism is an independent predictor of surgical outcome.://000166914800018 Times Cited: 18ISI:000166914800018NINDS, Clin Epilepsy Sect, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. Theodore, WH, NINDS, Clin Epilepsy Sect, Epilepsy Res Branch, NIH, Bldg 10,Room 5N-250,10 Ctr Dr,MSC 1408, Bethesda, MD 20892 USA.~?OvXu, B. Grafman, J. Gaillard, W. D. Ishii, K. Vega-Bermudez, F. Pietrini, P. Reeves-Tyer, P. DiCamillo, P. Theodore, W.2001Conjoint and extended neural networks for the computation of speech codes: The neural basis of selective impairment in reading words and pseudowords267-277Cerebral Cortex113Mar(The computation of speech codes (i.e, phonology) is an important aspect of word reading. Understanding the neural systems and mechanisms underlying phonological processes provides a foundation for the investigation of language in the brain. We used high-resolution three-dimensional positron emission tomography (PET) to investigate neural systems essential for phonological processes. The burden of neural activities on the computation of speech codes was maximized by three rhyming tasks (rhyming words, pseudowords and words printed in mixed letter cases). Brain activation patterns associated with these tasks were compared with those of two baseline tasks involving visual feature detection. Results suggest strong left lateralized epicenters of neural activity in rhyming irrespective of gender. Word rhyming activated the same brain regions engaged in pseudoword rhyming, suggesting conjoint neural networks for phonological processing of words and pseudowords. However, pseudoword rhyming induced the largest change in cerebral blood flow and activated more voxels in the left posterior prefrontal regions and the left inferior occipital-temporal junction. In addition, pseudoword rhyming activated the left supramarginal gyrus, which was not apparent in word rhyming. These results suggest that rhyming pseudowords requires active participation of extended neural systems and networks not observed for rhyming words, The implications of the results on theories and models of visual word reading and on selective reading dysfunctions after brain lesions are discussed.://000167286100008 Times Cited: 55ISI:000167286100008NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Xu, B, NINDS, Epilepsy Res Branch, NIH, 5N 250 Bldg 10 Ctr Dr, Bethesda, MD 20892 USA. ~?PGaillard, W. D. Balsamo, L. Xu, B. Grandin, C. B. Braniecki, S. H. Papero, P. H. Weinstein, S. Conry, J. Pearl, P. L. Sachs, B. Sato, S. Jabbari, B. Vezina, L. G. Frattali, C. Theodore, W. H.2002TLanguage dominance in partial epilepsy patients identified with an fMRI reading task256-265 Neurology592Jul Background: fMRI language tasks readily identify frontal language areas; temporal activation has been less consistent. No studies have compared clinical visual judgment to quantitative region of interest (ROI) analysis. Objective: To identify temporal language areas in patients with partial epilepsy using a reading paradigm with clinical and ROI interpretation. Methods: Thirty patients with temporal lobe epilepsy, aged 8 to 56 years, had 1.5-T fMRI. Patients silently named an object described by a sentence compared to a visual control. Data were analyzed with ROI analysis from t-maps. Regional asymmetry indices (AI) were calculated ([L-R]/[L+R]) and language dominance defined as >0.20. t-Maps were visually rated by three readers at three t thresholds. Twenty-one patients had intracarotid amobarbital test (IAT). Results: The fMRI reading task provided evidence of language lateralization in 27 of 30 patients with ROI analysis. Twenty-five were left dominant, two right, one bilateral, and two were nondiagnostic; IAT and fMRI agreed in most patients, three had partial agreement, none overtly disagreed. Interrater agreement ranged between 0.77 to 0.82 (Cramer V; p < 0.0001); agreement between visual and ROI reading with IAT was 0.71 to 0.77 (Cramer V; p < 0.0001). Viewing data at lower thresholds added interpretation to 12 patients on visual analysis and 8 with ROI analysis. Conclusions: An fMRI reading paradigm can identify language dominance in frontal and temporal areas. Clinical visual interpretation is comparable to quantitative ROI analysis.://000176875400020 Times Cited: 43ISI:000176875400020;George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurosci, Washington, DC USA. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Radiol, Washington, DC USA. Natl Inst Neurol Disorders & Stroke, Epilepsy Res Branch, Bethesda, MD USA. NIH, Speech Language Pathol Sect, Dept Rehabil Med, Ctr Clin, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD USA. Univ Catholique Louvain, St Luc Univ Hosp, Dept Radiol, Brussels, Belgium. Gaillard, WD, Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA.