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(Reprinted with permission from The Journal of Neuropsychiatry and Clinical Neurosciences 2015; 27:7-18).

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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.

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In this study, healthy volunteers were scanned using functional magnetic resonance imaging (fMRI) to investigate the neural systems involved in processing the threatening content conveyed via visually presented "threat words." The neural responses elicited by these words were compared to those elicited by matched neutral control words. The results demonstrate that linguistic threat, when presented in written form, can selectively engage areas of lateral temporal and inferior frontal cortex, distinct from the core language areas implicated in aphasia. Additionally, linguistic threat modulates neural activity in visceral/emotional systems (amygdala, parahippocampal gyrus and periaqueductal gray), and at earlier stages of the visual-linguistic processing stream involved in visual word form representations (ventral occipitotemporal cortex). We propose a model whereby limbic activation modulates activity at multiple nodes along the visual-linguistic-semantic processing stream, including a perisylvian "semantic access network" involved in decoding word meaning, suggesting a dynamic interplay between feedforward and feedback processes.

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Persecutory delusions are a clinically important symptom in schizophrenia associated with social avoidance and increased violence. Few studies have investigated the neurobiology of persecutory delusions, which is a prerequisite for developing novel treatments. The aim of this two-paradigm functional magnetic resonance imaging (fMRI) study is to characterize social "real world" and linguistic threat brain activations linked to persecutory delusions in schizophrenia (n=26) using instructed-fear/safety and emotional word paradigms. Instructed-fear/safety activations correlated to persecutory delusion severity demonstrated significant increased lateral orbitofrontal cortex and visual association cortex activations for the instructed-fear vs. safety and instructed-fear vs. baseline contrasts; decreased lateral orbitofrontal cortex and ventral occipital-temporal cortex activations were observed for the instructed-safety stimuli vs. baseline contrast. The salience network also showed divergent fear and safety cued activations correlated to persecutory delusions. Emotional word paradigm analyses showed positive correlations between persecutory delusion severity and left-lateralized linguistic and hippocampal-parahippocampal activations for the threat vs. neutral word contrast. Visual word form area activations correlated positively with persecutory delusions for both threat and neutral word vs. baseline contrasts. This study links persecutory delusions to enhanced neural processing of threatening stimuli and decreased processing of safety cues, and helps elucidate systems-level activations associated with persecutory delusions in schizophrenia.

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Adaptive behavior requires neural systems that mediate the evaluation of stimuli in terms of the well-being of the organism and generate subsequent goal-directed behavior. The authors provide an overview of these systems, with an emphasis on those related to positive motivation/approach. The authors outline the contributions of various disciplines to the current understanding of these systems and discuss their dysfunction in the context of multiple neuropsychiatric disorders in terms of deficits, dysregulation, excess, and related syndromes. Illustrative examples are provided, with an emphasis on functional neuroimaging studies. This approach can provide a foundation for conceptualization, diagnosis, and targeted neuromodulatory therapeutics of neuropsychiatric disorders.

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All spoken languages express words by sound patterns, and certain patterns (e.g., blog) are systematically preferred to others (e.g., lbog). What principles account for such preferences: does the language system encode abstract rules banning syllables like lbog, or does their dislike reflect the increased motor demands associated with speech production? More generally, we ask whether linguistic knowledge is fully embodied or whether some linguistic principles could potentially be abstract. To address this question, here we gauge the sensitivity of English speakers to the putative universal syllable hierarchy (e.g., blif ≻ bnif ≻ bdif ≻ lbif) while undergoing transcranial magnetic stimulation (TMS) over the cortical motor representation of the left orbicularis oris muscle. If syllable preferences reflect motor simulation, then worse-formed syllables (e.g., lbif) should (i) elicit more errors; (ii) engage more strongly motor brain areas; and (iii) elicit stronger effects of TMS on these motor regions. In line with the motor account, we found that repetitive TMS pulses impaired participants' global sensitivity to the number of syllables, and functional MRI confirmed that the cortical stimulation site was sensitive to the syllable hierarchy. Contrary to the motor account, however, ill-formed syllables were least likely to engage the lip sensorimotor area and they were least impaired by TMS. Results suggest that speech perception automatically triggers motor action, but this effect is not causally linked to the computation of linguistic structure. We conclude that the language and motor systems are intimately linked, yet distinct. Language is designed to optimize motor action, but its knowledge includes principles that are disembodied and potentially abstract.

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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.

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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.

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Most functional neuroimaging studies of major depressive disorder (MDD) employ univariate methods of statistical analysis to localize abnormalities of neural activity. Less has been done to investigate functional relations between these regions, or with regions not usually implicated in depression. Examination of intraneuronal and interneural network relations is important for the advancement of emerging network models for MDD. Principal component analysis (PCA), a multivariate statistical method, was used to examine differences in functional connectivity between 10 unmedicated patients with MDD and 12 healthy subjects engaged in a positive word viewing task. In healthy subjects, principal component (PC) 1 (33% variance) revealed functional connectivity of task-specific sensory, linguistic, and motor regions, along with functional anticorrelations in the default mode network; PC2 (10% variance) displayed functional connectivity of areas involved in emotional processing. This segregation of functions did not occur in the depressed group, where regions involved in emotional functions appeared in PC1 (34% variance) co-varying with those involved in linguistic, motor, and default mode network processing. The lack of segregation of emotional processing from cognitive and sensorimotor functions may represent a systems level neural substrate for a core phenomenon of depression: the interconnection of affective disturbance with experience, cognition, and behavior.

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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.

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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.

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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.

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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.

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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.

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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.

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OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: These findings suggest specific frontolimbic neural substrates associated with core clinical features of emotional and behavioral dyscontrol in borderline personality disorder.

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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.

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