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ABSTRACT: Psychosis is a devastating, prevalent condition considered to involve dysfunction of frontal and medial temporal limbic brain regions as key nodes in distributed brain networks involved in emotional regulation. The psychoses of epilepsy represent an important, though understudied, model relevant to understanding the pathophysiology of psychosis in general. In this review, we (1) discuss the classification of epilepsy-related psychoses and relevant neuroimaging and other studies; (2) review structural and functional neuroimaging studies of schizophrenia focusing on evidence of frontal-limbic dysfunction; (3) report our laboratory's PET, fMRI, and electrophysiological findings; (4) describe a theoretical framework in which frontal hypoactivity and intermittent medial temporal hyperactivity play a critical role in the etiopathology of psychosis both associated and unassociated with epilepsy; and (5) suggest avenues for future research.
Epilepsy & Behavior 12/2011; 23(2):113-22. · 2.34 Impact Factor
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Tracy Butler,
Masanori Ichise,
Andrew F Teich,
Elizabeth Gerard,
Joseph Osborne,
Jacqueline French,
Orrin Devinsky,
Ruben Kuzniecky,
Frank Gilliam,
Fahad Pervez,
Frank Provenzano,
Stanley Goldsmith,
Shankar Vallabhajosula,
Emily Stern, David Silbersweig
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ABSTRACT: BACKGROUND AND PURPOSE: Evidence from animal models and examination of human epilepsy surgery specimens indicates that inflammation plays an important role in epilepsy. Positron emission tomography (PET) using [C11]PK11195, a marker of activated microglia, provides a means to visualize neuroinflammation in vivo in humans. We hypothesize that in patients with active epilepsy, [C11]PK11195 PET (PK-PET) may be able to identify areas of focally increased inflammation corresponding to the seizure onset zone. METHODS: A young woman with intractable epilepsy underwent PK-PET as part of an approved research study. PK-PET results were compared with results from other clinical studies. RESULTS: PK-PET revealed an area of focally increased radiotracer uptake in the right frontal lobe corresponding to this patient's seizure focus as identified by ictal and interictal 18F-fluorodeoxyglucose (FDG)-PET and EEG. Routine brain magnetic resonance imaging (MRI) was initially considered normal, though high-resolution studies showed possible subtle dysplasia of the right frontal lobe. The patient underwent a right frontal lobe resection, and pathological evaluation showed focal cortical dysplasia with activated microglia. CONCLUSIONS: PK-PET can identify neuroinflammation associated with subtle focal cortical dysplasia, and may therefore have a clinical role in guiding epilepsy surgery for patients with difficult-to-localize seizure foci. J Neuroimaging 2011;XX:1-3.
Journal of neuroimaging: official journal of the American Society of Neuroimaging 01/2011; · 1.72 Impact Factor
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Oliver Tuescher,
Xenia Protopopescu,
Hong Pan,
Marylene Cloitre,
Tracy Butler,
Martin Goldstein,
James C Root,
Almut Engelien,
Daniella Furman,
Michael Silverman,
Yihong Yang,
Jack Gorman,
Joseph LeDoux, David Silbersweig,
Emily Stern
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ABSTRACT: Most functional neuroimaging studies of panic disorder (PD) have focused on the resting state, and have explored PD in relation to healthy controls rather than in relation to other anxiety disorders. Here, PD patients, posttraumatic stress disorder (PTSD) patients, and healthy control subjects were studied with functional magnetic resonance imaging utilizing an instructed fear conditioning paradigm incorporating both Threat and Safe conditions. Relative to PTSD and control subjects, PD patients demonstrated significantly less activation to the Threat condition and increased activity to the Safe condition in the subgenual cingulate, ventral striatum and extended amygdala, as well as in midbrain periaquaeductal grey, suggesting abnormal reactivity in this key region for fear expression. PTSD subjects failed to show the temporal pattern of activity decrease found in control subjects.
Journal of anxiety disorders 11/2010; 25(2):251-7. · 2.68 Impact Factor
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ABSTRACT: Cognitive-behavioural interventions have been shown to change brain functioning. We used an emotional linguistic go/nogo functional magnetic resonance imaging (fMRI) design to determine changes of brain activation patterns of panic disorder (PD) patients following short-term psychodynamic inpatient treatment. Nine PD patients underwent fMRI before and after treatment; 18 healthy controls were scanned twice at the same interval (4 weeks). In the go/nogo design, responses to panic-specific negative words were compared with linguistically matched positive and neutral words. According to hypotheses, patients rated affective words more strongly than controls and selectively recalled negative vs. positive/neutral words. Before treatment, high limbic (hippocampus and amygdala) activation was accompanied by low prefrontal activation to negative words. Inhibition-related activation patterns indicated difficulties of behavioural regulation in emotional context. At treatment termination, panic-related symptoms had improved significantly, and fronto-limbic activation patterns were normalized. Our results indicate that short-term psychodynamic treatment leads to changes in fronto-limbic circuitry not dissimilar to previous findings on cognitive-behavioural treatments.
Psychiatry Research 10/2010; 184(2):96-104. · 2.52 Impact Factor
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01/2010; , ISBN: 9780470479216
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James C Root,
Oliver Tuescher,
Amy Cunningham-Bussel,
Hong Pan,
Jane Epstein,
Margaret Altemus,
Marylene Cloitre,
Martin Goldstein,
Michael Silverman,
Daniella Furman,
Joseph Ledoux,
Bruce McEwen,
Emily Stern, David Silbersweig
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ABSTRACT: Frontolimbic structures involved in fear conditioning have also been associated with hypothalamic-pituitary-adrenal (HPA)-axis modulation, including amygdaloid, hippocampal, and ventromedial prefrontal cortex regions. Although HPA-axis function and endocrine changes have been investigated in the context of stress provocation, much research has not been conducted using functional neuroimaging in the study of the HPA axis and frontolimbic function in response to emotional stimuli. Using functional magnetic resonance imaging, the association of blood-oxygen-level dependent signal with salivary cortisol in response to an emotional visual scene paradigm was investigated, with prescan and postscan salivary cortisol analyzed as a covariate of interest during specific conditions. Cortisol reactivity to the paradigm was positively associated with amygdalar and hippocampal activity and negatively associated with ventromedial prefrontal cortex activity in conditions involving emotional imagery.
Neuroreport 04/2009; 20(4):429-34. · 1.66 Impact Factor
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Amy C Cunningham-Bussel,
James C Root,
Tracy Butler,
Oliver Tuescher,
Hong Pan,
Jane Epstein,
Daniel S Weisholtz,
Michelle Pavony,
Michael E Silverman,
Martin S Goldstein,
Margaret Altemus,
Marylene Cloitre,
Joseph Ledoux,
Bruce McEwen,
Emily Stern, David Silbersweig
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ABSTRACT: The development and exacerbation of many psychiatric and neurologic conditions are associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis as measured by aberrant levels of cortisol secretion. Here we report on the relationship between the amplitude of diurnal cortisol secretion, measured across 3 typical days in 18 healthy individuals, and blood oxygen level dependant (BOLD) response in limbic fear/stress circuits, elicited by in-scanner presentation of emotionally negative stimuli, specifically, images of the World Trade Center (WTC) attack. Results indicate that subjects who secrete a greater amplitude of cortisol diurnally demonstrate less brain activation in limbic regions, including the amygdala and hippocampus/parahippocampus, and hypothalamus during exposure to traumatic WTC-related images. Such initial findings can begin to link our understanding, in humans, of the relationship between the diurnal amplitude of a hormone integral to the stress response, and those neuroanatomical regions that are implicated as both modulating and being modulated by that response.
Psychoneuroendocrinology 02/2009; 34(5):694-704. · 5.81 Impact Factor
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ABSTRACT: Magnetic resonance imaging (MRI) in association with Jacobian-modulated voxel-based morphometry (VBM) was used to test for regional variation in gray matter over the menstrual cycle. T1-weighted anatomical images were acquired using a spoiled gradient recalled acquisition sequence in 21 women. Each subject was scanned twice: once during the postmenstrual late-follicular phase (Days 10-12 after onset of menses), and once during the premenstrual late-luteal phase (1-5 days before the onset of menses). Gray matter was relatively increased in the right anterior hippocampus and relatively decreased in the right dorsal basal ganglia (globus pallidus/putamen) in the postmenstrual phase. Verbal declarative memory was increased in the postmenstrual vs. premenstrual phase. This first report of human brain structural plasticity associated with the endogenous menstrual cycle extends well-established animal findings of hormone-mediated hippocampal plasticity to humans, and has implications for understanding alterations in cognition and behavior across the menstrual cycle.
Hippocampus 10/2008; 18(10):985-8. · 5.18 Impact Factor
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Xenia Protopopescu,
Oliver Tuescher,
Hong Pan,
Jane Epstein,
James Root,
Luke Chang,
Margaret Altemus,
Margaret Polanecsky,
Bruce McEwen,
Emily Stern, David Silbersweig
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ABSTRACT: Premenstrual dysphoric disorder (PMDD) is a prevalent disorder in the spectrum of affective illness, and is associated with significant morbidity. The neurobiology of this underdiagnosed and undertreated illness is poorly understood. A functional magnetic resonance imaging (fMRI) probe of fronto-limbic function was used to advance understanding of PMDD pathophysiology.
We applied BOLD fMRI and Statistical Parametric Mapping to study neural response to emotional words in the context of an emotional Go/NoGo inhibitory control task. We examined alterations in this response across the menstrual cycle, in the premenstrual (late luteal) phase and the postmenstrual (late follicular) phase.
In the premenstrual (vs. postmenstrual) phase, PMDD subjects, compared with asymptomatic subjects, showed an increased amygdala response to negative vs. neutral stimuli, and a decreased ventral striatum response to positive vs. neutral stimuli. PMDD subjects failed to show the asymptomatic subjects' patterns of increased medial and decreased lateral orbitofrontal cortex (OFC) response to negative vs. neutral stimuli in the premenstrual vs. postmenstrual phase. This decreased premenstrual medial OFC response to negative stimuli in PMDD subjects was further enhanced in the context of behavioral inhibition.
Further studies with larger numbers of subjects are needed.
The results support a neurobiological model of enhanced negative emotional processing, diminished positive emotional processing, and diminished top-down control of limbic activity in PMDD during the premenstrual phase. These findings provide a basis for a neurocircuitry model of PMDD, and have implications for studies of mood/emotional regulation across the human menstrual cycle in health and disease.
Journal of Affective Disorders 06/2008; 108(1-2):87-94. · 3.52 Impact Factor
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David Silbersweig,
John F Clarkin,
Martin Goldstein,
Otto F Kernberg,
Oliver Tuescher,
Kenneth N Levy,
Gary Brendel,
Hong Pan,
Manfred Beutel,
Michelle T Pavony,
Jane Epstein,
Mark F Lenzenweger,
Kathleen M Thomas,
Michael I Posner,
Emily Stern
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ABSTRACT: The authors sought to test the hypothesis that in patients with borderline personality disorder, the ventromedial prefrontal cortex and associated regions would not be activated during a task requiring motor inhibition in the setting of negative emotion. Such a finding would provide a plausible neural basis for the difficulty borderline patients have in modulating their behavior during negative emotional states and a potential marker for treatment interventions.
A specifically designed functional magnetic resonance imaging (fMRI) activation probe was used, with statistical parametric mapping analyses, to test hypotheses concerning decreased prefrontal inhibitory function in the context of negative emotion in patients with borderline personality disorder (N=16) and healthy comparison subjects (N=14). 3-T fMRI scanning was used to study brain activity while participants performed an emotional linguistic go/no-go task.
Analyses confirmed that under conditions associated with the interaction of behavioral inhibition and negative emotion, borderline patients showed relatively decreased ventromedial prefrontal activity (including medial orbitofrontal and subgenual anterior cingulate) compared with healthy subjects. In borderline patients, under conditions of behavioral inhibition in the context of negative emotion, decreasing ventromedial prefrontal and increasing extended amygdalar-ventral striatal activity correlated highly with measures of decreased constraint and increased negative emotion, respectively.
These findings suggest specific frontolimbic neural substrates associated with core clinical features of emotional and behavioral dyscontrol in borderline personality disorder.
American Journal of Psychiatry 01/2008; 164(12):1832-41. · 12.54 Impact Factor
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ABSTRACT: Ventral anterior cingulate cortex (vACC) is a highly interconnected brain region considered to reflect the sometimes competing demands of cognition and emotion. A reciprocal relationship between vACC and dorsal ACC (dACC) may play a role in maintaining this balance between cognitive and emotional processing. Using functional MRI in association with a cognitively-demanding visuospatial task (mental rotation), we found that only women demonstrated vACC suppression and inverse functional connectivity with dACC. Sex differences in vACC functioning--previously described under conditions of negative emotion--are extended here to cognition. Consideration of participant sex is essential to understanding the role of vACC in cognitive and emotional processing.
Human Brain Mapping 12/2007; 28(11):1206-12. · 5.88 Impact Factor
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Martin Goldstein,
Gary Brendel,
Oliver Tuescher,
Hong Pan,
Jane Epstein,
Manfred Beutel,
Yihong Yang,
Katherine Thomas,
Kenneth Levy,
Michael Silverman,
Jonathon Clarkin,
Michael Posner,
Otto Kernberg,
Emily Stern, David Silbersweig
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ABSTRACT: Neural substrates of behavioral inhibitory control have been probed in a variety of animal model, physiologic, behavioral, and imaging studies, many emphasizing the role of prefrontal circuits. Likewise, the neurocircuitry of emotion has been investigated from a variety of perspectives. Recently, neural mechanisms mediating the interaction of emotion and behavioral regulation have become the focus of intense study. To further define neurocircuitry specifically underlying the interaction between emotional processing and response inhibition, we developed an emotional linguistic go/no-go fMRI paradigm with a factorial block design which joins explicit inhibitory task demand (i.e., go or no-go) with task-unrelated incidental emotional stimulus valence manipulation, to probe the modulation of the former by the latter. In this study of normal subjects focusing on negative emotional processing, we hypothesized activity changes in specific frontal neocortical and limbic regions reflecting modulation of response inhibition by negative stimulus processing. We observed common fronto-limbic activations (including orbitofrontal cortical and amygdalar components) associated with the interaction of emotional stimulus processing and response suppression. Further, we found a distributed cortico-limbic network to be a candidate neural substrate for the interaction of negative valence-specific processing and inhibitory task demand. These findings have implications for elucidating neural mechanisms of emotional modulation of behavioral control, with relevance to a variety of neuropsychiatric disease states marked by behavioral dysregulation within the context of negative emotional processing.
NeuroImage 08/2007; 36(3):1026-40. · 5.89 Impact Factor
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ABSTRACT: Network approaches to analysis of functional neuroimaging data provide a powerful means with which to understand the complex functioning of the brain in health and disease. To illustrate how such approaches can be used to investigate sex differences in neurocognition, we applied the multivariate technique of Principal Components Analysis (PCA) to an fMRI dataset obtained during performance of mental rotation – a classic visuospatial task known to give rise to sex differences in performance. In agreement with prior results obtained using univariate methods, PCA identified a core mental rotation network (principal component [PC]1, accounting for 53.1% of total variance) that included activation of bilateral frontal, parietal, occipital and occipitotemporal regions. Expression of PC1 was similar in men and women, and was positively correlated with level of education. PC2, which accounted for 5.7% of total variance, was differentially expressed by men and women, and indicated greater mental rotation-associated neural activity in women in such high-order cortical regions such as prefrontal cortex and superior parietal lobule, in accord with prior findings, and with the idea that women may take a more “top-down” approach to mental rotation. By quantifying, in a data-driven fashion, the contribution of factors such as sex and education to patterns of brain activity, these findings put the magnitude of neural sex differences during mental rotation into perspective, confirming the commonsense notion that, as humans, men and women are more alike than they are different, with between-individual variability (such as level of education, which, importantly, is modifiable) generally outweighing between-sex variability. This work exemplifies the role that multivariate analysis can play in identifying brain functional networks, and in quantifying their involvement under specific conditions and in different populations.
Clinical Neuroscience Research 05/2007; 6(6):391-398. · 0.80 Impact Factor
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ABSTRACT: The present study aimed at validating a computerized mental rotation task developed for use in functional Magnetic Resonance Imaging (fMRI) studies. Eighty-three females and 74 males completed the computerized task, two pencil-and-paper tests of mental rotation, and reported their high school grades in mathematics, English, and history. The computerized task involved the presentation of pairs of three-dimensional stimuli that differed in orientation by 0, 40, 80, 120, or 160 degrees. Results showed significant gender differences in favor of males in the three main tasks, although gender interacted with angle of rotation in the computerized task. Evidence for concurrent validity was obtained in the form of significant correlations between performance on tasks relevant to mental rotation (paper and pencil tests and mathematics grades), whereas discriminant validity was demonstrated by a lack of correlation with tasks deemed irrelevant to mental rotation (English and history grades). These findings support the use of our computerized mental rotation task as a valid measure of mental rotation abilities in fMRI studies.
Journal of Clinical and Experimental Neuropsychology 09/2006; 28(6):928-39. · 2.13 Impact Factor
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ABSTRACT: Functional MRI during performance of a validated mental rotation task was used to assess a neurobiological basis for sex differences in visuospatial processing. Between-sex group analysis demonstrated greater activity in women than in men in dorsalmedial prefrontal and other high-order heteromodal association cortices, suggesting women performed mental rotation in an effortful, "top-down" fashion. In contrast, men activated primary sensory cortices as well as regions involved in implicit learning (basal ganglia) and mental imagery (precuneus), consistent with a more automatic, "bottom-up" strategy. Functional connectivity analysis in association with a measure of behavioral performance showed that, in men (but not women), accurate performance was associated with deactivation of parieto-insular vestibular cortex (PIVC) as part of a visual-vestibular network. Automatic evocation by men to a greater extent than women of this network during mental rotation may represent an effective, unconscious, bottom-up neural strategy which could reasonably account for men's traditional visuospatial performance advantage.
NeuroImage 09/2006; 32(1):445-56. · 5.89 Impact Factor
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Xenia Protopopescu,
Hong Pan,
Oliver Tuescher,
Marylene Cloitre,
Martin Goldstein,
Almut Engelien,
Yihong Yang,
Jack Gorman,
Joseph LeDoux,
Emily Stern, David Silbersweig
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ABSTRACT: Neurocircuitry models of panic disorder have hypothesized that the panic attack itself stems from loci in the brainstem including the ascending reticular system and respiratory and cardiovascular control centers. Voxel-based morphometry with acobian modulation was used to examine gray matter volume changes in 10 panic disorder patients and 23 healthy controls. The panic disorder patients had a relatively increased gray matter volume in the midbrain and rostral pons of the brainstem. Increased ventral hippocampal and decreased regional prefrontal cortex volumes were also noted at a lower significance threshold. This finding has implications for pathophysiologic models of panic disorder, and provides structural evidence for the role of the brainstem in neurocircuitry models of panic disorder.
Neuroreport 04/2006; 17(4):361-3. · 1.66 Impact Factor
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ABSTRACT: Hallucinations and paranoid delusions are prominent among the positive symptoms of schizophrenia. Such psychotic symptoms are notable for their aberrant representations of, and relation to, the external world and for the emotional/motivational valence associated with the representations. As mesolimbic structures, including the amygdala and ventral striatum, are thought to play a significant role in imparting emotional valence to external stimuli, we here examine the mesolimbic findings of H215O PET studies designed to probe the functional neuroanatomy of psychosis.Patients with schizophrenia (including those with active hallucinations, those with active paranoid delusions, and those without active positive symptoms at the time of scanning) and healthy control subjects were studied. An event-related PET paradigm was used to identify the neural correlates of hallucinations, and a modified emotional stroop paradigm (with threat versus neutral words) was used to test the hypothesis that paranoid patients would have increased mesolimbic activity in response to threat, and even in response to neutral stimuli.The findings suggest that the positive psychotic symptoms of hallucinations and delusions share similar functional neuroanatomical features of increased mesotemporal and ventral striatal activity in the setting of decreased prefrontal activity. The pattern is evident even in a neutral context, unlike the case for normal subjects, who show such features only in response to threat. The implications of these findings for a pathophysiology of psychosis will be discussed in the context of the behavioral neuroanatomical literature in animals and humans.
Annals of the New York Academy of Sciences 02/2006; 877(1):562 - 574. · 3.15 Impact Factor
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Advances in neurology 02/2006; 99:115-29.
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ABSTRACT: The orbitofrontal cortex (OFC) has been implicated in the representation of emotional stimuli, assignment of emotional valence/salience to stimuli, stimulus-reinforcement association learning, motivation, and socio-emotional control. Using functional magnetic resonance imaging in female subjects without premenstrual mood symptoms, we found that OFC activity to emotional linguistic stimuli varies depending on the menstrual cycle phase. Specifically, anterior-medial OFC activity for negative vs. neutral stimuli was increased premenstrually and decreased postmenstrually. The inverse pattern was seen in the lateral OFC. These findings suggest that specific subregional OFC activity to emotional stimuli is modulated across the menstrual cycle. The data also demonstrate that menstrual cycle phase is an important consideration in further studies attempting to elucidate the neural substrates of affective representation.
Proceedings of the National Academy of Sciences 12/2005; 102(44):16060-5. · 9.68 Impact Factor
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Tracy Butler,
Hong Pan,
Jane Epstein,
Xenia Protopopescu,
Oliver Tuescher,
Martin Goldstein,
Marylene Cloitre,
Yihong Yang,
Elizabeth Phelps,
Jack Gorman,
Joseph Ledoux,
Emily Stern, David Silbersweig
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ABSTRACT: Functional magnetic resonance imaging in association with an instructed fear/anticipatory anxiety paradigm was used to explore sex differences in the human fear response. During anticipation of mild electrodermal stimulation, women, as compared with men, demonstrated increased activity in the subgenual anterior cingulate cortex and functionally related regions of the insula and brainstem. The subgenual anterior cingulate cortex is a region critical for emotional control implicated in the pathogenesis of psychiatric disease. Present findings suggest a contributory neural substrate for the greater susceptibility of women to anxiety and affective disorders, and emphasize the importance of considering participant sex when designing and interpreting functional neuroimaging studies.
Neuroreport 09/2005; 16(11):1233-6. · 1.66 Impact Factor
