Development and Psychopathology 17 2005 1197 1206 Copyright 2005 Cambridge University Press Printed in the United States of America DOI 10 10170S095457940505056X Defining the neurocircuitry of borderline personality disorder Functional neuroimaging approaches GARY R BRENDEL EMILY STERN and DAVID A SILBERSWEIG Weill Medical College of Cornell University Abstract Functional neuroimaging recently has been used to localize brain dysfunction in borderline personality disorder BPD Initial studies have examined baseline activity or emotional reactivity and our group has investigated what we consider to be a crucial interaction between negative emotion and behavioral dys control This research is beginning to identify abnormal frontolimbic circuitry likely underlying core clinical features of this condition We review the evidence for dysfunction in specific frontolimbic regions leading to a mechanistic model of symptom formation in BPD In addition we offer an integration of these neuroimaging findings with developmental perspectives on the emergence of borderline psychopathology focusing on the ways in which early psychosocial experience may interact with developing brain systems We also consider possible mechanisms of psychotherapeutic change at the neural systems level in BPD Finally we propose that future neuroimaging studies of BPD should integrate multiple levels of observation structural functional neurochemical genetic and clinical in a model driven fashion to further understand the dynamic relationship between biological and psychological factors in the development and treatment of this difficult condition Using a variety of imaging technologies and methodologies neuroimaging investigations are shedding light on brain structure and function in both normal and pathological states including psychotic mood anxiety and developmental disorders Dougherty Rauch 2001 Stern Silbersweig 2001 These varied approaches include using structural neuroimaging positron emission tomography PET and functional magnetic resonance imaging f MRI in the setting of symptom provocation studies cognitive activation paradigms and resting state studies By defining the dysfunctional neural circuitry in individuals with these conditions neuroimaging studies provide the possibility of enhanced diagnostic specificity novel targets for therapeutic interventions and more reliable predictors of treatment response Address correspondence and reprint requests to Gary R Brendel 295 Central Park West Suite 2 New York NY 10024 E mail grbrendel verizon net Initially focused on the investigation of Axis I disorders psychiatric neuroimaging researchers are beginning to study the functional neuroanatomy of Axis II disorders including borderline personality disorder BPD BPD is a complex psychiatric disorder characterized by affect dysregulation and behavioral impulsivity Individuals with this condition experience rapid alterations of mood and intense emotional responses as well as impulsive potentially self destructive behaviors substance abuse self mutilations suicidal behaviors binge eating sexual promiscuity Focusing on these domains of emotion and behavior neuroimaging studies have begun to elucidate the neural correlates of this disorder Functional neuroimaging studies using cognitive activation paradigms in which subjects are presented with emotional stimuli have begun to examine neural dysfunctions associated with emotional reactivity in individuals with BPD An fMRI study using negative versus neutral valenced images showed activations in bilateral amygdala bilateral fusiform gyri left 1197 1198 medial prefrontal Brodmann area BA 10 and right ventrolateral prefrontal BA 47 cortices in BPD subjects compared with normal controls Herpertz et al 2001 In another fMRI study investigators found greater activation in the left amygdala in response to facial expressions of emotion happy sad fearful in BPD patients versus normal control subjects Donegan et al 2003 A PET study by Schmahl Elzinga et al 2003 in which subjects listened to personalized scripts of abandonment experiences found increased activity in bilateral dorsolateral prefrontal cortex DLPFC BAs 8 9 10 and decreased activity in right dorsal anterior cingulate BAs 24 32 left superior0middle temporal gyri left fusiform gyrus BA 37 left visual association cortex BA 19 and right amygdala0hippocampus in BPD subjects compared with non BPD subjects who had comparable sexual abuse histories Although the direction of change in neural activation between BPD subjects and controls varies in these studies probably related to the specific methodologies used these results nonetheless support the broad notion of dysfunction in limbic and prefrontal regions in this disorder In addition frontolimbic amygdala0hippocampus orbitofrontal cortex OFC volume loss Rusch et al 2003 Schmahl Vermetten Elzinga Bremner 2003 Tebartz van Elst et al 2003 provides further evidence of dysfunction in these regions and suggests an underlying neuropathological correlate in BPD in regions that can be associated with the symptomatology of this disorder 18 F Fluorodeoxyglucose PET FDG PET imaging studies of BPD subjects consistently have demonstrated evidence of frontal dysfunction most prominent in the prefrontal cortical areas De la Fuente et al 1997 Juengling et al 2003 Soloff Meltzer Greer Constantine Kelly 2000 Metabolic challenge FDG PET neuroimaging studies using fenfluramine a serotonergic agonist have found blunted neural responses in a variety of regions including medial orbital dorsolateral and ventromedial prefrontal cortices as well as in anterior cingulate cortex in BPD subjects Siever et al 1999 Soloff et al 2000 Overall these studies support the hypothesis that diminished serotonergic function in PFC G R Brendel E Stern and D A Silbersweig a region with neurotransmitter and neuroanatomical systems known to be involved in emotional regulation and inhibitory behavioral control may constitute a biologic diathesis for disinhibition impulsivity and affect dysregulation in individuals with BPD Using PET with a 11 C methyl l tryptophan a MTrp an l tryptophan analog to assess brain serotonin 5 HT synthesis capacity Leyton et al 2001 found significantly lower a MTrp trapping in male BPD subjects compared with healthy controls in bilateral medial frontal cortices extending into the OFC bilateral anterior cingulate cortex left superior temporal gyrus BA 22 bilateral fusiform gyri BAs 19 37 left globus