Frontolimbic Circuitry Research Articles

Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species

Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.

Long-term consequences of childhood maltreatment: Altered amygdala functional connectivity.

Childhood maltreatment is a serious individual, familial, and societal threat that compromises healthy development and is associated with lasting alterations to emotion perception, processing, and regulation (Cicchetti & Curtis, 2005; Pollak, Cicchetti, Hornung, & Reed, 2000; Pollak & Tolley-Schell, 2003). Individuals with a history of maltreatment show altered structural and functional brain development in both frontal and limbic structures (Hart & Rubia, 2012). In particular, previous research has identified hyperactive amygdala responsivity associated with childhood maltreatment (e.g., Dannlowski et al., 2012). However, less is known about the impact of maltreatment on the relationship between the amygdala and other brain regions. The present study employed an emotion processing functional magnetic resonance imaging task to examine task-based activation and functional connectivity in adults who experienced maltreatment as children. The sample included adults with a history of substantiated childhood maltreatment (n = 33) and comparison adults (n = 38) who were well matched on demographic variables, all of whom have been studied prospectively since childhood. The maltreated group exhibited greater activation than comparison participants in the prefrontal cortex and basal ganglia. In addition, maltreated adults showed increased amygdala connectivity with the hippocampus and prefrontal cortex. The results suggest that the intense early stress of childhood maltreatment is associated with lasting alterations to frontolimbic circuitry.

Alterations in Amygdala-Prefrontal Functional Connectivity Account for Excessive Worry and Autonomic Dysregulation in Generalized Anxiety Disorder

BackgroundGeneralized anxiety disorder (GAD) is characterized by the core symptom of uncontrollable worry. Functional magnetic resonance imaging studies link this symptom to aberrant functional connectivity between the amygdala and prefrontal cortex. Patients with GAD also display a characteristic pattern of autonomic dysregulation. Although frontolimbic circuitry is implicated in the regulation of autonomic arousal, no previous study to our knowledge combined functional magnetic resonance imaging with peripheral physiologic monitoring in these patients to test the hypothesis that core symptoms of worry and autonomic dysregulation in GAD arise from a shared underlying neural mechanism. MethodsWe used resting-state functional magnetic resonance imaging and the measurement of parasympathetic autonomic function (heart rate variability) in 19 patients with GAD and 21 control subjects to define neural correlates of autonomic and cognitive responses before and after induction of perseverative cognition. Seed-based analyses were conducted to quantify brain changes in functional connectivity with the right and left amygdala. ResultsBefore induction, patients showed relatively lower connectivity between the right amygdala and right superior frontal gyrus, right paracingulate/anterior cingulate cortex, and right supramarginal gyrus than control subjects. After induction, such connectivity patterns increased in patients with GAD and decreased in control subjects, and these changes tracked increases in state perseverative cognition. Moreover, decreases in functional connectivity between the left amygdala and subgenual cingulate cortex and between the right amygdala and caudate nucleus predicted the magnitude of reduction in heart rate variability after induction. ConclusionsOur results link functional brain mechanisms underlying worry and rumination to autonomic dyscontrol, highlighting overlapping neural substrates associated with cognitive and autonomic responses to the induction of perseverative cognitions in patients with GAD.

Amygdala on the Lookout.

results present an explanatory challenge: why would the amygdala be hypoactive in paranoid individuals who exhibit heightened threat perception and elevated physiological arousal? To explain this paradoxical finding, some investigators hypothesized that reduced frontal control over the amygdala due to dysconnectivity of frontolimbic circuitry could lead to hypervigilanceand misattribution of fear to incoming signals (3). AnotherpossibilityisthatmethodologicallimitationsofBOLD fMRI have obstructed a more accurate quantification of amygdala activity. In this issue of the Journal, a new study conducted by Pinkham and colleagues (5) offers a methodological explanation for discrepant findings concerning aberrant amygdala activity in paranoid schizophrenia. The authors definitively demonstrate higher baseline amygdala activity in paranoid compared with nonparanoid patients with schizophrenia, by employing arterial spin labeling perfusion MRI. Arterial spin labeling allows for a noninvasive and quantitative measurement of regional cerebral blood flow (CBF) by using magneticallylabeledarterialbloodwaterasanendogenoustracer (asopposedtoexogenousradioactivetracersusedinpositron emission tomography) (6). There are both important methodological and conceptual advances here worthy of note. In addition to arterial spin labeling, the authors acquired BOLD fMRI data while participants rated photographs of faces for trustworthiness. By measuring resting state regional CBF and task-related BOLD activity in the same participants, the authors were able to examine group differences in baseline amygdala activity alongside differences in task-related fluctuations of amygdalaactivity.Suchcomparisonsareparticularlyrelevant to schizophrenia, as prior evidence of amygdala hypoactivation relied on BOLD contrasts blind to potential group differences in baseline activity. Indeed, Pinkham and colleagues found that acutely paranoid patients exhibited higher resting CBF in the bilateral amygdala compared with nonparanoid patients and healthy comparison subjects, who did not differ from each other. On the other hand, the BOLD fMRI task analysis revealed a general trend of amygdala hypoactivation in paranoid compared with nonparanoid participants. Thus, observed taskrelated amygdala hypoactivity likely reflects higher baseline amygdala activity that mitigates the stimulus-driven signal change detected by the BOLD contrast. Additional wholebrain group comparisons found greater CBF in the internal capsule, the corpus callosum, and portions of the inferior temporal and fusiform gyri in paranoid compared with nonparanoid patients. Overall, these results suggest that paranoia

Brain activation in response to overt and covert fear and happy faces in women with borderline personality disorder.

Borderline personality disorder (BPD) is a serious condition involving emotion dysregulation. Past research has identified BPD-associated differences within fronto-limbic circuitry during conditions of processing negative emotion. Functional magnetic resonance imaging (fMRI) paradigms that incorporate overt and covert (masked) presentations of emotional stimuli can provide complementary information about neural systems underlying emotion processing (e.g., both slow [overt] and fast [covert; automatic] processing pathways). This study examined brain activation during processing of overt and covert presentations of emotional faces in 12 women with BPD and 12 age-matched healthy controls. To assess a range of emotional valence and arousal, we examined responses to fear, happy and neutral expressions. All participants underwent an fMRI scanning session in which participants passively viewed emotional faces. Scanning sessions consisted of 5 runs including: (1) Overt Fear (OF) versus Neutral (N), (2) Covert Fear (CF) versus Covert Neutral (CN), (3) Overt Happy (OH) versus N, (4) Covert Happy (CH) versus CN, and (5) N versus fixation. We compared whole-brain activation between groups for each run. In response to overt fear, BPD patients showed greater activation both in left amygdala and in several frontal cortical regions. There were no significant differences in brain activation in response to overt happy faces. In response to covert fear and covert happy stimuli, the BPD group also showed greater activation than controls in several regions including frontal and temporal cortical regions, as well as cerebellum and thalamus. These findings add to prior reports suggesting increased amygdala activation in BPD, but we found this only in the overt fear versus fixation condition. In this sample, BPD patients showed hyper-activation, rather than hypo-activation, of cortical regulatory regions during overt fear. Enhanced cortical recruitment in response to covert fear and happy faces in BPD could reflect a more extended response system in which stimuli that typically only activate automatic pathways are additionally tapping into cortical regulatory systems. The observation of this pattern both in response to fear and in response to happy presentations suggests that the effect of arousal may be as or more impactful than the effect of emotional valence.

Clarifying the heterogeneity in psychopathic samples: Towards a new continuum of primary and secondary psychopathy

Psychopathic individuals identified through contemporary instruments vary considerably in personality and etiological background, which creates confusion in practice and inconsistency in data. The goal of this paper is to clarify this heterogeneity and introduce a new typology to narrow down psychopathic subcategories. Towards this end, we will discuss the conceptual history of psychopathy, compare the construct-validity of different psychopathy measures (DSM, PCL-R, PPI-R, and TriPM), and review cluster-analytic studies to identify more homogenous categories. In line with the existing literature, the psychopathic population is broadly divided into a primary and secondary category which diverge crucially in personality (reward/punishment sensitivity, neuroticism, impulsivity, hostility) and etiology (genetic contributions, fronto-limbic circuitry, serotonergic functioning, and testosterone/cortisol endocrinology). Secondary psychopathy may be situated on a continuum with the antisocial or borderline personality disorder because it represents a more severe but not qualitatively different form of environment-contingent emotional disturbance (e.g., prefrontal cortex malfunctioning, serotonin deficiency, impaired predictive allostasis), whereas primary psychopathy is a unique condition that is strongly rooted in a constitutionally defined emotional deficiency (e.g., limbic hyporesponsivity, serotonin hyperstability, dampened reactive allostasis). However, both primary and secondary psychopathic samples show high levels of within-group heterogeneity and may be placed on their own continuum of, respectively, self-control and affect instability. Concluding, we will introduce a new continuum of primary psychopathy (controlled to disinhibited) and secondary psychopathy (detached to unstable) and discuss how these subtypes may differ on a number of psychopathy measures, personality profiles, and endophenotypic pathways. Finally, future directions for resolving conceptual issues are discussed.

Abnormal cortico-limbic connectivity during emotional processing correlates with symptom severity in schizophrenia

BackgroundImpaired emotional processing is a core feature of schizophrenia (SZ). Consistent findings suggested that abnormal emotional processing in SZ could be paralleled by a disrupted functional and structural integrity within the fronto-limbic circuitry. The effective connectivity of emotional circuitry in SZ has never been explored in terms of causal relationship between brain regions. We used functional magnetic resonance imaging and Dynamic Causal Modeling (DCM) to characterize effective connectivity during implicit processing of affective stimuli in SZ. MethodsWe performed DCM to model connectivity between amygdala (Amy), dorsolateral prefrontal cortex (DLPFC), ventral prefrontal cortex (VPFC), fusiform gyrus (FG) and visual cortex (VC) in 25 patients with SZ and 29 HC. Bayesian Model Selection and average were performed to determine the optimal structural model and its parameters. ResultsAnalyses revealed that patients with SZ are characterized by a significant reduced top-down endogenous connectivity from DLPFC to Amy, an increased connectivity from Amy to VPFC and a decreased driving input to Amy of affective stimuli compared to HC. Furthermore, DLPFC to Amy connection in patients significantly influenced the severity of psychopathology as rated on Positive and Negative Syndrome Scale. ConclusionsResults suggest a functional disconnection in brain network that contributes to the symptomatic outcome of the disorder. Our findings support the study of effective connectivity within cortico-limbic structures as a marker of severity and treatment efficacy in SZ.

Translational Research in Bipolar Disorders

Translational Research in Bipolar Disorders

Easy to remember, difficult to forget: The development of fear regulation

Fear extinction learning is a highly adaptive process that involves the integrity of frontolimbic circuitry. Its disruption has been associated with emotional dysregulation in stress and anxiety disorders. In this article we consider how age, genetics and experiences shape our capacity to regulate fear in cross-species studies. Evidence for adolescent-specific diminished fear extinction learning is presented in the context of immature frontolimbic circuitry. We also present evidence for less neural plasticity in fear regulation as a function of early-life stress and by genotype, focusing on the common brain derived neurotrophin factor (BDNF) Val66Met polymorphism. Finally, we discuss this work in the context of exposure-based behavioral therapies for the treatment of anxiety and stress disorders that are based on principles of fear extinction. We conclude by speculating on how such therapies may be optimized for the individual based on the patient's age, genetic profile and personal history to move from standard treatment of care to personalized and precision medicine.

White Matter Correlates of Adolescent Depression: Structural Evidence for Frontolimbic Disconnectivity

Despite the significant prevalence of adolescent depression, little is known about the neuroanatomical basis of this disorder. Functional dysregulation in frontolimbic circuitry has been suggested as a key neural correlate of adult and adolescent depression impeding emotional regulation. However, less is known about whether this dysregulation is overlaid onimpaired white matter microstructure. Guided by neuroimaging findings, we test the a priori hypotheses that adolescent depression is associated with alterations in white matter microstructure in the uncinate fasciculus (UF) and cingulum bundles. Diffusion tensor magnetic resonance imaging (DTI) data were obtained on 52 unmedicated adolescents with major depressive disorder (MDD) and 42 matched controls. We calculated fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) for bilateral UF and cingulum. We also completed a voxelwise comparison of participants with depression and control participants using tract-based spatial statistics (TBSS). Adolescents with depression had significantly lower FA and higher RD in bilateral UF; no significant differences were observed in cingulum. TBSS results additionally revealed lower FA values in the white matter associated with the limbic-cortical-striatal-thalamic circuit, corpus callosum, and anterior and superior corona radiata. Unmedicated adolescent depression is associated with reduced fractional anisotropy in emotion regulatory networks, which may underlie the functional differences in frontolimbic circuitry characterizing depressive disorder. Given the relatively recent onset of depression in our sample, our findings in the context of the current literature provide preliminary evidence that reduced fractional anisotropy in the UF could be a predisposing risk factor for depression.

Age and gender modulate the neural circuitry supporting facial emotion processing in adults with major depressive disorder.

Emotion processing, supported by frontolimbic circuitry known to be sensitive to the effects of aging, is a relatively understudied cognitive-emotional domain in geriatric depression. Some evidence suggests that the neurophysiological disruption observed in emotion processing among adults with major depressive disorder (MDD) may be modulated by both gender and age. Therefore, the present study investigated the effects of gender and age on the neural circuitry supporting emotion processing in MDD. Cross-sectional comparison of fMRI signal during performance of an emotion processing task. Outpatient university setting. One hundred adults recruited by MDD status, gender, and age. Participants underwent fMRI while completing the Facial Emotion Perception Test. They viewed photographs of faces and categorized the emotion perceived. Contrast for fMRI was of face perception minus animal identification blocks. Effects of depression were observed in precuneus and effects of age in a number of frontolimbic regions. Three-way interactions were present between MDD status, gender, and age in regions pertinent to emotion processing, including frontal, limbic, and basal ganglia. Young women with MDD and older men with MDD exhibited hyperactivation in these regions compared with their respective same-gender healthy comparison (HC) counterparts. In contrast, older women and younger men with MDD exhibited hypoactivation compared to their respective same-gender HC counterparts. This the first study to report gender- and age-specific differences in emotion processing circuitry in MDD. Gender-differential mechanisms may underlie cognitive-emotional disruption in older adults with MDD. The present findings have implications for improved probes into the heterogeneity of the MDD syndrome.

EPA-0625 – White matter diffusion tensor imaging microstructure correlates of adolescent depression: structural evidence for frontolimbic disconnectivity

Despite the significant prevalence of adolescent depression, little is known about the neuroanatomical basis of this disorder. Functional dysregulation in frontolimbic circuitry has been suggested as a key neural correlate of adult and adolescent depression impeding emotional regulation. However, less is known about whether this dysregulation is overlaid on impaired white matter microstructure. Guided by neuroimaging findings, we test the a priori hypotheses that adolescent depression is associated with alterations in white matter microstructure in the 1) uncinate fasciculus (UF) 2) cingulum bundles, and 3) fibers linking subgenual anterior cingulate cortex (sgACC) and amygdala. Diffusion tensor magnetic resonance imaging (DTI) data were obtained on 52 un-medicated adolescents with major depressive disorder and 42 matched controls. We calculated fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) for bilateral UF, cingulum, and sgACC-amygdala fibers using probabilistic tractography. We also completed a voxelwise comparison of depressed and control participants using tract-based spatial statistics (TBSS). Depressed adolescents had significantly lower FA and higher RD in bilateral UF and right sgACC-amygdala tracts. TBSS results additionally revealed lower FA values in the white matter associated with the limbic-cortical-striatal-thalamic circuit, corpus callosum, and anterior and superior corona radiata. Adolescent depression is associated with reduced white matter integrity in emotion regulatory networks, which may underlie the functional differences in frontolimbic circuitry often observed in adolescent depression. We offer evidence that poor myelination of the white matter tracts supporting emotion regulation may contribute to the etiology of early-onset depression.

Increased Prefrontal Cortical Thickness Is Associated with Enhanced Abilities to Regulate Emotions in PTSD-Free Women with Borderline Personality Disorder

Previous studies suggest that amygdala, insula and prefrontal cortex (PFC) disintegrity play a crucial role in the failure to adequately regulate emotions in Borderline Personality Disorder (BPD). However, prior results are confounded by the high rate of comorbidity with Posttraumatic Stress Disorder (PTSD), which itself has been associated with changes in frontolimbic circuitry. We thus scrutinized the link between PFC, amygdala, insula, and the ability to regulate emotions, contrasting 17 women with BPD without comorbid PTSD to 27 non-clinical control women and in addition to those with BPD and PTSD (n = 14). BPD women without PTSD, but not those with comorbid PTSD, had increased cortical thickness in the dorsolateral PFC (DLPFC) in comparison to control women. Furthermore, cortical thickness in the DLPFC of BPD women without PTSD positively correlated with emotion regulation scores and furthermore was positively associated with amygdala volume, as well as cortical thickness of the insula. Our findings highlight the importance of disentangling the impact of BPD and PTSD on the brain and suggest possible compensatory mechanisms for the impaired emotion regulation in BPD women without PTSD.

White matter deficits in first episode schizophrenia: An activation likelihood estimation meta-analysis

Diffusion tensor imaging (DTI) has been widely used in psychiatric research and has provided evidence of white matter abnormalities in first episode schizophrenia (FES). The goal of the present meta-analysis was to identify white matter deficits by DTI in FES. A systematic search was conducted to collect DTI studies with voxel-wised analysis of the fractional anisotropy (FA) in FES. The coordinates of regions with FA changes were meta-analyzed using the activation likelihood estimation (ALE) method which weighs each study on the basis of its sample size. A total of 8 primary studies were selected, including 271 FES patients and 297 healthy controls. Among these studies, 52 regions showed reductions in the FA in FES while 2 regions had increased FA. Consistent FA reductions in the white matter of the right deep frontal and left deep temporal lobes were identified in all FES patients relative to healthy controls. Fiber tracking showed that the main tracts involved were the cingulum bundle, the left inferior longitudinal fasciculus, the left inferior fronto-occipital fasciculus and the interhemispheric fibers running through the corpus callosum. The current findings provide evidence confirming the lack of connection in the fronto-limbic circuitry at the early stages of the schizophrenia. Because the coordinates reported in the primary literature were highly variable, future investigations with large samples would be required to support the identified white matter changes in FES.

The Teenage Brain

Fear learning is an adaptive, evolutionarily conserved process that allows people to respond appropriately to threats in the environment. These threats can vary across different contexts and across the life course. Taking into account the high degree of neural and behavioral conservation across species in fear regulation and its underlying neural circuitry, we examined how fear learning changes across contexts and over the course of development, focusing specifically on the environmentally changing and challenging period of adolescence. We show two surprising developmental findings specific to adolescents, relative to older and younger individuals: (a) diminished fear to previously aversive contexts and (b) heightened fear to previously aversive cues. These behavioral changes are paralleled by developmental changes in frontolimbic circuitry. We discuss how these evolutionarily conserved mechanisms may be essential to survival of the species, given the changing environmental demands (social, sexual, and physical) of adolescence. Our findings also have important implications for unremitting forms of fear at the core of anxiety-related disorders, which peak during adolescence, and for when during development specific treatments for these disorders may be most effective.

边缘性人格障碍的病因机制<br>Pathogenetic Mechanisms of the Borderline Personality Disorder

边缘性人格障碍是以持久而普遍的认知、情绪和行为失调为特征的一种严重而复杂的行为障碍。从发展心理病理学的视角来看，边缘性人格障碍与童年期不良家庭环境、混乱的依恋关系、家庭史因素等心理社会风险因素有关，也与5-羟色胺、多巴胺等神经递质的功能缺损，前额边缘环路失调，自主神经功能失调有关，尤其重要的是边缘性人格障碍的形成可能是环境风险因素与脆弱的神经生物因素交互作用共同影响的结果。对边缘性人格病因机制考察的未来研究应该更加注重追踪研究，从多层次、多领域考察心理社会因素与生物学因素的交互在BPD发病中的作用。 Borderline personality disorder (BPD), which is characterized by persistent and pervasive cognitive, emotional, and behavioral dysregulation, is among the most severe and perplexing behavioral disorders. From the developmental psychopathology approach, Borderline personality disorder is associated with psychological and social risk factors including poor family environments during childhood, disrupted attachment relationships and family history factors, and it is related to dysfunctional neurotransmitter systems, including serotonin, dopamine and so on. It is also related to dysfunction of frontolimbic circuitry and the peripheral nervous system. Most importantly, the emergence of BPD was the results of the interaction between environmental risk factors and vulnerable neurobiological factors across development. Future researches about pathogenetic mechanisms of the borderline personality disorder should focus on longitudinal or developmental studies and examine the role of the interaction between environmental risk factors and neurobiological factors in BPD from other fields and more comprehensive assessments of more methods.

Neurocognitive profiles of people with borderline personality disorder

This review summarizes recent neurocognitive research to better delineate the nosology, prognostication and cause underlying borderline personality disorder (BPD). BPD had marked clinical heterogeneity with high comorbidity. Executive dysfunction in this disorder was linked to suicidality and treatment adherence, and may serve as an endophenotype. BPD was also characterized by cognitive distortions such as risky decision-making, deficient feedback processing, dichotomous thinking, jumping to conclusion, monocausal attribution and paranoid cognitive style. Social cognition deficits recently described in BPD include altered social inference and emotional empathy, hypermentalization, poorer facial emotional recognition and facial expressions. In electrophysiological studies, BPD was found to have predominantly right hemispheric deficit in high-order cortical inhibition. Reduced left orbitofrontal activity by visual evoked potential and magnetoencephalography correlated with depressive symptoms and functional deterioration. Brain structures implicated in BPD include the hippocampus, dorsolateral prefrontal cortex and anterior cingulate cortex. Abnormal anatomy and functioning of frontolimbic circuitry appear to correlate with cognitive deficits. Frontolimbic structural and functional abnormalities underlie the broad array of cognitive abnormalities in BPD. Further research should espouse broader considerations of effects of comorbidity and clinical heterogeneity, and include community samples and, possibly, longitudinal designs.

Sensorimotor Modulation of Mood and Depression: In Search of an Optimal Mode of Stimulation

Depression involves a dysfunction in an affective fronto-limbic circuitry including the prefrontal cortices, several limbic structures including the cingulate cortex, the amygdala, and the hippocampus as well as the basal ganglia. A major emphasis of research on the etiology and treatment of mood disorders has been to assess the impact of centrally generated (top-down) processes impacting the affective fronto-limbic circuitry. The present review shows that peripheral (bottom-up) unipolar stimulation via the visual and the auditory modalities as well as by physical exercise modulates mood and depressive symptoms in humans and animals and activates the same central affective neurocircuitry involved in depression. It is proposed that the amygdala serves as a gateway by articulating the mood regulatory sensorimotor stimulation with the central affective circuitry by emotionally labeling and mediating the storage of such emotional events in long-term memory. Since both amelioration and aggravation of mood is shown to be possible by unipolar stimulation, the review suggests that a psychophysical assessment of mood modulation by multimodal stimulation may uncover mood ameliorative synergisms and serve as adjunctive treatment for depression. Thus, the integrative review not only emphasizes the relevance of investigating the optimal levels of mood regulatory sensorimotor stimulation, but also provides a conceptual springboard for related future research.

Differential relations between fronto‐limbic metabolism and executive function in patients with remitted bipolar I and bipolar II disorder

The aim of this study was to investigate the relationship between resting brain glucose metabolism and cognitive profiles in patients with remitted bipolar I disorder (BD-I) and bipolar II disorder (BD-II). We hypothesized that BD-I patients (compared to BD-II patients) would perform worse on tests of cognitive function because of abnormal metabolism in the prefrontal cortex and other mood-related brain areas. Thirty-four patients with remitted bipolar disorder (BD) (BD-I = 17, BD-II = 17) under treatment and 17 well-matched healthy controls received both fluorodeoxyglucose ((18) F-FDG) positron emission tomography (PET) and neuropsychological tests of attention, memory, and executive function. Clinical features in patients with BD-I and BD-II were comparable. Executive function, as indicated by performance on the Wisconsin Card Sorting Test, was significantly worse (i.e., higher percentage of errors, lower percentage of conceptual level responses, and fewer categories completed) in BD-I patients than in BD-II patients and healthy subjects. No difference in attention and memory tests was found among these three groups. Brain PET analysis showed that BD-I patients (compared to BD-II patients) had significantly lower glucose uptake in the bilateral anterior cingulum, insula, striatum, and part of the prefrontal cortex, and higher glucose uptake in the left parahippocampus. Further analyses revealed significant correlations between poor executive function and abnormal glucose uptake in other brain areas in BD-I patients. There are neurobiological differences between subtypes of BD. BD-I is associated with more impaired fronto-limbic circuitry, which might account for reduced executive function in BD-I patients during remission.

Medial prefrontal dysfunction and prolonged amygdala response during instructed fear processing in borderline personality disorder

Objectives. Affective dysregulation is a clinical hallmark of borderline personality disorder (BPD). This study used an instructed fear task combined with functional MRI (fMRI) and skin conductance response (SCR) to test hypotheses about mechanisms of disturbed fronto-limbic neural circuitry underlying dysfunctional emotional processing in BPD. Methods. Female BPD patients and matched control subjects were exposed to two visual stimuli during fMRI scanning and SCR recording. Subjects were instructed shortly before scanning that one stimulus (Threat) potentially represents an aversive event whereas another stimulus (Safe) represents safety. The aversive event (electrodermal stimulation) itself was only experienced before this instruction and never occurred during fMRI scanning. Results. Both groups showed stronger SCR to Threat compared to Safe indicating differential fear response which habituated over time. BPD compared to control subjects did not show fMRI signal decrease of amygdala activity or relative ventromedial prefrontal cortex (vmPFC) activity increase over time. Moreover, BPD patients showed increased connectivity of the amygdala with vmPFC but decreased connectivity of subgenual ACC with dorsal ACC compared to control subjects. Conclusions. Prolonged amygdala response and a functional disconnection between ventral and dorsal mPFC regions may be part of the neural mechanisms underlying emotional dysregulation in BPD patients.