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Trauma-focused cognitive behavioral therapy (CBT) is an important component of evidence-based treatment for post-traumatic stress disorder (PTSD), but the efficacy of treatment varies from individual to individual. It is hypothesized that some of this variability derives from interindividual differences in the brain’s intrinsic response to trauma-related stimuli and in activity of executive functional regions. We sought to characterize these differences using functional magnetic resonance imaging (fMRI) in patients about to undergo CBT for PTSD. Blood oxygenation level-dependent (BOLD) signal was measured in 12 individuals with PTSD related to sexual trauma while they read words with positive, neutral, and negative content. Some negative words had PTSD-relevant themes while others did not. We hypothesized that PTSD-relevant words, would evoke emotional processes likely to be engaged by the CBT process, and would be most likely to activate brain circuitry important for CBT success. A group-level analysis showed that the rostral dorsomedial prefrontal cortex (rdmPFC) activated to a greater degree in response to PTSD-relevant words than other word types. This activation was strongest among patients with the best CBT response, particularly in the latter part of the task, when differences between individuals were most pronounced. We propose that the rdmPFC activation observed in this study reflects the engagement of neural processes involved in introspection and self-reflection. CBT may be more effective for individuals with a greater ability to engage these processes.

Highlights • Task-based functional cooccurrence (tbFC) elucidates role of BNST in human PTSD neurocircuitry. • The BNST is hyperactive during the processing of trauma-related words in PTSD. • BNST activity correlates to PTSD symptom severity and reduced diurnal cortisol index. • The BNST has positive tbFC with negative emotion- and stress-related neurocircuitry. • The BNST has negative tbFC with executive function and stress regulation neurocircuitry., Background The bed nucleus of the stria terminalis (BNST) plays an important role in rodent posttraumatic stress disorder (PTSD), but evidence to support its relevance to human PTSD is limited. We sought to understand the role of the BNST in human PTSD via fMRI, behavioral, and physiological measurements. Methods 29 patients with PTSD (childhood sexual abuse) and 23 healthy controls (HC) underwent BOLD imaging with an emotional word paradigm. Symptom severity was assessed using the Clinician-Administered PTSD Scale and HPA-axis dysfunction was assessed by measuring the diurnal cortisol amplitude index (DCAI). A data-driven multivariate analysis was used to determine BNST task-based functional co-occurrence (tbFC) across individuals. Results In the trauma-versus-neutral word contrast, patients showed increased activation compared to HC in the BNST, medial prefrontal cortex (mPFC), posterior cingulate gyrus (PCG), caudate heads, and midbrain, and decreased activation in dorsolateral prefrontal cortex (DLPFC). Symptom severity positively correlated with activity in the BNST, caudate head, amygdala, hippocampus, dorsal anterior cingulate gyrus (dACG), and PCG, and negatively with activity in the medial orbiotofrontal cortex (mOFC) and DLPFC. Patients and HC showed marked differences in the relationship between the DCAI and BOLD activity in the BNST, septal nuclei, dACG, and PCG. Patients showed stronger tbFC between the BNST and closely linked limbic and subcortical regions, and a loss of negative tbFC between the BNST and DLPFC. Conclusions Based upon novel data, we present a new model of dysexecutive emotion processing and HPA-axis dysfunction in human PTSD that incorporates the role of the BNST and functionally linked neurocircuitry.

It has been hypothesized that breast cancer and its chemotherapy can impart functional neural changes via an overlap with biological mechanisms associated with aging. Here we used fMRI to assess whether changes in neural activity accompanying visual episodic memory encoding and retrieval suggest altered activations according to patterns seen in functional imaging of cognitive aging. In a prospective longitudinal design, breast cancer patients (n = 13) were scanned during memory encoding and retrieval before and after chemotherapy treatment, and compared to healthy-age matched controls (n = 13). Our results indicate that despite equivalent behavioral performance, encoding and retrieval resulted in increased activation of prefrontal regions for the breast cancer group compared to controls for both before and after chemotherapy treatment. This was accompanied by decreased activity in posterior brain regions after chemotherapy, particularly those involved in visual processing, for the breast cancer group compared to controls. These findings are discussed as evidence for a possible anterior shift in neural processing to compensate for deficiencies in posterior brain regions, consistent with an accelerated aging account. Cancer and chemotherapy can impact brain regions underlying episodic memory, leading to additional recruitment of control regions, which may be linked to mechanisms related to aging.

Aims Borderline personality disorder (BPD) is characterized by self-regulation deficits, including impulsivity and affective lability. Transference-focused psychotherapy (TFP) is an evidence-based treatment proven to reduce symptoms across multiple cognitive–emotional domains in BPD. This pilot study aimed to investigate neural activation associated with, and predictive of, clinical improvement in emotional and behavioral regulation in BPD following TFP. Methods BPD subjects (n = 10) were scanned pre- and post-TFP treatment using a within-subjects design. A disorder-specific emotional–linguistic go/no-go functional magnetic resonance imaging paradigm was used to probe the interaction between negative emotional processing and inhibitory control. Results Analyses demonstrated significant treatment-related effects with relative increased dorsal prefrontal (dorsal anterior cingulate, dorsolateral prefrontal, and frontopolar cortices) activation, and relative decreased ventrolateral prefrontal cortex and hippocampal activation following treatment. Clinical improvement in constraint correlated positively with relative increased left dorsal anterior cingulate cortex activation. Clinical improvement in affective lability correlated positively with left posterior-medial orbitofrontal cortex/ventral striatum activation, and negatively with right amygdala/parahippocampal activation. Post-treatment improvements in constraint were predicted by pre-treatment right dorsal anterior cingulate cortex hypoactivation, and pre-treatment left posterior-medial orbitofrontal cortex/ventral striatum hypoactivation predicted improvements in affective lability. Conclusions These preliminary findings demonstrate potential TFP-associated alterations in frontolimbic circuitry and begin to identify neural mechanisms associated with a psychodynamically oriented psychotherapy.

Rapid assessment of emotions is important for detecting and prioritizing salient input. Emotions are conveyed in spoken words via verbal and non-verbal channels that are mutually informative and unveil in parallel over time, but the neural dynamics and interactions of these processes are not well understood. In this paper, we review the literature on emotion perception in faces, written words, and voices, as a basis for understanding the functional organization of emotion perception in spoken words. The characteristics of visual and auditory routes to the amygdala – a subcortical center for emotion perception – are compared across these stimulus classes in terms of neural dynamics, hemispheric lateralization, and functionality. Converging results from neuroimaging, electrophysiological, and lesion studies suggest the existence of an afferent route to the amygdala and primary visual cortex for fast and subliminal processing of coarse emotional face cues. We suggest that a fast route to the amygdala may also function for brief non-verbal vocalizations (e.g., laugh, cry), in which emotional category is conveyed effectively by voice tone and intensity. However, emotional prosody which evolves on longer time scales and is conveyed by fine-grained spectral cues appears to be processed via a slower, indirect cortical route. For verbal emotional content, the bulk of current evidence, indicating predominant left lateralization of the amygdala response and timing of emotional effects attributable to speeded lexical access, appears more consistent with an indirect cortical route to the amygdala. Top-down linguistic modulation may play an important role for prioritized perception of emotions in words. Understanding the neural dynamics and interactions of emotion and language perception is important for selecting potent stimuli and devising effective training and/or treatment approaches for the alleviation of emotional dysfunction across a range of neuropsychiatric states.

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.

This article provides a survey of major methodological and analytic developments in the use of functional neuroimaging to study complex structural and functional brain activity and connectivity, including data analysis methods devised to distill network properties from high-dimensional and multimodal datasets. The goal of this survey is to provide those in the broader neuroscientific community with an understanding of these developments sufficient to facilitate an informed reading of the literature, and a thoughtful approach to their use in the investigation of questions in their own areas of interest. Practical methodological considerations for assessing and designing functional neuroimaging studies are provided, as are examples of the types of questions that can be addressed by various techniques.

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.

The reorganization of the adult central nervous system after damage is a relatively new area of investigation. Neuroimaging methods, such as functional magnetic resonance imaging, diffusion tensor imaging, and positron emission tomography, have the ability to identify, in vivo, some of the processes involved in these neuroplastic changes and can help with diagnosis, prognosis, and potentially treatment approaches. In this article, traumatic brain injury and stroke are used as examples in which neural plasticity plays an important role in recovery. Basic concepts related to brain remodeling, including spontaneous reorganization and training-induced recovery, as well as characteristics of reorganization in successful recovery, are reviewed. The microscopic and molecular mechanisms that underlie neural plasticity and neurogenesis are briefly described. Finally, exciting future directions for the evaluation, diagnosis, and treatment of severe brain injury are explored, with an emphasis on how neuroimaging can help to inform these new approaches.

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.

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.

Background: 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. Methods: 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. Results: 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. Limitations: Further studies with larger numbers of subjects are needed. Conclusions: 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. © 2007 Elsevier B.V. All rights reserved.

Using functional magnetic resonance imaging and an experimental paradigm of instructed fear, we observed a striking pattern of decreased activity in primary motor cortex with increased activity in dorsal basal ganglia during anticipation of aversive electrodermal stimulation in 42 healthy participants. We interpret this pattern of activity in motor neurocircuitry in response to cognitively-induced fear in relation to evolutionarily-conserved responses to threat that may be relevant to understanding normal and pathological fear in humans.

Background Subclinical doses of propofol produce anterograde amnesia, characterized by an early failure of memory consolidation. It is unknown how propofol affects the amygdala-dependent emotional memory system, which modulates consolidation in the hippocampus in response to emotional arousal and neurohumoral stress. We present an event-related functional magnetic resonance imaging study of the effects of propofol on the emotional memory system in human subjects. Methods Thirty-five healthy subjects were randomized to receive propofol, at an estimated brain concentration of 0.90 μg ml −1 , or placebo. During drug infusion, emotionally arousing and neutral images were presented in a continuous recognition task, while blood-oxygen-level-dependent activation responses were acquired. After a drug-free interval of 2 h, subsequent memory for successfully encoded items was assessed. Imaging analysis was performed using statistical parametric mapping and behavioural analysis using signal detection models. Results Propofol had no effect on the stereotypical amygdalar response to emotional arousal, but caused marked suppression of the hippocampal response. Propofol caused memory performance to become uncoupled from amygdalar activation, but it remained correlated with activation in the posterior hippocampus, which decreased in proportion to amnesia. Conclusions Propofol is relatively ineffective at suppressing amygdalar activation at sedative doses, but abolishes emotional modulation and causes amnesia via mechanisms that commonly involve hyporesponsiveness of the hippocampus. These findings raise the possibility that amygdala-dependent fear systems may remain intact even when a patient has diminished memory of events. This may be of clinical importance in the perioperative development of fear-based psychopathologies, such as post-traumatic stress disorder. Clinical trial registration NCT00504894.

Most of the functional neuroimaging studies of depression have focused primarily on the resting state or responses to negatively valenced stimuli. However, depression consists not only of an accentuation of negative affective processing but of an inability to experience pleasure or positive motivation. The authors tested the hypothesis that depressed subjects would show less activation than healthy comparison subjects, in response to positive stimuli, in ventral striatal regions associated with processing of reward and positive stimuli.Positive, negative, and neutral words were presented to 10 unmedicated depressed patients and 12 healthy comparison subjects in the context of a 3T functional magnetic resonance imaging (MRI) paradigm. Image processing and analysis were performed using statistical parametric mapping with a mixed-effects model. Significant differences in neural responses were assessed, examining group, condition, and interaction effects of interest within the context of a general linear model.Relative to comparison subjects, depressed patients demonstrated significantly less bilateral ventral striatal activation to positive stimuli, correlating with decreased interest/pleasure in and performance of activities. They also displayed decreased activation to positive stimuli in a dorsomedial frontal region associated with processing of self-related stimuli. Responses of depressed subjects to negative stimuli were consistent with the growing literature on frontolimbic dysfunction in depression.This finding 1) supports a pathophysiological model of depression that includes reward/motivational pathway dysfunction, 2) suggests a contributing neural substrate of the inability to experience pleasure or engage in rewarding activities, 3) provides greater specification of abnormalities of basal ganglia function in depression, and 4) may help guide treatment approaches.

Current progress in the cognitive neurosciences is highly relevant to the development of psychoanalytic theory and practice. Neuroscience is today becoming mature enough to provide empirical biological approaches for the investigation of psychoanalytic models and observations. The current state of functional neuroimaging techniques is reviewed, selected paradigms and findings relevant to psychotherapy research are presented, and ways to pursue the dialogue between psychoanalysts and neuroscientists are discussed, as are some related obstacles and pitfalls. The emerging dialogue between psychoanalysts and neuroscientists may help not only to reestablish a solid position of psychodynamic theory and treatment in contemporary medicine, but also to bridge the division between “psychological” and “somatic” treatments, and gain important insights into the mind-brain relationship.

Geriatric depression (GD) is an increasingly prevalent condition with specific clinical features and comorbidities. The neurobiology of this condition has only recently begun to be elucidated. The structural and functional neuroimaging literature relevant to a systems-level neurobiological understanding of GD is reviewed. A positron emission tomography (PET) imaging activation study of GD is described. This study utilized neurocognitive activation probes, as well as resting measures, to examine fronto-limbic abnormalities associated with clinical features, neuropsychological profiles, and treatment outcome in GD. Such ongoing work helps to establish models and test hypotheses concerning the neural substrates and pathophysiology of this devastating neuropsychiatric condition. In so doing, it provides a foundation for the development of more specific, biologically-based diagnostic and treatment strategies.

Cortical field boundaries of sensory areas can be physiologically defined. The delineation of the human auditory cortical architecture remains incomplete. Here we used systematic variation of pitch and duration of sinusoidal tones to define auditory cortical fields along Heschl's gyrus with a silent, event-related fMRI scanning technique that allowed us to determine spatially small shifts of neuronal responses. Thus, we were able to establish higher-resolution tonotopic maps. Acoustic intervals of two octaves correspond to an average 2-mm anatomical distance along Heschl's gyrus. We also demonstrate that one tonotopic map with a medio-lateral low- to high-frequency gradient is located on the lateral half of Heschl's gyrus, which might correspond to field R in primates. Furthermore, we studied cortical responses to brief (50-ms) transients with fMRI and demonstrate that silent, event-related fMRI is capable of measuring significant blood oxygen level-dependent effect to such brief events in the acoustic domain. Our results add to current knowledge on the number and precise localization of multiple tonotopic maps in human auditory cortex. More specifically, they support the hypothesis that there may be two primary auditory cortical fields with mirror tonotopic organization on Heschl's gyrus in man.

Functional neuroimaging allows the non-invasive identification of distributed patterns of human brain activity associated with perceptual, congnitive, emotional and behavioral processes, in health and disease. Work in this field is methodologically intensive, requiring an interdisciplinary team of scientists to develop and apply rapidly advancing techniques. Here we focus upon the principles and methods of functional imaging, from hypothesis generation and study design, to subject recruitment and clinical characterization, neuropsychological paradigm development, image acquisition, image processing and statistical analysis, and data interpretation. The strengths and limitations of the various techniques are discussed, with an emphasis on positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), which have proven to be powerful tools for human brain mapping. The integration of these techniques with electroencephalography (EEG) and magnetoencephalography (MEG), which provide greater temporal information, is outlined. An understanding of such methodological issues is a necessary prerequisite to the development of new imaging methods with improved capabilities, to the careful application of existing methods to neuropsychological problems, and to the critical examination of planned or published studies.

Attentional modulation of normal sensory processing has a two-fold impact on human brain activity: activation of a network of localized brain regions is associated with paying attention, and activation of specific sensory regions is enhanced relative to passive stimulation. The mechanisms underlying attentional modulation of perception in patients with lesions of sensory cortices are less well understood. Here we report a unique patient suffering from extensive bilateral destruction of the auditory cortices (including the primary auditory fields) who demonstrated conscious perception of the onset and offset of sounds only when selectively attending to the auditory modality. This is the first description of such an attentively modulated 'deaf-hearing' phenomenon and its neural correlates, using H(2)(15)O-PET. Increases in cerebral blood flow associated with conscious awareness of sound that was achieved by listening attentively (compared with identical auditory stimulation presented when the patient was inattentive) were found bilaterally in the lateral (pre)frontal cortices, the spared middle temporal cortices and the cerebellar hemispheres. We conclude that conscious awareness of sounds may be achieved in the absence of the primary auditory cortex, and that selective, 'top-down' attention, associated with prefrontal systems, exerts a crucial modulatory effect on auditory perception within the remaining auditory system.

We have suggested that cerebrovascular disease may predispose, precipitate, or perpetuate some late-life depressive syndromes. The mechanisms of “vascular depression” include disruption of cortico-striato-pallido-thalamo-cortical (CSPTC) pathways or their modulating systems. This view is supported by the presentation of vascular depression, which consists of depressive symptoms, cognitive abnormalities, as well as neuroimaging findings that may result from CSPTC impairment. Moreover, clinical and electrophysiological evidence of CSPTC impairment, an abnormality frequently found in patients with vascular depression, appears to be associated with poor response to antidepressant treatment and early relapse and recurrence. The vascular depression hypothesis provides the conceptual background for studies that may have clinical and theoretical impact. Agents influencing dopamine, acetylcholine, and opioid neurotransmitters may be studied in vascular depression, since these are essential neurotransmitters of the frontostriatal circuitry. Drugs used for prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurological recovery from ischemic lesions. Finally, identification of specific relationships between specific symptoms, cognitive deficits, and disability may lead to interventions that target the patients' deficits as well as their interactions with psychosocial factors known to contribute to depression. Research can clarify the pathways to vascular depression by focusing on the site of lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors.

Conscious sensory perception and its modulation by volition are integral to human mental life. Functional neuroimaging techniques provide a direct means of identifying and characterizing in vivo the systems-level patterns of brain activity associated with such mental functions. In a series of positron emission tomography activation experiments, we and our colleagues have examined a range of normal and abnormal auditory states that, when contrasted, provide dissociations relevant to the question of the neural substrates of sensory awareness. These dissociations include sensory awareness in the presence and absence of external sensory stimuli, the transition from sensory unawareness to awareness (or vice versa) in the presence of sensory stimuli, and sensory awareness with and without volition. The auditory states studied include hallucinations, mental imagery, cortical deafness modulated by attention, and hearing modulated by sedation. The results of these studies highlight the distributed nature of the functional neuroanatomy that is sufficient, if not necessary, for sensory awareness. The probable roles of unimodal association (as compared with primary) cortices, heteromodal cortices, limbic/paralimbic regions and subcortical structures (such as the thalamus) are discussed. In addition, interactions between pre– and post–rolandic regions are examined in the context of top–down, volitional modulation of sensory awareness.

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.

H2(15)O-PET was used to investigate the functional anatomy of recovery in a patient (J.B.) with bilateral perisylvian strokes and auditory agnosia, who partially regained the ability to recognize environmental sounds, but remained clinically word-deaf. The patient and a group of six normal volunteers were scanned in the following three conditions: (i) passive listening to environmental sounds; (ii) categorization of environmental sounds; (iii) at rest. In normal subjects, passive listening as compared with rest was associated with significant activations in the auditory cortices and posterior thalami, and in the inferior parietal lobe and anterior insula/frontal opercular region on the right. In J.B., activations were observed in the spared auditory cortex and inferior parietal lobe of the right hemisphere and in regions adjacent to the perisylvian lesion in the left hemisphere (anterior insula/frontal opercular region, middle temporal gyrus and inferior parietal lobe). The recovered function, as measured by categorization of sounds compared with passive listening, in J.B. was associated with bilateral activation of a distributed network comprising (pre)frontal, middle temporal and inferior parietal cortices, as well as the right cerebellum and the right caudate nucleus. In addition, there was a left-sided activation of the anterior cingulate gyrus. In normal subjects, the same categorization task led to activation of a network comprising (pre)frontal, middle temporal and inferior parietal cortices in the left hemisphere only. These results suggest that bilateral activation (with recruitment of areas homologous to those known to be responsible for normal function), the engagement of peri-infarct regions, and the involvement of a more widespread neocortical network, are mechanisms of functional reorganization after injury that may enable recovery from, or compensation for, cognitive deficits.

One of the limitations of anatomical based imaging approaches is its relative inability to identify whether specific brain functions may be compromised by the location of brain lesions or contemplated brain surgeries. For this reason, methods for identifying the regions of eloquent brain that should not be disturbed are absolutely critical to the surgeon. By accurately identifying these regions preoperatively, virtually every pre-surgical decision from the surgical approach, operative goals (biopsy, sub-total vs. gross-total resection), and the potential need for awake craniotomy with intraoperative cortical-mapping is affected. Of the many techniques available to the surgeon, functional magnetic resonance imaging (fMRI) has become the primary modality of choice due to the ability of MRI to serve as a “one-stop shop” for assessing both anatomy and functionality of the brain. Given their prevalence, brain tumors serve as the model pathology for the included discussion; however, a similar case can be made for the use of fMRI in other neurological conditions, most notably epilepsy. The value of fMRI was validated in 2007 when the Centers for Medicare and Medicaid Services (CMS) established three new current procedural terminology (CPT) codes for clinical fMRI based upon its use for pre-therapeutic planning. In this article we will discuss the specific requirements for establishing an fMRI program, including specific software and hardware requirements. In addition, the nature of the fMRI CPT codes will be discussed.

Neurosurgical treatment of psychiatric disorders has been influenced by evolving neurobiological models of symptom generation. The advent of functional neuroimaging and advances in the neurosciences have revolutionized understanding of the functional neuroanatomy of psychiatric disorders. This article reviews neuroimaging studies of depression from the last 3 decades and describes an emerging neurocircuitry model of mood disorders, focusing on critical circuits of cognition and emotion, particularly those networks involved in the regulation of evaluative, expressive and experiential aspects of emotion. The relevance of this model for neurotherapeutics is discussed, as well as the role of functional neuroimaging of psychiatric disorders.

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.

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 visuospa- tial 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. Hum Brain Mapp 28:1206-1212, 2007. V C 2007 Wiley-Liss, Inc.

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.

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.

It is well known that natural languages share certain aspects of their design. For example, across languages, syllables like blif are preferred to lbif. But whether language universals are myths or mentally active constraints-linguistic or otherwise-remains controversial. To address this question, we used fMRI to investigate brain response to four syllable types, arrayed on their linguistic well-formedness (e.g., blif≻bnif≻bdif≻lbif, where ≻ indicates preference). Results showed that syllable structure monotonically modulated hemodynamic response in Broca's area, and its pattern mirrored participants' behavioral preferences. In contrast, ill-formed syllables did not systematically tax sensorimotor regions-while such syllables engaged primary auditory cortex, they tended to deactivate (rather than engage) articulatory motor regions. The convergence between the cross-linguistic preferences and English participants' hemodynamic and behavioral responses is remarkable given that most of these syllables are unattested in their language. We conclude that human brains encode broad restrictions on syllable structure.

OBJECTIVE: The authors assessed frontotemporal function in patients with geriatric depression, a debilitating and increasingly prevalent disorder that has not been examined with brain activation paradigms. METHOD: Six depressed elderly patients and five healthy comparison subjects underwent high-sensitivity [15O]H2O positron emission tomography scans during a paced word generation task and a resting condition. RESULTS: Bilateral activation deficits were noted in the dorsal anterior cingulate gyrus and hippocampus of the depressed geriatric patients relative to the comparison subjects. Patients had memory deficits that correlated with lower hippocampal activity during both rest and activation. CONCLUSIONS: These initial findings suggest that hippocampal and dorsal anterior cingulate hypoactivation may constitute contributing neural substrates of geriatric depression. They also suggest that hippocampal dysfunction is related to the memory dysfunction characteristic of this disorder.

Auditory sensory processing in the human cerebral cortex is disturbed in several neurological and neuropsychiatric disorders, ranging from devastating perceptual deficits in neuropsychological syndromes such as cortical deafness and auditory agnosia to the problem of involuntary hallucinatory perception in schizophrenia. With modern non-invasive functional imaging techniques (e.g., PET, fMRI, and MEG), the normal auditory cortical functional anatomy can now be studied in humans in vivo, as well as its disruption in pathological conditions. This article will summarize current knowledge on human central auditory perception in health and disease, with an emphasis on recent functional neuroimaging studies, in the context of clinical and basic neuroscientific knowledge. New strategies include a focus on the role of other, non-temporal brain areas for auditory processing, particularly in the frontal lobes, and the combined use of techniques offering both precise spatial and temporal resolution. One step towards this goal has been the recent development of a silent, event-related fMRI scanning technique.

Background: Executive control of cognition, emotion, and behavior are disrupted in the manic state of bipolar disorder. Whereas frontal systems are implicated in such dysfunction, the localization of functional brain abnormalities in the manic state is not well understood. Methods: We utilized a high-sensitivity H 2 15 0 positron emission tomography technique to investigate regions of increased brain activity in mania, compared to euthymia, in bipolar disorder. Results: The principal findings were manic state-related increased activity in left dorsal anterior cingulate, and left head of caudate. Conclusions: The findings suggest that the manic state of bipolar disorder may be associated with heightened activity in a frontal cortical–subcortical neural system that includes the anterior cingulate and caudate.

A perfusion-based event-related functional MRI method for the study of brain activation is presented. In this method, cerebral blood flow (CBF) was measured using a recently developed multislice arterial spin-labeling (ASL) perfusion imaging method with rapid spiral scanning. Temporal resolution of the perfusion measurement was substantially improved by employing intertrial subtraction and stimulus-shifting schemes. Perfusion and blood oxygenation level-dependent (BOLD) signals were obtained simultaneously by subtracting or adding the control and labeled images, respectively, in the same data sets. The impulse response function (IRF) of perfusion during brain activation was characterized for multiple stimulus durations and compared to the simultaneously acquired BOLD response. The CBF response curve preceded the BOLD curve by 0.21 s in the rising phase and 0.64 s in the falling phase. Linear additivity of the CBF and BOLD responses was assessed with rapidly repeated stimulations within single trials, and departure from linearity was found in both responses, characterized as attenuated amplitude and delayed rising time. Event-related visual and sensorimotor activation experiments were successfully performed with the new perfusion technique.

A new data acquisition method for silent, event-related functional MRI in which scanner acoustic noise does not interfere with brain activation is introduced and evaluated in an auditory tonotopic mapping experiment. This method takes into account the hemodynamic-response characteristics of the brain during activation, associated with both task performance and scanner noise. A data acquisition scheme was designed to collect task-induced brain activation signals without interference of scanner noise on stimulus delivery or on the measured response. The advantages of the technique were demonstrated in a tonotopic mapping experiment of human auditory cortex. Tonotopic maps obtained by the technique in normal subjects showed distinct spatial shifts of the activation foci in the lateral part of Heschl's gyrus with changing stimulus frequency, whereas no systematic shift was shown in a conventional event-related experiment using the same stimulation paradigm. Signal change in the activation foci with the new technique was 54% larger than with the conventional technique, suggesting an increased dynamic range of the signal change associated with task-induced brain activation under silent conditions.

Background: Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects. Methods: A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96). Results: A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex. Conclusions: Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.

Objective: This study investigated prefrontal cortex function in the manic state of bipolar disorder. Method: High-sensitivity [ 15 O]H2O positron emission tomography and a word generation activation paradigm were used to study regional cerebral blood flow in five manic and six euthymic individuals with bipolar disorder and in five healthy individuals. Results: Decreased right rostral and orbital prefrontal cortex activation during word generation and decreased orbitofrontal activity during rest were associated with mania. Conclusions: The data support the presence of rostral and orbital prefrontal dysfunction in primary mania. These findings, when seen in the context of the human brain lesion and the behavioral neuroanatomic literatures, may help to explain some of the neurobehavioral abnormalities characteristic of the manic state. (Am J Psychiatry 1999; 156:1986‐1988)

HALLUCINATIONS, perceptions in the absence of external stimuli, are prominent among the core symptoms of schizophrenia. The neural correlates of these brief, involuntary experiences are not well understood, and have not been imaged selectively. We have used new positron emission tomography (PET) methods1,2 to study the brain state associated with the occurrence of hallucinations in six schizophrenic patients. Here we present a group study of five patients with classic auditory verbal hallucinations despite medication, demonstrating activations in subcortical nuclei (thalamic, stri-atal), limbic structures (especially hippocampus), and paralimbic regions (parahippocampal and cingulate gyri, as well as orbito-frontal cortex). We also present a case study of a unique, drug-naive patient with visual as well as auditory verbal hallucinations, demonstrating activations in visual and auditory/linguistic association cortices as part of a distributed cortical–subcortical network. Activity in deep brain structures, identified with group analysis, may generate or modulate hallucinations, and the particular neo-cortical regions entrained in individual patients may affect their specific perceptual content. The interaction of these distributed neural systems provides a biological basis for the bizarre reports of schizophrenic patients.

(2001). Functional Neuroimaging and Neuropsychology: Convergence, Advances and New Directions. Journal of Clinical and Experimental Neuropsychology: Vol. 23, No. 1, pp. 1-2.