Part I
1
Chi C. Chan, Daniel H. Vaccaro, Nina L. J. Rose, Laura E. Kessler, and Erin A. Hazlett
Advances in neuroimaging methods have provided a window into the brain in vivo and have been critical to the understanding of the neural substrates and brain circuits involved in psychiatric disorders. In personality disorders, neuroimaging techniques have been used to examine mechanisms underlying the disturbances in interpersonal relations, affect regulation, impulsivity, and cognitive processes seen in these disorders.
Structural neuroimaging techniques provide static anatomical information about the brain. Early neuroimaging studies used computed tomography (CT), which combines multiple X-ray images taken from different angles to produce cross-sectional images or “slices” of anatomy. Studies that used CT primarily examined ventricular size and ventricle-brain ratios. CT studies then gave way to magnetic resonance imaging (MRI), a technique that does not involve harmful radiation but uses powerful magnetic fields and radio waves to create images that surpass CT in spatial resolution. MRI provides greater soft tissue contrast and anatomical detail. The development of diffusion tensor imaging (DTI) provided a measure of white matter tract coherence by measuring the diffusion characteristics of water molecules along the axon. The scalar unit that is most often used in DTI studies is fractional anisotropy (FA), which quantifies the degree to which diffusion is directionally constrained. In general, lower FA is a putative measure of decreased white matter integrity.
Functional neuroimaging methods provide information on the neural substrates and circuits involved in brain functioning while the individual is at rest or performing a behavioral task. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) track the path of a radiolabeled ligand to measure metabolic processes in tissues and organs. The radiotracer to use depends on the physiological system of interest to the study. For example, fluorodeoxyglucose (18FDG) is a glucose-analog radiotracer commonly used in PET studies, and its uptake is a proxy for glucose metabolism. Functional magnetic resonance imaging (fMRI) noninvasively measures the brain’s blood oxygen level dependent (BOLD) signal as a proxy for neural activity. Spatially separate brain regions are considered “functionally connected” if their BOLD signals are temporally correlated, and the degree of functional connectivity can be compared between groups.
A comprehensive review of the literature is beyond the scope of this chapter; therefore, the most robust and relevant structural and functional neuroimaging findings in personality disorders will be discussed. In keeping with the current categorization of personality disorders in the DSM-5, we primarily discuss studies that specifically include individuals diagnosed with a personality disorder, and at times supplement with those that only characterize the possession of a level of a trait (e.g., psychometric schizotypy, impulsivity). Due to the scarcity of literature in many of the personality disorders and to allow for a deeper analysis in the space provided, this chapter will focus on schizotypal personality disorder, borderline personality disorder, and antisocial personality disorder as hallmark examples and will conclude with direction for how this literature can move forward to include the full range of personality disorders.
Schizotypal Personality Disorder
Schizotypal personality disorder (SPD) is characterized by pervasive interpersonal deficits, cognitive-perceptual distortions, and eccentric behavior resulting in impaired functioning (American Psychiatric Association, 2013). It is the Cluster A personality disorder that has received the most research attention in the area of neuroimaging, due to its relationship with schizophrenia as part of the schizophrenia spectrum. SPD shares genetic, phenomenological, and neurobiological features with schizophrenia (Siever & Davis, 2004), but without the frank psychosis and more severe cognitive and functional difficulties. Similar to schizophrenia, individuals with SPD exhibit impairments in multiple cognitive domains, particularly working memory and processing speed (McClure, Harvey, Bowie, Iacoviello, & Siever, 2013). SPD is considered the prototypical schizophrenia-spectrum disorder as it falls in the middle of the spectrum and allows for the study of protective and vulnerability factors for psychosis, without the confounds associated with schizophrenia such as chronic psychosis, recurrent institutionalization, and long-term antipsychotic use. Many of the studies were driven by findings in schizophrenia with the aim of determining how brain abnormalities in SPD are similar to or different from those observed in schizophrenia.
Structural Neuroimaging
MRI studies in schizophrenia consistently report volume reductions in the temporal and frontal lobes (Shepherd, Laurens, Matheson, Carr, & Green, 2012), making these areas a particular focus in SPD. One of the most robust findings in SPD is reduced gray matter volume in the lateral temporal lobe, particularly in the superior temporal gyrus (e.g., Dickey et al., 1999; Goldstein et al., 2009; Takahashi et al., 2010) and in its component parts including Heschl’s gyrus (Dickey et al., 2002) and planum temporal (Kawasaki et al., 2004; Takahashi et al., 2006). Volume reduction has also been reported in the middle (Asami et al., 2013; Hazlett et al., 2014; Koo et al., 2006) and inferior temporal gyri (Asami et al., 2013; Downhill et al., 2001). Many of the reported findings were predominantly in the left hemisphere (Fervaha & Remington, 2013; Hazlett, Goldstein, & Kolaitis, 2012) where language processing is localized. Indeed there is evidence that reduced temporal volumes are associated with odd speech (Dickey et al., 2003), as well as greater overall SPD symptom severity (Goldstein et al., 2009) and negative symptoms (Asami et al., 2013).
Medial temporal lobe volume reductions have been reported in the posterior fusiform gyrus (Takahashi et al., 2006), hippocampus (Dickey et al., 2007; Suzuki et al., 2005), insula and entorhinal cortex (Yoneyama et al., 2003), and amygdala (Suzuki et al., 2005). Furthermore, reduction of the normal hemispheric asymmetry has been found in the middle and inferior temporal gyri (Chan et al., 2018), while increased asymmetry was found in the parahippocampal gyrus (Dickey et al., 1999). Follow-up studies show that volume reduction in regions of the temporal lobe remains stable in SPD over approximately three years, whereas there is progressive deterioration in the early phase of schizophrenia (Takahashi et al., 2010, 2011). Individuals with SPD seem to share temporal lobe abnormalities with schizophrenia, but they are generally less severe, widespread, and progressive.
In contrast to temporal lobe findings, the frontal lobe appears to be less affected in SPD than in schizophrenia. Although volume reduction has been reported in the right superior prefrontal (Koo et al., 2006) and left inferior frontal regions (Kawasaki et al., 2004), these abnormalities are less severe than the widespread volume reduction in medial and lateral frontal cortex seen in schizophrenia (Kawasaki et al., 2004). Furthermore, Yoneyama et al. (2003) did not find any differences in orbitofrontal and medial frontal regions. Interestingly, studies have reported increased volume in the dorsolateral prefrontal cortex (Hazlett, Buchsbaum, Haznedar, et al., 2008; Suzuki et al., 2005) and the inferior frontal lobe (Matsui et al., 2008). The relatively mild, negative, or opposite frontal lobe findings in SPD compared with schizophrenia serve as the basis for the theory that temporal lobe abnormalities contribute to the clinical and cognitive symptoms of SPD while a preserved frontal lobe is a protective factor against the development of frank psychosis (Hazlett, Buchsbaum, Haznedar, et al., 2008; Siever & Davis, 2004). Indeed, temporal lobe volume reductions have been shown to predict SPD group membership and severity of symptoms, while greater sparing and larger volume of frontal lobe regions such as the dorsolateral prefrontal cortex were associated with better outcomes, including less severe symptoms in SPD (Hazlett et al., 2014).
Subcortical areas have received less research attention. In the anterior cingulate, some studies have found no difference in SPD compared with healthy controls (Goldstein et al., 2009; Haznedar et al., 2004), while schizophrenia patients showed reduced volume (Takahashi et al., 2002). However, one study (Hazlett, Buchsbaum, Haznedar, et al., 2008) found smaller cingulate gray matter volume in areas of the anterior cingulate and dorsal posterior cingulate. There is also evidence in SPD of reduced volume of white matter fibers that connect the frontal lobe and thalamus (Suzuki et al., 2004) and shortened length of the interthalamic adhesion, a band of tissue connecting bilateral thalamic masses (Takahashi et al., 2008). In the thalamus, SPD individuals show reduced volume in the pulvinar (which has temporal lobe projections), while schizophrenia patients show reduced volume in both the pulvinar and mediodorsal nuclei (which has frontal lobe projections; Byne et al., 2001).
In addition to abnormalities in cortical volume, evidence also suggests disrupted neural connectivity in schizophrenia based on DTI studies that report lower fractional anisotropy (FA), a putative measure of white matter integrity, in white matter tracts that connect cortical regions (Ellison-Wright & Bullmore, 2009; Kubicki et al., 2007; Wheeler & Voineskos, 2014). Lener et al. (2015) conducted a DTI study comparing individuals with schizophrenia, SPD, and healthy controls. They found a spectrum pattern in which FA was highest in controls, intermediate in SPD, and lowest in schizophrenia in the inferior longitudinal fasciculus (temporal-occipital tract) and the genu of the corpus callosum. Results of later studies also support these findings in SPD (Sun et al., 2016; Zhang et al., 2017). The uncinate fasciculus (a frontotemporal white matter tract) has also been shown to have lower FA bilaterally in SPD relative to healthy controls (Gurrera et al., 2007; Nakamura et al., 2005), which was associated with greater cognitive and clinical symptoms (Nakamura et al., 2005). In contrast, the cingulum bundle (with prefrontal, parietal, and temporal lobe connections) and the anterior limb of the internal capsule (thalamo-frontal tract) showed lower FA in the schizophrenia patients but not in the SPD individuals (Lener et al., 2015), which supports previous negative findings in these tracts in SPD (Hazlett, Collazo, et al., 2012; Nakamura et al., 2005).
Taken together, structural neuroimaging studies indicate volume reduction of the temporal lobe and decreased structural integrity in white matter tracts in SPD. These abnormalities resemble those seen in schizophrenia, albeit to a lesser extent and may represent a vulnerability to schizophrenia which manifest in the attenuated subthreshold psychotic symptoms of SPD. Frontal lobe volume reductions are relatively minimal in SPD and there is even evidence of increased frontal lobe volume, which may be a protective factor against psychosis.
Functional Neuroimaging
Complementary to findings in brain structure, neuroimaging studies have also found abnormal brain function in SPD. Mirroring the structural findings in the frontal and temporal lobe, Buchsbaum et al. (2002) reported that SPD patients exhibited reduced glucose metabolism in the temporal lobe that was intermediate between schizophrenia and healthy controls, whereas they did not exhibit reduction in metabolic rates in the frontal lobe and the cingulate. It is important to note that the schizophrenia and SPD patients were neuroleptic-naïve or neuroleptic-free at the time of the study, reducing the confound of medication status. Similarly, Thompson et al. (2014) did not find an increase in prefrontal dopamine receptor availability as seen in schizophrenia (Abi-Dargham et al., 2002). In the striatum, individuals with SPD show increased glucose metabolism compared with healthy controls and schizophrenia patients, which was associated with fewer psychotic-like symptoms and may be protective against psychosis (Shihabuddin et al., 2001).
In response to various tasks, individuals with SPD exhibit abnormalities in activation of structures in frontal and temporal lobes, thalamus, basal ganglia, and limbic system. Compared to healthy controls, SPD patients show increased activation in the superior temporal gyrus when passively processing tones, which was associated with greater odd speech and impaired verbal learning (Dickey et al., 2008). In a study comparing healthy controls, SPD, and borderline personality disorder groups, the SPD group demonstrated the highest overall peak activation in the amygdala when viewing unpleasant, neutral, and pleasant pictures (Hazlett, Zhang, et al., 2012). Hazlett and colleagues (Hazlett, Buchsbaum, Zhang et al., 2008) found that both patients with schizophrenia and individuals with SPD utilized frontal-striatal-thalamic (FST) circuitry inefficiently during a sensorimotor gating task: schizophrenia patients did not recruit the FST enough during task-relevant stimuli, and SPD patients allocated excessive FST resources during task-irrelevant auditory stimuli. In contrast to abnormal increased activation during sensory and affective tasks, working memory tasks reveal decreased activation in SPD in frontal and parietal regions (Koenigsberg et al., 2005) and in the superior temporal gyrus, frontal regions, and insula (Vu et al., 2013).
Along with distinct brain regions found to be abnormal in schizophrenia and SPD, there is also evidence of disruptions in the ongoing intrinsic neural activity in the brain. The default mode network (DMN) is a network of brain areas that are activated during rest, when the brain is not actively engaged in any cognitive tasks. It is composed of a widely distributed network of regions where activity is in temporal synchrony (Raichle et al., 2001). Research has shown altered DMN functional connectivity in schizophrenia that correlates with clinical features (Huang et al., 2010; Rotarska-Jagiela et al., 2010). Two studies have reported significant differences in resting state functional connectivity between SPD and healthy controls. Zhang et al. (2014) first showed that resting state functional connectivity was increased in the bilateral superior temporal gyrus and striatum, and decreased in frontal regions, consistent with previous research showing similar resting-state hypofrontality in schizophrenia (Garrity et al., 2007; Hill et al., 2004). Zhu et al. (2017) examined functional connectivity in the precuneus, a functional hub of the DMN, and found abnormal connectivity with medial and lateral temporal regions. Moreover, lower connectivity between the precuneus and parahippocampus was associated with increased schizotypal symptoms. These results are similar to schizophrenia research by Kraguljac, White, Hadley, Reid, and Lahti (2014) who reported deficits in resting state functional connectivity between the precuneus and hippocampus.
Functional neuroimaging studies are consistent with structural MRI findings of attenuated temporal lobe abnormalities in SPD relative to schizophrenia. Individuals with SPD show decreased temporal lobe glucose metabolism while glucose metabolism and dopamine receptor availability in the frontal lobe appear to be normal. SPD is also marked by increased brain activation during auditory, affective, and sensory processing, which may be associated with cognitive and clinical symptoms. There may also be disruptions in the intrinsic neural network connectivity that support cognitive functions characterized by hyperconnectivity of the temporal regions, hypoconnectivity in frontal regions, and aberrant patterns of increased and decreased connectivity in the precuneus.
Conclusions for Neuroimaging Studies in SPD
Studying SPD as a schizophrenia-spectrum disorder provides a unique opportunity to understand vulnerability and protective factors from the psychosis in schizophrenia. A fairly consistent pattern of findings is that temporal lobe abnormalities in SPD are similar to those in schizophrenia but less marked, while SPD seems to show relative sparing of the frontal lobe abnormalities that is characteristic of schizophrenia. The literature generally supports the notion that the relatively less marked abnormalities in the frontal lobe may be protective against the development of frank psychosis (Buchsbaum et al., 1997; Siever & Davis, 2004). Firm conclusions are difficult to draw from the functional neuroimaging literature given the relatively small number of studies and variety of tasks used. However, there appears to be abnormal functional connectivity and brain activation to sensory, affective, and working memory tasks that involve both increased and decreased activation/connectivity. These results suggest inefficient recruitment of brain regions that may be associated with the clinical symptoms and cognitive impairments in SPD.
Additional studies that directly compare SPD, schizophrenia, and healthy controls are needed to understand brain abnormalities across the schizophrenia spectrum. At the same time, new studies that involve other personality disorders as comparison groups will help delineate the specificity of SPD abnormalities. For example, Goldstein et al. (2009) reported that individuals with SPD had smaller superior temporal gyrus volume than healthy controls as well as individuals with borderline personality disorder. Functional neuroimaging findings would benefit from replication using more homogeneous methodology. SPD is a difficult-to-recruit population given the relatively low base rate, their non-treatment-seeking nature, and increased resources necessary to establish the pervasive patterns of personality dysfunction for accurate diagnosing. As a result, many studies are limited by small sample sizes, which may be addressed by multi-site collaborations. Using neuroimaging methods to understand the vulnerability and protective neural mechanisms that underlie SPD may provide neural targets for treatment and prevention efforts in the schizophrenia spectrum.
Borderline Personality Disorder
Individuals with borderline personality disorder (BPD) exhibit a pervasive pattern of instability of personal relationships, self-image, affects, and marked impulsivity (American Psychiatric Association, 2013). This disorder is associated with increased suicide risk (Oldham, 2006) and a high prevalence of childhood adversity (Zanarini et al., 1997). BPD is recognized as having a multifaceted etiology that stems from an interaction of genetic and environmental factors (Leichsenring, Leibing, Kruse, New, & Leweke, 2011). Of all the personality disorders, BPD is the most studied in terms of neuroimaging methods examining the neurobiology. These studies have largely focused on identifying the neural circuitry associated with affect dysregulation and behavioral impulsivity, which involves limbic and prefrontal regions of the brain.
Structural Neuroimaging
BPD was initially derived from noticing a group of patients who were on the “border” between neurosis and psychosis (Kernberg, 1967). As such, early studies focused on comparing schizophrenia and BPD (Gunderson & Singer, 1975) or so-called borderline personality organization (Kernberg, 1967). However, CT studies did not find ventricular enlargement in BPD that was characteristic of schizophrenia (Lucas, Gardner, Cowdry, & Pickar, 1989; Schulz et al., 1983). More recently, MRI studies have reported morphological abnormalities in various structures considered to be implicated in the affective dysregulation and impulsivity symptoms of BPD. Individuals with BPD show reduced hippocampus and amygdala volume (Nunes et al., 2009; Ruocco, Amirthavasagam, & Zakzanis, 2012; Schulze, Schmahl, & Niedtfeld, 2016) with an average of 13 percent and 11 percent reductions, respectively (Ruocco et al., 2012). Furthermore, these changes are not a result of psychotropic medication status, comorbid depression, posttraumatic stress disorder (PTSD), or substance use disorder (Ruocco et al., 2012). Because these structures are involved in the regulation of emotions and behavior during stress (Daniels, Richter, & Stein, 2004; Gregg & Siegel, 2001), they may be neurobiological correlates for some of the symptoms and characteristics associated with BPD such as aggression, affective dysregulation, emotional outbursts, and difficulties in social relationships. For example, smaller hippocampus volumes have been linked to greater intrusion and hyperarousal symptoms (Irle, Lange, & Sachsse, 2005) and increased hospitalization and aggressive behavior (Zetzsche et al., 2007).
The anterior cingulate cortex (ACC) is of particular interest in BPD given its role in cognitive and emotional processing. The dorsal portion has interconnections with prefrontal and motor areas, and is implicated in modulation of attention and executive functions; the anterior portion has connections with limbic regions and orbitofrontal cortex (among other areas) and is involved in affective functions such as emotion regulation and motivation (Bush, Luu, & Posner, 2000). BPD individuals show smaller ACC volume (e.g., (Hazlett et al., 2005; Minzenberg, Fan, New, Tang, & Siever, 2008; Soloff et al., 2012), which was found to be associated with increased parasuicidal behavior and impulsivity (Whittle et al., 2009). Other frontal lobe regions with connections to the ACC and implicated in modulation of emotional and cognitive activity have also been shown to be smaller in BPD, including the frontal lobe as a whole (Lyoo, Han, & Cho, 1998), dorsolateral prefrontal cortex (Brunner et al., 2010), and orbital frontal cortex (Brunner et al., 2010; Chanen et al., 2008; Tebartz van Elst et al., 2003).
Volumetric abnormalities also have been reported in other regions, including reduction of the middle temporal gyri and inferior frontal gyrus, and greater volume in the supplementary motor area, cerebellum, and middle frontal gyrus (Schulze et al., 2016). A study by Soloff et al. (2012) comparing individuals with BPD with and without a history of a suicide attempt found that attempters had diminished gray matter concentration in the middle inferior orbitofrontal cortex, insular cortex, fusiform gyrus, and parahippocampal gyri. Directly comparing BPD with SPD patients and healthy controls, Goldstein et al. (2009) reported that the BPD patients did not exhibit the volume reduction in the superior temporal gyrus that was observed in the SPD patients.
A number of white matter structures are also affected in BPD. The corpus callosum (CC) is a large fiber bundle connecting the two hemispheres of the brain. FA in the CC has been shown to be lower in BPD compared with healthy controls (Carrasco et al., 2012; Gan et al., 2016), and may be associated with increased suicidal behavior (Lischke et al., 2017). Individuals with BPD also show decreased FA in the fornix, a bundle of white matter fiber in the limbic system that is implicated in memory (Gan et al., 2016; Maier-Hein et al., 2014; Whalley et al., 2015), which was found to be associated with greater symptom severity, for example, avoidance of abandonment and affective instability (Whalley et al., 2015). Reduced FA in the fornix appears to be specific to BPD when compared with a group of mixed psychiatric diagnoses (Maier-Hein et al., 2014). Findings in the cingulum and the uncinate fasciculus are mixed. Specifically examining these two tracts, Lischke et al. (2015) found lower FA in the uncinate fasciculus but not the cingulum while Whalley et al. (2015) found the opposite, that is, lower FA in portions of the cingulum but not the uncinate fasciculus.
Several studies have examined white matter microstructure in the frontal cortex, an area considered to be important for emotion regulation and behavioral control. Decreased FA has been found in orbitofrontal areas in BPD (Carrasco et al., 2012) and anterior frontal regions in BPD with self-injurious behaviors (Grant et al., 2007), but not in inferior frontal regions (Rusch et al., 2007). Other findings in BPD include abnormalities in association fibers that connect cortical regions in the same hemisphere. New et al. (2013) examined healthy adults, healthy adolescents, adults with BPD, and adolescents with BPD. They reported decreased inferior longitudinal fasciculus (ILF) FA in BPD adolescents compared with their healthy peers, but no difference in the two adult groups. Healthy adolescents had higher ILF FA than all of the other groups. Given that FA in the ILF develops in an inverted “U” shape as it increases through adolescence and decreases in adulthood (Hasan et al., 2010), the findings suggest that peak FA normally seen in adolescence is not achieved in those with BPD. Reduced white matter integrity has also been found in the inferior frontal occipital fasciculus (Ninomiya et al., 2018) and uncinate fasciculus (Lischke et al., 2015), although New et al. (2013) only found reductions in the adolescent and not the adult BPD group.
Taken together, individuals with BPD show significantly reduced volume of limbic regions involved in behavioral and emotional responses, including the hippocampus, amygdala, and anterior cingulate cortex. Moreover, these abnormalities may be associated with BPD symptom severity including suicidal behavior. There is also evidence of reduced volume in prefrontal areas involved in the modulation of cognitive and affective processing. Some studies in adolescents have found decreased frontal lobe volume but not amygdala or hippocampal volume (Brunner et al., 2010; Chanen et al., 2008), suggesting that structural alterations in limbic regions may not be present in the early stage of the BPD illness. White matter structural integrity appears to be reduced in the corpus callosum, limbic areas (e.g., fornix), frontal regions, and cortical association fibers, with some evidence that these abnormalities may be specific to BPD as opposed to other clinical disorders (Maier-Hein et al., 2014), or to adolescents with BPD as opposed to adults (New et al., 2013).
Functional Neuroimaging
The functioning of the serotonin system is of particular interest in BPD given its role in impulsive behavior (Coccaro, 1992), as impulsivity is a core feature of BPD. Pharmacologic challenge studies consistently show altered response to serotonergic stimulation in fronto-limbic areas and circuitry in BPD (Soloff, Meltzer, Greer, Constantine, & Kelly, 2000), BPD with comorbid intermittent explosive disorder patients (New et al., 2007), and individuals with major depressive disorder (MDD) and comorbid BPD (Oquendo et al., 2005). Interestingly, symptom improvement in aggression with a selective serotonin reuptake inhibitor (SSRI) appears to correspond to increased glucose metabolism in cingulate and orbital frontal cortex, suggesting that SSRIs normalize prefrontal cortex metabolism in impulsive aggressive patients with BPD (New et al., 2004). There is also evidence of sex differences in the serotonergic system functioning in BPD. For example, only males exhibited decreased glucose uptake in the left temporal lobe in response to serotonergic stimulation (Soloff, Meltzer, Becker, Greer, & Constantine, 2005), only female BPD subjects show greater binding in medial temporal and occipital cortex than males when compared with same-gender controls (Soloff, Chiappetta, Mason, Becker, & Price, 2014), and BPD traits are more closely associated with serotonin binding in females than males (Soloff et al., 2014).
Given the heightened emotional reactivity and difficulty in emotion regulation observed in BPD, the majority of task-based fMRI studies have focused on emotion processing using a wide range of methods. Individuals with BPD exhibit prolonged or enhanced amygdala activity when viewing or anticipating emotional stimuli (Hazlett, Zhang, et al., 2012; Kamphausen et al., 2013; Scherpiet et al., 2014), engaging in a cognitive task while being distracted by emotional stimuli (Holtmann et al., 2013; Jacob et al., 2013; Krause-Utz et al., 2012), and engaging in social cognitive tasks (Frick et al., 2012; Mier et al., 2013). Furthermore, there appears to be increased functional connectivity between the amygdala and other brain regions, including the rostral anterior cingulate (Cullen et al., 2011) and right dorsomedial prefrontal cortex and hippocampus (Krause-Utz et al., 2014) during processing of emotional stimuli. Individuals with BPD show hyper-responsivity to negative stimuli in the amygdala and hippocampus (Schulze et al., 2016), and this response is eliminated by medication use (Ruocco, Amirthavasagam, Choi-Kain, & McMain, 2013; Schulze et al., 2016). Physical pain also appears to produce deactivation in the amygdala (Niedtfeld et al., 2012; Schmahl et al., 2006) and anterior cingulate gyrus (Schmahl et al., 2006) in BPD patients, which may explain the use of self-injurious behavior to manage emotions. There is also enhanced activity in the posterior cingulate gyrus and insula, and decreased activity in the dorsolateral prefrontal cortex (Ruocco et al., 2013; Schulze et al., 2016).
To better understand the symptoms of emotional dysregulation and impulsivity in BPD, researchers have examined the neural substrates underlying top-down control of affective responses. Areas of the prefrontal cortex exert inhibitory control over limbic structures (Rosenkranz & Grace, 2002). One study found that under conditions of behavioral inhibition in the context of negative emotion, reduced ventromedial prefrontal activity in BPD patients was associated with measures of decreased self-reported constraint (Silbersweig et al., 2007). BPD patients also showed increased amygdala and ventral striatum activity, which was associated with greater self-reported negative emotion. These results suggest enhanced sensitivity of the amygdala and difficulty recruiting frontal regions to inhibit limbic responses. When provoked to aggression, BPD patients with intermittent explosive disorder responded more aggressively behaviorally and exhibit increased glucose metabolism in orbitofrontal cortex and amygdala compared with healthy controls (New et al., 2009). This suggests a hypersensitivity to provocation in BPD with intermittent explosive disorder. While it was thought that decreased orbitofrontal cortex activity promotes aggression, there is likely a complex relationship between the orbitofrontal cortex and amygdala (Blair, 2004).
Self-injurious behavior is frequently observed in BPD and has led to attempts at understanding the function of self-harm and brain reactions to physical pain. Niedtfeld et al. (2012) showed that when BPD patients experienced physical pain while viewing emotional pictures, they demonstrated enhanced negative connectivity (i.e., a greater negative correlation) between limbic and medial and dorsolateral prefrontal regions than healthy controls. Therefore, physical pain may enhance the ability of the prefrontal cortex to inhibit the limbic system in BPD, attenuating the hyperactivation in limbic areas. Dialectical behavior therapy (DBT) is a cognitive behavioral treatment that heavily targets maladaptive behaviors associated with BPD, including self-injurious acts. Niedtfeld et al. (2017) showed that DBT weakened amygdala deactivation in response to physical pain during negative emotional stimuli. This indicates DBT may modulate the effectiveness of self-injurious behaviors to decrease emotion dysregulation, suggesting the potential to replace self-harm acts with more adaptive coping strategies. Additionally, DBT has been shown to decrease activity in the posterior cingulate and insula in response to negative stimuli (Schnell & Herpertz, 2007) and to improve amygdala habituation to unpleasant pictures, which was associated with improved self-reported difficulties with emotion regulation (Goodman et al., 2014). Using an imaging-genetics approach, recent work suggests that amygdala habituation deficiency to unpleasant pictures is modulated by a brain-derived neurotrophic factor genotype in healthy controls and BPD patients (Perez-Rodriguez et al., 2017). Identifying genetically modulated neural biomarkers that contribute to emotion processing and habituation abnormalities holds promise for developing novel therapeutic targets for BPD.
Individuals with BPD show altered default mode network, with complex patterns of increased and decreased activity in areas of the cingulate cortex, prefrontal cortex, and precuneus (Amad & Radua, 2017; Visintin et al., 2016). However, overlap between PTSD and BPD, as well as heterogeneity in BPD, make it difficult to draw strong conclusions about specific disturbances in the DMN (Amad & Radua, 2017). Other forms of network disturbance reported include decreased inter-network connectivity of the central executive network involved in cognitive control and increased inter-network connectivity of the salience network involved in emotion-related activity (Doll et al., 2013), although another study found differences in network connectivity between BPD and bipolar disorder, but not BPD and controls (Das, Calhoun, & Malhi, 2014).
Studies examining seed-based analysis of resting state functional connectivity have reported increased amygdala connectivity with a cluster consisting of the insula, orbitofrontal cortex, and putamen (Krause-Utz et al., 2014), decreased amygdala connectivity with right ventral anterior cingulate cortex and orbital frontal cortex (Baczkowski et al., 2017), disturbed connectivity mainly distributed in the frontotemporal and limbic lobes that was not correlated with clinical symptoms (Lei et al., 2017), and increased functional connectivity from the noradrenergic locus coeruleus to the anterior cingulate cortex, which was positively correlated with the degree of motor impulsivity (Wagner et al., 2018).
In summary, functional neuroimaging studies reveal that BPD is associated with altered serotonin system functioning in fronto-limbic regions of the brain. Limbic structures including the amygdala and hippocampus are hyper-responsive to emotional and negative stimuli and show increased connectivity to other brain regions. However, medication and physical pain appears to deactivate the amygdala, which may explain symptom improvement with medication in some individuals and the use of self-injurious behavior by BPD patients to manage emotions. Increased limbic activity concurrent with reduced prefrontal region activity suggest enhanced emotional responsivity and difficulty recruiting frontal regions to inhibit limbic responses. Dialectical behavior therapy also appears to work by decreasing neural activity to unpleasant stimuli. Furthermore, the evidence suggests that there is altered resting state activity in the default mode network characterized by both increased and decreased activity in a number of frontal and limbic brain regions.
Conclusions for Neuroimaging Studies in BPD
Neuroimaging studies in BPD have focused on frontal and limbic regions considered to be implicated in the emotion dysregulation and impulsivity characteristics of the disorder. The predominant theory is that there is a failure of prefrontal areas to appropriately modulate limbic regions. Empirical evidence indicates that individuals with BPD exhibit a combination of reduced volume and increased activity in the amygdala and anterior cingulate cortex. Volume reduction has also been consistently found in the hippocampus and dorsolateral and orbital regions of the frontal lobe. Furthermore, there is altered structural connectivity characterized by decreased structural integrity in interhemispheric and fronto-limbic white matter tracts including the corpus callosum and fornix. Functional neuroimaging suggests that individuals with BPD demonstrate altered serotonergic system functioning, exaggerated reactivity in frontal and limbic areas in reaction to emotional stimuli, and disruptions in resting state network connectivity.
The BPD neuroimaging literature is limited by methodological differences. While some studies use BPD samples with comorbid conditions such as intermittent explosive disorder (New et al., 2007) and attention deficit hyperactivity disorder (Rusch et al., 2010), other studies exclude for comorbidities (Grant et al., 2007). The heterogeneous nature of BPD and its high comorbidity with other conditions including anxiety, mood, impulse control, and substance use disorders (Lenzenweger, Lane, Loranger, & Kessler, 2007) make it difficult to disentangle potential confounds. For example, different combinations of hippocampal, anterior cingulate cortex, and amygdala volume loss are also frequently found in posttraumatic stress disorder (Kuhn & Gallinat, 2013), bipolar disorder (Altshuler, Bartzokis, Grieder, Curran, & Mintz, 1998; Haldane & Frangou, 2004), major depressive disorder (Frodl, Meisenzahl, Zetzsche, Born, et al., 2002; Frodl, Meisenzahl, Zetzsche, Bottlender, et al., 2002; Lange & Irle, 2004) and women with a history of severe abuse (Stein, Koverola, Hanna, Torchia, & McClarty, 1997). Furthermore, a study by Brunner et al. (2010) found that both adolescents with BPD and a clinical control group with mixed psychiatric diagnoses had reduced dorsolateral prefrontal cortex volume compared with healthy controls, suggesting that these brain changes are not specific to BPD. Still, other studies have found decreased hippocampal (Irle et al., 2005; Weniger, Lange, Sachsse, & Irle, 2009) and amygdala (Weniger et al., 2009) volume in BPD patients regardless of comorbid PTSD, suggesting that PTSD is not necessary for these changes. White matter abnormalities have also been shown to be specific to BPD when compared with a mixed psychiatric group (Maier-Hein et al., 2014).
A history of childhood trauma is common in individuals with severe mental illness, and a positive relationship between reported childhood trauma and greater volume reduction in the hippocampus and amygdala has been reported across BPD studies (Brambilla et al., 2004; Driessen et al., 2000; Rusch et al., 2003; Schmahl et al., 2003; Tebartz van Elst et al., 2003). Therefore, it is possible that childhood trauma as an environmental factor may in part underlie the neuropathology of BPD and other disorders with similar neurobiological markers. Future neuroimaging studies may wish to examine individuals with childhood trauma and the nature of their differential trajectory to later clinical presentations or lack thereof. Moreover, while there is empirical support for frontal and limbic abnormalities in BPD, this conceptualization does not seem to account for the range of findings in other neural substrates and circuitry. Further investigation into other relevant neural circuitry implicated in cognitive and affective processing would further our understanding of BPD. Finally, more studies that examine neural changes following pharmacological or psychosocial intervention are needed to shed light on mechanisms of change with intervention.
Antisocial Personality Disorder
Individuals with antisocial personality disorder (ASPD) exhibit pervasive disregard for the rights of others, beginning in childhood and continuing into adulthood (American Psychiatric Association, 2013). The current DSM-5 diagnostic criteria for ASPD is heavily based on observable behaviors such as repeated unlawful activity, lying, physical fights, and failure to honor financial responsibility. However, underlying personality structures such as manipulativeness, callousness, lack of empathy, and deceitfulness are alternative models for ASPD that are often used by researchers. The construct of psychopathy is frequently associated with ASPD, and is characterized by marked emotional deficits in guilt and remorse, callousness, and socially deviant behaviors. The most widely used measured of psychopathy is the Hare Psychopathy Checklist – Revised (Herve, Hayes, & Hare, 2003) with score cutoffs used for a categorical determination of “psychopathy” that vary depending on clinical and research purposes. While psychopathy and ASPD are sometimes viewed as being interchangeable, their diagnostic criteria and measurement instruments render them overlapping but distinct. Most individuals high in psychopathy would likely meet criteria ASPD but not all individuals with ASPD are psychopaths (Ogloff, 2006). There is a small number of neuroimaging studies that use samples with a clearly defined ASPD diagnosis derived from clinical interview, but most studies focus on distinct characteristics of ASPD, such as antisocial behavior (e.g., violence, aggression) and traits (e.g., callousness, psychopathy). This method expands our understanding of various antisocial behaviors but at the same time, introduces heterogeneity in sample characteristics. Furthermore, while prevalence of ASPD in the general population is estimated to be 1 percent in females and 3 percent in males (Coid, Yang, Tyrer, Roberts, & Ullrich, 2006), prevalence in prisons has been estimated to be 21 percent in females and 47 percent in males (Fazel & Danesh, 2002). As such, many studies include males involved in the legal system. The present section will focus on studies of individuals clinically diagnosed ASPD supplemented by information from studies of antisocial behaviors and traits.
Structural Neuroimaging
The most common brain area of focus for neuroimaging studies in individuals with antisocial behavior is the frontal lobe implicated in the regulation of impulse and aggression, although some studies have also examined the temporal lobe. A meta-analysis of structural and functional neuroimaging studies of broadly defined antisocial behavior (e.g., psychopathy, violence, aggression, criminal offenders) found reduced structure and function in the right orbitofrontal cortex, left dorsolateral prefrontal cortex, and right anterior cingulate cortex (Yang & Raine, 2009). Raine, Lencz, Bihrle, LaCasse, and Colletti (2000) found that individuals with a DSM diagnosis of ASPD had reduced prefrontal gray matter volume of 11 percent compared with a control group. Individuals with ASPD have been shown to have reduced cortical thickness in the orbitofrontal and lateral frontal cortex, as well as the insula, middle temporal gyrus, and bank of the superior temporal sulcus (Jiang et al., 2016), and thinner cortex in these regions was associated with less impulse control (Jiang et al., 2016). Research in psychopathy has fairly consistently found reduced gray matter volume in the temporal lobe including the amygdala (Yang, Raine, Narr, Colletti, & Toga, 2009), hippocampus (Laakso et al., 2001), superior temporal gyrus (Muller, Sommer, et al., 2008), and anterior temporal cortex (de Oliveira-Souza et al., 2008). In a review by Blair (2010) of four studies (De Brito et al., 2009; de Oliveira-Souza et al., 2008; Muller, Ganssbauer, et al., 2008; Tiihonen et al., 2008) that used voxel-based morphology, an automated technique that reduces subjectivity in image processing, three of the four found structural abnormalities in the orbitofrontal cortex and insula and all four found abnormalities in the superior temporal cortex.
The meta-analysis by Yang and Raine (2009) on broadly defined antisocial behavior did not find any moderating effects of violence or comorbidity on prefrontal cortex volume. However, it is important to note that some studies designed to tease apart effects from comorbid conditions have found significant effects. For example, medial frontal cortical thinning was found to be specific to violent individuals with ASPD when compared with nonviolent and violent individuals with ASPD or schizophrenia (Narayan et al., 2007). A study of violent offenders with ASPD and psychopathy, violent offenders with ASPD but no psychopathy, and healthy non-offenders reported that only violent offenders with ASPD and psychopathy exhibited reduced gray matter volume bilaterally in the dorsolateral prefrontal cortex and temporal poles (Gregory et al., 2012). Duration of alcoholism and years of education may also account for volume reductions in the frontal cortex in ASPD (Laakso et al., 2002). One study (Schiffer et al., 2011) contrasted four groups of males: violent offenders with substance use disorders (SUD), violent offenders without SUD, non-offenders with SUD, and non-offenders without SUD. They found that greater volume in multiple mesolimbic areas including the nucleus accumbens, amygdala, and caudate, as well as smaller volume in the insula, were specific to violent offenders and that reduced gray matter volumes in the frontal lobe were specific to those with SUD.
DTI studies reveal that disruption in white matter tracts across association pathways that connect cortical areas of the same hemisphere are found in individuals with broadly defined antisocial behavior (Waller, Dotterer, Murray, Maxwell, & Hyde, 2017). These tracts include the uncinate fasciculus, cingulum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and superior longitudinal fasciculus. Furthermore, individuals clinically diagnosed with ASPD exhibit decreased white matter integrity in the frontal lobes bilaterally and the left posterior portion of the brain (Sundram et al., 2012). Jiang and colleagues (Jiang, Shi, Liu, et al., 2017) investigated 20 individuals with ASPD and no other personality disorder compared with 23 healthy controls. They found abnormalities in the bilateral superior longitudinal fasciculus, left superior corona radiate, and inferior fronto-occipital fasciculus, which were associated with greater self-reported impulsivity and risky behavior. There is also some evidence of reduced coherence of the corpus callosum and projection fibers that connect cortical and subcortical centers (e.g., internal capsule, corona radiata) in ASPD (Sundram et al., 2012) and women with conduct disorder (Lindner et al., 2016). As with the MRI studies, there is evidence that white matter structural abnormalities may be associated with comorbid psychopathy; for example, lower FA in the uncinate fasciculus was observed in incarcerated males with psychopathy relative to those without psychopathy (Motzkin, Newman, Kiehl, & Koenigs, 2011).
In summary, individuals with ASPD or antisocial behaviors exhibit decreased volume in the frontal regions including the orbitofrontal cortex and dorsolateral prefrontal cortex, as well as medial and lateral temporal lobes. Additionally, there is decreased integrity in a number of white matter tracts that connect cortical regions in the same hemisphere of the brain. Importantly, there may be significant effects of comorbid conditions, particularly psychopathy and substance use, in these structural abnormalities.
Functional Neuroimaging
Among studies that included a clinical diagnosis, Goyer et al. (1994) did not find any difference between ASPD and controls on frontal cortex metabolism during an auditory discrimination task (while finding differences between BPD and controls). However, Kuruoğlu et al. (1996) showed that among patients with alcoholism who had ASPD versus those with other personality disorders including dependent PD, narcissistic PD, and paranoid PD, those with ASPD had significantly reduced regional cerebral blood flow in the frontal cortex.
Serotonin system functioning is implicated in impulsive aggression and has been investigated in ASPD. In a sample of individuals with a history of violent aggression who also met criteria for ASPD or conduct disorder and healthy controls, Meyer et al. (2008) found that lower serotonergic receptor binding potential in the dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate, and medial temporal cortex was associated with more severe impulsivity in the group with violent aggression. Furthermore, abnormalities in serotonin system functioning in non-callous individuals with high impulsive aggression were found to be associated with greater childhood adversity (Rylands et al., 2012). Monoamine oxidase-A (MAO-A) metabolizes amine neurotransmitters implicated in aggressive behavior, such as serotonin. MAO-A level was found to be lower in ASPD compared with healthy controls in the orbitofrontal cortex, ventral striatum, prefrontal/anterior cingulate cortex, thalamus, and hippocampus (Kolla, Matthews, et al., 2015). In ASPD, lower MAO-A level in the ventral striatum has been associated with greater self-reported impulsivity (Kolla, Dunlop, et al., 2015; Kolla et al., 2016) and more risky performance on a gambling task (Kolla, Dunlop, et al., 2015).
The majority of fMRI studies in ASPD have been conducted by a group of researchers at China’s Central South University. They report a number of activation abnormalities, including decreased resting state activity in the orbitofrontal cortex, temporal pole, inferior temporal gyrus, and cerebellum (Liu, Liao, Jiang, & Wang, 2014), and increased activity in the occipital cortex and inferior temporal gyrus (Tang, Jiang, Liao, Wang, & Luo , 2013). Studies of resting state functional connectivity have found increased functional connectivity within the default mode network (Tang et al., 2016) but uncoupling between the default mode network and the attention network (Tang et al., 2013) in individuals with ASPD. Jiang and colleagues (Jiang, Shi, Liao, et al., 2017) used whole-brain network analysis and reported that brain networks in ASPD are less functionally integrated, less modular, and less connected within and between modules, particularly in the fronto-parietal control network. In ASPD, greater connectivity between the striatum and dorsomedial prefrontal cortex, as well as between the striatum and hippocampus, were associated with less impulsivity (Kolla et al., 2016).
Task-based fMRI studies in individuals with ASPD have revealed greater activation of the dorsolateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobe when lying (Jiang et al., 2013). While this study did not have a control group, these areas are consistent with regions implicated in cognitive control and working memory involved in deception (Christ, Van Essen, Watson, Brubaker, & McDermott, 2009). Interestingly, the investigators rated capacity for deceitfulness based on a clinician administered personality interview. They found that increased clinical ratings of capacity for deceitfulness were associated with decreased contrast in the fMRI between truth and lie conditions. This result suggests that individuals with ASPD who are skilled at lying or lie frequently may require less cognitive effort to lie.
Taken together, the literature suggests that individuals with ASPD have serotonergic system function abnormalities that are associated with symptoms of impulsive aggression. Furthermore, individuals with ASPD have altered resting state brain activity and functional connectivity, including in the default mode network and central executive network. For individuals with ASPD and high capacity for deception, there is less evidence of differential activity in brain areas implicated in cognitive control when lying versus truth-telling.
Conclusions for Neuroimaging Studies in ASPD
Neuroimaging studies in ASPD are scarcer than in other PDs. However, studies on antisocial behavior, albeit broadly defined, have provided additional information on brain abnormalities associated with behaviors and characteristics of individuals with ASPD. ASPD has been demonstrated to be heterogeneous (Poythress et al., 2010), and comorbid conditions such as psychopathy and substance use have been shown to affect brain structure (Gregory et al., 2012; Schiffer et al., 2011). Nevertheless, there is consistent evidence that individuals with ASPD exhibit volume reduction and cortical thinning in areas of the prefrontal cortex including orbitofrontal and dorsolateral prefrontal regions. They also show volume reduction in temporal lobe structures including the amygdala, hippocampus, superior temporal gyrus, and insula. White matter structure compromise is demonstrated in the uncinate fasciculus as well as a number of commissural, association, and projection fibers. These structural abnormalities may be associated with the increased impulsivity and risky behaviors characteristic of ASPD. Functional imaging studies suggest that individuals with ASPD have decreased cerebral blood flow in the frontal cortex, and that there is pre- and post-synaptic serotonergic system dysfunction. There appears to be decreased resting state functional activity in frontal, temporal, and cerebellar regions, but increased activity in the occipital cortex. Alterations in brain network functional connectivity in the dorsal attention network and the fronto-parietal control network may also be implicated.
A major challenge for future studies is to disentangle effects associated with ASPD from those resulting from comorbid conditions. Well-designed studies that compare and contrast groups with and without certain characteristics (e.g., psychopathy) and comorbid conditions (e.g., substance use) would help advance this endeavor. Furthermore, some characteristics of ASPD, particularly impulsivity, are also present in other conditions such as bipolar disorder, borderline personality disorder, and substance use disorders. The NIH’s Research Domain Criteria approach (Insel et al., 2010) suggests that it will be important for future studies to examine whether the underlying neural circuitry involved is common across these disorders.
Overall Summary and Future Directions
Neuroimaging research examining the neurobiology of personality disorders is not as plentiful compared with studies of other psychiatric illnesses. Yet, it is clear that research in this area has been fruitful. Studies characterize SPD as having a pattern of decreased temporal lobe volume and white matter tract integrity, dysfunctional striatal dopamine activity, and inefficient recruitment of brain areas during task performance. These findings are similar to schizophrenia, albeit to a lesser degree, suggesting neurobiological vulnerability to schizophrenia. In contrast, the relatively intact frontal lobe may be a protective factor against frank psychosis. The most promising findings in BPD suggest that a diminished top-down control of affective responsivity, which likely involves decreased activity, size, and/or functional connectivity of prefrontal cortex regions combined with increased limbic activity, may underlie the affective hyper-responsivity observed in this disorder. In addition, neuroimaging findings point to a role for serotonin in this affective disinhibition and dysregulation. Findings in ASPD implicate volume reduction in the prefrontal and temporal lobes, as well as white matter structural abnormalities in the impulsivity seen in this disorder. There is also emerging evidence of decreased activity in frontal regions and altered brain network functional connectivity in the attention network and the fronto-parietal control networks.
Several brain regions appear to be implicated in all three of the personality disorders covered in this chapter, particularly the prefrontal cortex, temporal lobe, limbic regions, and a number of white matter tracts. Therefore, the pattern of abnormalities can provide key information on the neural basis of each personality disorder. For example, while SPD appears to be predominantly associated with abnormalities in temporal and striatal regions, BPD and ASPD share alterations in prefrontal and limbic regions. This is consistent with the impulsivity and aggression that are common to both BPD and ASPD and that places them in the same cluster. However, the limbic hyperactivity seen in BPD is not consistently found in ASPD. Additional studies that directly compare personality disorders with each other are needed to clarify shared and distinct neurobiological mechanisms. One promising avenue may be a transdiagnostic approach that examines the neurobiological basis of personality constructs across personality disorders. Given the emerging dimensional conceptualization of personality disorders, future studies should investigate the domains (i.e., negative affect, detachment, antagonism, disinhibition, and psychoticism) of the multidimensional personality trait model in the Emerging Measures and Models of the DSM-5. Additionally, since SPD is frequently used to better understand vulnerability and protective factors for schizophrenia, more studies including longitudinal designs are needed that directly compare SPD and schizophrenia.
It will be important for future research to establish consensus on methodology in personality disorders research, such as which tasks to use that best elicit psychological constructs of interest. The heterogeneous methodology currently used likely contributes to inconsistent findings and limits the ability to draw strong conclusions. Also, careful consideration of sample characteristics, including sample size, gender, and particularly comorbid conditions will help identify moderating factors that contribute to variance. Finally, many studies fail to find direct correlations between neuroimaging abnormalities and specific symptoms, which is likely due to the complexity of the mechanisms by which brain abnormalities result in the behaviors associated with personality disorders. Continued development of integrated theories and use of rigorous methods that can infer causality will provide a better understanding of the neural mechanisms underlying personality pathology.
Acknowledgment
This work was supported in part by the Mental Illness Research, Education, and Clinical Center at the James J. Peters VA Medical Center, Bronx, NY and a VA Research Career Scientist Award to Dr. Hazlett (IK6 CX001738–01).
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