Role of the motor system in language knowledge.

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.

Frontolimbic neural circuit changes in emotional processing and inhibitory control associated with clinical improvement following transference-focused psychotherapy in borderline personality disorder.

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.

The neuropsychiatric spectrum of motivational disorders.

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.

Neuroimaging of frontal-limbic dysfunction in schizophrenia and epilepsy-related psychosis: toward a convergent neurobiology.

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.

Failure to segregate emotional processing from cognitive and sensorimotor processing in major depression.

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.

Toward a functional neuroanatomy of premenstrual dysphoric disorder.

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.

Failure of frontolimbic inhibitory function in the context of negative emotion in borderline personality disorder.

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.

Lack of ventral striatal response to positive stimuli in depressed versus normal subjects.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

The Neuropsychiatric Spectrum of Motivational Disorders.

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

Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects.

BACKGROUND: Previous neuroimaging studies have demonstrated exaggerated amygdala responses to negative stimuli in posttraumatic stress disorder (PTSD). The time course of this amygdala response is largely unstudied and is relevant to questions of habituation and sensitization in PTSD exposure therapy. METHODS: We applied blood oxygen level dependent functional magnetic resonance imaging and statistical parametric mapping to study amygdala responses to trauma-related and nontrauma-related emotional words in sexual/physical abuse PTSD and normal control subjects. We examined the time course of this response by separate analysis of early and late epochs. RESULTS: PTSD versus normal control subjects have a relatively increased initial amygdala response to trauma-related negative, but not nontrauma-related negative, versus neutral stimuli. Patients also fail to show the normal patterns of sensitization and habituation to different categories of negative stimuli. These findings correlate with measured PTSD symptom severity. CONCLUSIONS: Our results demonstrate differential time courses and specificity of amygdala response to emotional and control stimuli in PTSD and normal control subjects. This has implications for pathophysiologic models of PTSD and treatment response. The results also extend previous neuroimaging studies demonstrating relatively increased amygdala response in PTSD and expand these results to a largely female patient population probed with emotionally valenced words.

Fear-related activity in subgenual anterior cingulate differs between men and women.

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.

Beyond the amygdala: Linguistic threat modulates peri-sylvian semantic access cortices.

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.

Altered threat and safety neural processing linked to persecutory delusions in schizophrenia: a two-task fMRI study.

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.

Language universals engage Broca's area.

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.

New and emerging imaging techniques for mapping brain circuitry.

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.

Identification of neural targets for the treatment of psychiatric disorders: the role of functional neuroimaging.

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.

Neural plasticity after acquired brain injury: evidence from functional neuroimaging.

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.