Cognitive deficits observed in schizophrenia are also frequently found in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD). Dopamine appears to be a particularly important modulator of cognitive processes such as those impaired in schizophrenia spectrum disorders. In a double-blind, placebo-controlled clinical trial, we administered pergolide, a dopamine agonist targeting D1 and D2 receptors, to 25 participants with SPD and assessed the effect of pergolide treatment, as compared with placebo, on neuropsychological performance. We found that the pergolide group showed improvements in visual-spatial working memory, executive functioning, and verbal learning and memory. These results suggest that dopamine agonists may provide benefit for the cognitive abnormalities of schizophrenia spectrum disorders.
schizotypal personality; schizotypy; schizophrenia spectrum; cognition; pergolide; dopamine; Schizophrenia/Antipsychotics; Dopamine; Cognition; Clinical Pharmacology/Trials; schizotypal personality; pergolide
N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multi-site NIMH initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results, from the COGS dataset, of auditory N100 amplitude and gating as candidate endophenotypes.
Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected 1st-degree relatives and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click2/click1 ratio were dependent variables. Heritability was estimated based on kinships, using Solar v.2.1.2. Group differences were examined after subjects were categorized as either “broad” or “narrow”, based on the presence (“broad”) or absence (“narrow”) of non-psychotic psychiatric co-morbidity.
Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. “Broad” and “narrow” patients both had impaired click1 amplitudes. “Broad” relatives, but not “narrow” relatives, exhibited similar impairments. There were no group differences for either click2 amplitude or the gating ratio.
N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric co-morbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.
schizophrenia; endophenotype; heritability; evoked potential; N100; gating
Startle and its inhibition by weak lead stimuli (“prepulse inhibition”: PPI) are studied to understand the neurobiology of information processing in patients and community comparison subjects (CCS). PPI has a strong genetic basis in infrahumans, and there is evidence for its heritability, stability and reliability in humans. PPI has gained increasing use as an endophenotype to identify vulnerability genes for brain disorders, including schizophrenia. Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies.
Within a 7-site investigation with multiple measures, the Consortium on the Genetics of Schizophrenia conducted a methodological study of acoustic startle and PPI in CCS. Methods were manualized, videotaped and standardized across sites with intensive in-person training sessions. Equipment was acquired and programmed at the “PPI site” (UCSD), and stringent quality assurance (QA) procedures were used. Testing was completed on 196 CCS over 2.5 years, with 5 primary startle dependent measures: eyeblink startle magnitude, habituation, peak latency, latency facilitation and PPI.
Analyses identified significant variability across sites in some but not all primary measures, and determined factors both within the testing process and subject characteristics that influenced a number of test measures. QA procedures also identified non-standardized practices with respect to testing methods and procedural “drift”, which may be particularly relevant to multi-site studies using these measures.
With thorough oversight and QA procedures, measures of acoustic startle PPI can be acquired reliably across multiple testing sites. Nonetheless, even among sites with substantial expertise in utilizing psychophysiological measures, multi-site studies using startle and PPI as dependent measures require careful attention to methodological procedures.
endophenotype; prepulse inhibition; schizophrenia; sex differences; startle
Working memory (WM) impairment is a promising candidate endophenotype for schizophrenia that could facilitate the identification of susceptibility genes for this disorder. The validity of this putative endophenotype was assessed by determining whether 149 probands with schizophrenia and 337 of their first-degree relatives demonstrated WM impairment as compared to 190 unaffected community comparison subjects. Subjects were participants in the Consortium on the Genetics of Schizophrenia (COGS) project, a seven-site research network that was established to investigate the genetic architecture of endophenotypes for schizophrenia. Participants received comprehensive clinical assessments and completed two verbal WM tasks, one requiring transient on-line storage and another requiring maintenance plus complex manipulation of information by reordering the stimuli. Schizophrenia probands performed worse than the other groups on both tasks, with larger deficits found for the more challenging reordering WM task. The probands’ relatives performed more poorly than community comparison subjects on both tasks, but the difference was significant only for the more challenging maintenance plus complex manipulation WM task. This WM impairment was not attributable to diagnoses of schizophrenia spectrum disorder, mood disorders, or substance use disorders in the relatives. In conjunction with evidence that WM abilities are substantially heritable, the current results support the validity and usefulness of verbal WM impairments in manipulation of information as endophenotypes for schizophrenia in large-scale genetic linkage and association studies.
Background: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health–funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment. Methods: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database. Results: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110). Discussion: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.
neurophysiology; neurocognitive; genes
The cingulate cortex frequently shows gray matter loss with age as well as gender differences in structure and function, but little is known about whether individual cingulate Brodmann areas show gender-specific patterns of age-related volume decline. This study examined age-related changes, gender differences, and the interaction of age and gender in the relative volume of cingulate gray matter in areas 25, 24, 31, 23, and 29, over seven decades of adulthood. Participants included healthy, age-matched men and women, aged 20–87 (n = 70). Main findings were: (1) The whole cingulate showed significant age-related volume declines (averaging 5.54% decline between decades, 20s–80s). Each of the five cingulate areas also showed a significant decline with age, and individual areas showed different patterns of decline across the decades: Smaller volume with age was most evident in area 31, followed by 25 and 24. (2) Women had relatively larger cingulate gray matter volume than men overall and in area 24. (3) Men and women showed different patterns of age-related volume decline in area 31, at midlife and late in life. By delineating normal gender differences and age-related morphometric changes in the cingulate cortex over seven decades of adulthood, this study improves the baseline for comparison with structural irregularities in the cingulate cortex associated with psychopathology. The Brodmann area-based approach also facilitates comparisons across studies that aim to draw inferences between age- and gender-related structural differences in the cingulate gyrus and corresponding differences in cingulate function.
Cingulate cortex; aging; gender differences; MRI; gray matter; morphometry
Schizotypal personality disorder (SPD) individuals and borderline personality disorder (BPD) individuals have been reported to show neuropsychological impairments and abnormalities in brain structure. However, relationships between neuropsychological function and brain structure in these groups are not well understood. This study compared visual-spatial working memory (SWM) and its associations with dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) gray matter volume in 18 unmedicated SPD patients with no BPD traits, 18 unmedicated BPD patients with no SPD traits, and 16 healthy controls (HC). Results showed impaired SWM in SPD but not BPD, compared with HC. Moreover, among the HC group, but not SPD patients, better SWM performance was associated with larger VLPFC (BA44/45) gray matter volume (Fisher's Z p-values<0.05). Findings suggest spatial working memory impairments may be a core neuropsychological deficit specific to SPD patients and highlight the role of VLPFC subcomponents in normal and dysfunctional memory performance.
working memory; borderline personality disorder; schizotypal personality disorder; dorsolateral prefrontal cortex; ventrolateral prefrontal cortex; MRI
Objective. Childhood maltreatment and familial psychopathology both lead to an increased risk of the development of posttraumatic stress disorder (PTSD) in adulthood. While family history of psychopathology has traditionally been viewed as a proxy for genetic predisposition, such pathology can also contribute to a stress-laden environment for the child. Method. Analyses were conducted to evaluate the joint effect of childhood abuse and a family history of major depressive disorder (MDD) on diagnoses of PTSD and MDD in a sample of 225 adults with DSM-IV Axis II disorders. Results. Results showed that the rate of PTSD in the presence of both childhood abuse and MDD family history was almost six-fold (OR = 5.89, P = .001) higher relative to the absence of both factors. In contrast, the rate of MDD in the presence of both factors was associated with a nearly three-fold risk relative to the reference group (OR = 2.75, P = .01). Conclusions. The results from this observational study contribute to a growing understanding of predisposing factors for the development of PTSD and suggest that joint effects of family history of MDD and childhood abuse on PTSD are greater than either factor alone.
Consistent with the clinical picture of milder symptomatology in schizotypal personality disorder (SPD) than schizophrenia, morphological studies indicate SPD abnormalities in temporal lobe regions but to a much lesser extent in prefrontal regions implicated in schizophrenia. Lower fractional anisotropy (FA), a measure of white-matter integrity within prefrontal, temporal, and cingulate regions has been reported in schizophrenia but has been little studied in SPD.
To examine temporal and prefrontal FA in 30 neuroleptic-naïve SPD patients and 35 matched healthy controls. We hypothesized that compared with healthy controls (HCs), SPD patients would exhibit lower FA in temporal and anterior cingulum regions but relative sparing in prefrontal regions.
We acquired diffusion tensor imaging (DTI) in all participants and examined FA in the white matter underlying Brodmann areas (BAs) in dorsolateral prefrontal (BA44,45,46), temporal (BA22,21,20), and cingulum (BA25,24,31,23,29) regions using multivariate-ANOVAs.
Compared with healthy controls, the SPD group had significantly lower FA in left temporal but not prefrontal regions. In the cingulum, FA was lower in the SPD group in posterior regions (BA31 and 23), higher in anterior (BA25) regions and lower overall in the right but not left cingulum. Among the SPD group, lower FA in the cingulum was associated with more severe negative symptoms (e.g., odd speech).
Similar to schizophrenia, our results indicate cingulum-temporal lobe FA abnormalities in SPD and suggest that cingulum abnormalities are associated with negative symptoms.
Diffusion tensor imaging; schizotypal personality disorder; dorsolateral prefrontal cortex; temporal lobe; cingulum; fractional anisotropy
There is decreased serotonergic function in impulsive aggression and borderline personality disorder (BPD), and genetic association studies suggest a role of serotonergic genes in impulsive aggression and BPD. Only one study has analyzed the association between the tryptophan-hydroxylase 2 (TPH2) gene and BPD. A TPH2 “risk” haplotype has been described that is associated with anxiety, depression and suicidal behavior.
We assessed the relationship between the previously identified “risk” haplotype at the TPH2 locus and BPD diagnosis, impulsive aggression, affective lability, and suicidal/parasuicidal behaviors, in a well-characterized clinical sample of 103 healthy controls (HCs) and 251 patients with personality disorders (109 with BPD). A logistic regression including measures of depression, affective lability and aggression scores in predicting “risk” haplotype was conducted.
The prevalence of the “risk” haplotype was significantly higher in patients with BPD compared to HCs. Those with the “risk” haplotype have higher aggression and affect lability scores and more suicidal/parasuicidal behaviors than those without it. In the logistic regression model, affect lability was the only significant predictor and it correctly classified 83.1% of the subjects as “risk” or “non-risk” haplotype carriers.
We found an association between the previously described TPH2 “risk” haplotype and BPD diagnosis, affective lability, suicidal/parasuicidal behavior, and aggression scores.
Borderline personality disorder; TPH2; suicidal behavior; affective instability; impulsive aggression
Psychometric properties of a short form of the Affective Lability Scale (ALS) that was developed in a nonclinical sample (i.e., undergraduate students) were examined in a sample of people diagnosed with Cluster B DSM-IV Axis II personality disorders (n=236), other personality disorders (n=180), and healthy comparison participants (n=164). The total score of the ALS-18 score correlated strongly with the original 54-item scale (r = .97) and aspects of convergent and discriminant validity of the ALS-18 subscales (Anxiety/Depression, Depression/Elation, and Anger) were evaluated using self-report measures of affective and psychosocial functioning in the domains of affect intensity, anxiety, anger, and minimization/denial. Clinical utility of the scale was also demonstrated; participants diagnosed with Cluster B personality disorders reported higher affective lability scores, and healthy control participants reported lower scores, relative to individuals with Cluster A or Cluster C personality disorders (p’s < .001). Confirmatory factor analyses were conducted and demonstrated reasonably good fit to the data but future research is needed to test the three factor substructure of the ALS-18 against alternative factor models in samples that include clinical and non-clinical participants.
affective lability scale; affect dysregulation; cluster B personality
Cognitive reappraisal is a commonly used and highly adaptive strategy for emotion regulation that has been studied in healthy volunteers. Most studies to date have focused on forms of reappraisal that involve reinterpreting the meaning of stimuli and have intermixed social and non-social emotional stimuli. Here we examined the neural correlates of the regulation of negative emotion elicited by social situations using a less studied form of reappraisal known as distancing. Whole brain fMRI data were obtained as participants viewed aversive and neutral social scenes with instructions to either simply look at and respond naturally to the images or to downregulate their emotional responses by distancing. Three key findings were obtained accompanied with the reduced aversive response behaviorally. First, across both instruction types, aversive social images activated the amygdala. Second, across both image types, distancing activated the precuneus and posterior cingulate cortex (PCC), intraparietal sulci (IPS), and middle/superior temporal gyrus (M/STG). Third, when distancing one’s self from aversive images, activity increased in dorsal anterior cingulate (dACC), medial prefrontal cortex (mPFC), lateral prefrontal cortex, precuneus and PCC, IPS, and M/STG, meanwhile, and decreased in the amygdala. These findings demonstrate that distancing from aversive social cues modulates amygdala activity via engagement of networks implicated in social perception, perspective-taking, and attentional allocation.
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Emotional Distancing; Emotion Regulation; fMRI
Borderline personality disorder (BPD) is often associated with symptoms of impulsive aggression, which pose a threat to patients themselves and to others. Preclinical studies show that orbital frontal cortex (OFC) plays a role in regulating impulsive aggression. Prior work has found OFC dysfunction in BPD.
We employed a task to provoke aggressive behavior, the Point Subtraction Aggression Paradigm (PSAP), which has never previously been used during functional brain imaging. Thirty-eight BPD patients with impulsive aggression (BPD-IED) and 36 age-matched healthy controls (HC) received 18FDG-PET on two occasions with a provocation and non-provocation version of the PSAP. For each participant, we measured mean relative glucose metabolism in cortical Brodmann areas (BAs) in each hemisphere; difference scores (Provoked–Non-provoked) were calculated. A whole brain exploratory analysis for the double difference of BPD-IED–HC for Provoked–Non-provoked was also conducted.
BPD-IED patients were significantly more aggressive than HC on the PSAP. BPD-IED patients also increased relative glucose metabolic rate (rGMR) in OFC and amygdala when provoked, while HC decreased rGMR in these areas. However, HC increased rGMR in anterior, medial, and dorsolateral prefrontal regions during provocation more than BPD-IED patients.
Patients responded aggressively and showed heightened rGMR in emotional brain areas, including amygdala and OFC in response to provocation, but not in more dorsal brain regions associated with cognitive control of aggression. In contrast, HC increased rGMR in dorsal regions of PFC during aggression provocation, brain regions involved in top-down cognitive control of aggression and, more broadly, of emotion.
brain imaging; Point Subtraction Aggression Paradigm; PSAP; emotion
Emotional instability is a defining feature of borderline personality disorder (BPD), yet little is understood about its underlying neural correlates. One possible contributing factor to emotional instability is a failure to adequately employ adaptive cognitive regulatory strategies such as psychological distancing.
To determine whether there are differences in neural dynamics underlying this control strategy, between BPD patients and healthy volunteers (HC’s), BOLD fMRI signals were acquired as 18 BPD and 16 HC subjects distanced from or simply looked at negative and neutral pictures depicting social interactions. Contrasts in signal between distance and look condition were compared between groups to identify commonalities and differences in regional activation.
BPD patients show a different pattern of activation compared to HC subjects when looking at negative vs. neutral pictures. When distancing vs. looking at negative pictures, both groups showed decreased negative affect in rating and increased activation of the dorsolateral prefrontal cortex, areas near/along the intraparietal sulcus (IPS), ventrolateral prefrontal cortex and posterior cingulate/precuneus regions. However, the BPD group showed less BOLD signal change in dorsal anterior cingulate cortex and IPS, less deactivation in the amygdala and greater activation in the superior temporal sulcus and superior frontal gyrus.
BPD and HC subjects display different neural dynamics while passively viewing social emotional stimuli. In addition, BPD patients do not engage the cognitive control regions to the extent that HC’s do when employing a distancing strategy to regulate emotional reactions, which may be a factor contributing to the affective instability of BPD.
Emotion; Cognitive Reappraisal; Social Cognitive Neuroscience; Psychological Distancing; Emotion Regulation; fMRI
Superior temporal gyrus (STG/BA22) volume is reduced in schizophrenia and to a milder degree in schizotypal personality disorder (SPD), representing a less severe disorder in the schizophrenia-spectrum. SPD and Borderline personality disorder (BPD) are severe personality disorders characterized by social and cognitive dysfunction. However, while SPD is characterized by social withdrawal/anhedonia, BPD is marked by hyper-reactivity to interpersonal stimuli and hyper-emotionality. This is the first morphometric study to directly compare SPD and BPD patients in temporal volume.
We compared three age-gender- and education-matched groups: 27 unmedicated SPD individuals with no BPD traits, 52 unmedicated BPD individuals with no SPD traits, and 45 healthy controls. We examined gray matter volume of frontal and temporal lobe Brodmann areas (BAs), and dorsal/ventral amygdala from 3T magnetic resonance imaging.
In the STG, an auditory association area reported to be dysfunctional in SPD and BPD, the SPD patients had significantly smaller volume than healthy controls and BPD patients. No group differences were found between BPD patients and controls. Smaller BA22 volume was associated with greater symptom severity in SPD patients. Reduced STG volume may be an important endophenotype for schizophrenia-spectrum disorders. SPD is distinct from BPD in terms of STG volume abnormalities which may reflect different underlying pathophysiological mechanisms and could help discriminate between them.
Schizotypal personality disorder; Borderline personality disorder; Schizophrenia; MRI; Brodmann area 22; Auditory cortex
Borderline personality disorder (BPD) is marked by aggression and impulsive, often self-destructive behavior. Despite the severe risks associated with BPD, relatively little is known about the disorder’s etiology. Identification of genetic correlates (endophenotypes) of BPD would improve the prospects of targeted interventions for more homogeneous subsets of borderline patients characterized by specific genetic vulnerabilities. The current study evaluated behavioral measures of aggression and impulsivity as potential endophenotypes for BPD. Subjects with BPD (N = 127), a non cluster B personality disorder (OPD N = 122), or healthy volunteers (HV N = 112) completed self report and behavioral measures of aggression, motor impulsivity and cognitive impulsivity. Results showed that BPD subjects demonstrated more aggression and motor impulsivity than HV (but not OPD) subjects on behavioral tasks. In contrast, BPD subjects self-reported more impulsivity and aggression than either comparison group. Subsequent analyses showed that among BPD subjects behavioral aggression was associated with self-reported aggression, while behavioral and self-report impulsivity measures were more modestly associated. Overall, the results provide partial support for the use of behavioral measures of aggression and motor impulsivity as endophenotypes for BPD, with stronger support for behavioral aggression measures as an endophenotype for aggression within BPD samples.
Borderline personality disorder; Endophenotype; Aggression; Impulsivity
This study examined the influence of various forms of childhood abuse on basal cortisol levels in a sample of adults with Axis II personality disorders. Participants included 63 adults (n=19 women) who provided basal plasma cortisol samples and completed the Childhood Trauma Questionnaire. Linear regression analyses that included all five subscales (i.e., sexual abuse, physical abuse, emotional abuse, physical neglect and emotional neglect) demonstrated that Physical abuse was related to lower cortisol levels (β = −.43, p=.007), consistent with prior literature. In contrast, Physical neglect was associated with higher cortisol (β = .36, p=.02), after controlling for other forms of abuse. Results are consistent with the view that childhood trauma has long-lasting neurobiological effects and suggest that different forms of trauma may have distinct biological effects.
personality disorder; cortisol; childhood trauma exposure
Prepulse inhibition (PPI) refers to a reduction in the amplitude of the startle eye-blink reflex to a strong sensory stimulus, the pulse, when it is preceded shortly by a weak stimulus, the prepulse. PPI is a measure of sensorimotor gating which serves to prevent the interruption of early attentional processing and it is impaired in schizophrenia-spectrum patients. In healthy individuals, PPI is more robust when attending to than ignoring a prepulse. Animal and human work demonstrate frontal-striatal-thalamic (FST) circuitry modulates PPI. This study used functional magnetic resonance imaging (fMRI) to investigate FST-circuitry during an attention-to-prepulse paradigm in 26 unmedicated schizophrenia-spectrum patients (13 schizotypal personality disorder (SPD), 13 schizophrenia) and 13 healthy controls. During 3T-fMRI acquisition and separately measured psychophysiological assessment of PPI, participants heard an intermixed series of high- and low-pitched tones serving as prepulses to an acoustic-startle stimulus. Event-related BOLD-response amplitude curves in FST regions traced on co-registered anatomical MRI were examined. Controls showed greater activation during attended than ignored PPI conditions in all FST regions--dorsolateral prefrontal cortex (Brodmann areas 46,9), striatum (caudate, putamen), and the thalamic mediodorsal nucleus (MDN). In contrast, schizophrenia patients failed to show differential BOLD responses in FST-circuitry during attended and ignored prepulses, whereas SPD patients showed greater-than-normal activation during ignored prepulses. Among the three diagnostic groups, lower left caudate BOLD activation during the attended PPI condition was associated with more deficient sensorimotor gating as measured by PPI. Schizophrenia-spectrum patients exhibit inefficient utilization of FST-circuitry during attentional modulation of PPI. Schizophrenia patients have reduced recruitment of FST-circuitry during task-relevant stimuli, whereas SPD patients allocate excessive resources during task-irrelevant stimuli. Dysfunctional FST activation, particularly in the caudate may underlie PPI abnormalities in schizophrenia-spectrum patients.
dorsolateral prefrontal cortex; caudate nucleus; putamen; thalamus; mediodorsal nucleus; fMRI; schizophrenia; schizotypal personality disorder; startle; prepulse inhibition; attention; sensorimotor gating
Frontolimbic dysfunction is observed in borderline personality disorder (BPD), with responses to emotional stimuli that are exaggerated in the amygdala and impaired in the anterior cingulate cortex (ACC). This pattern of altered function is consistent with animal models of stress responses and depression, where hypertrophic changes in the amygdala and atrophic changes in the ACC are observed. We tested the hypothesis that BPD patients exhibit gross structural changes that parallel the respective increases in amygdala activation and impairment of rostral/subgenual ACC activation.
12 unmedicated outpatients with BPD by DSM-IV and 12 normal control (NC) subjects underwent a high-resolution T1-weighted structural MRI scan. Relative gray matter concentration (GMC) in spatially-normalized images was evaluated by standard voxel-based morphometry, with voxel-wise subject group comparisons by t test constrained to amygdala and rostral/subgenual ACC.
The BPD group was significantly higher than NC in GMC in the amygdala. In contrast, the BPD group showed significantly lower GMC than the NC group in left rostral/subgenual ACC.
This sample of BPD patients exhibits gross structural changes in gray matter in cortical and subcortical limbic regions that parallel the regional distribution of altered functional activation to emotional stimuli among these same subjects. While the histological basis for GMC changes in adult clinical populations is poorly-known at present, the observed pattern is consistent with the direction of change, in animal models of anxiety and depression, of neuronal number and/or morphological complexity in both the amygdala (where it is increased) and ACC (where it is decreased).
borderline personality disorder; frontolimbic; amygdala; anterior cingulate cortex; gray matter; voxel-based morphometry
Magnetic resonance (MR) imaging studies have revealed fronto-temporal cortical gray matter volume reductions in schizophrenia. However, whether age- and sex-matched unmedicated schizotypal personality disorder (SPD) patients share some or all of the structural brain-imaging characteristics of schizophrenia patients has not been studied. We examined cortical gray/white matter volumes in a large sample of unmedicated schizophrenia-spectrum patients (n=79 SPD, n=57 schizophrenia) and 148 healthy controls. MR images were reoriented to standard position parallel to the anterior-posterior commissure line, segmented into gray and white matter tissue types, and assigned to Brodmann areas (BAs) using a postmortem-histological atlas. Group differences in regional volume of gray and white matter in the BAs was examined with MANOVA. Schizophrenia patients had reduced gray matter volume widely across the cortex but more marked in frontal and temporal lobes. SPD patients had reductions in the same regions but only about half that observed in schizophrenia and sparing in key regions including BA10. In schizophrenia, greater fronto-temporal volume loss was associated with greater negative symptom severity and in SPD, greater interpersonal and cognitive impairment. Overall, our findings suggest that increased prefrontal volume in BA10 and sparing of volume loss in temporal cortex (BAs 22 and 20) may be a protective factor in SPD which reduces vulnerability to psychosis.
MRI; schizophrenia; schizotypal personality disorder; frontal lobe volume; temporal lobe volume; cingulate gyrus; negative symptoms; gray matter volume; white matter volume
Clinical hallmarks of borderline personality disorder (BPD) include social and emotional dysregulation. We tested a model of frontolimbic dysfunction in facial emotion processing in BPD. Groups of 12 unmedicated adults with BPD by DSM-IV and 12 demographically-matched healthy controls (HC) viewed facial expressions (Conditions) of neutral emotion, fear and anger, and made gender discriminations during rapid event-related functional magnetic resonance imaging (fMRI). Analysis of variance of Region of Interest signal change revealed a statistically significant effect of the Group-by-Region-by-Condition interaction. This was due to the BPD group exhibiting a significantly larger magnitude of deactivation (relative to HC) in the bilateral rostral/subgenual anterior cingulate cortex (ACC) to fear and in the left ACC to fear minus neutral; and significantly greater activation in the right amygdala to fear minus neutral. There were no significant between-group differences in ROI signal change in response to anger. In voxel-wise analyses constrained within these ROIs, the BPD group exhibited significant changes in the fear minus neutral contrast, with relatively less activation in the bilateral rostral/subgenual ACC, and greater activation in the right amygdala. In the anger minus neutral contrast this pattern was reversed, with the BPD group showing greater activation in the bilateral rostral/subgenual ACC and less activation in the bilateral amygdala. We conclude that adults with BPD exhibit changes in fronto-limbic activity in the processing of fear stimuli, with exaggerated amygdala response and impaired emotion-modulation of ACC activity. The neural substrates underlying processing of anger may also be altered. These changes may represent an expression of the volumetric and serotonergic deficits observed in these brain areas in BPD.
anterior cingulate cortex; amygdala; fear; anger; functional magnetic resonance imaging
A functional polymorphism of the gene coding for Catechol-O-methyltrasferase (COMT), an enzyme responsible for the degradation of the catecholamine dopamine (DA), epinephrine, and norepinephrine, is associated with cognitive deficits. However, previous studies have not examined the effects of COMT on context processing, as measured by the AX-CPT, a task hypothesized to be maximally relevant to DA function. 32 individuals who were either healthy, with schizotypal personality disorder, or non-cluster A, personality disorder (OPD) were genotyped at the COMT Val158Met locus. Met/Met (n = 6), Val/Met (n = 10), Val/Val (n = 16) individuals were administered a neuropsychological battery, including the AX-CPT and the N-back working memory test. For the AX-CPT, Met/Met demonstrated more AY errors (reflecting good maintenance of context) than the other genotypes, who showed equivalent error rates. Val/Val demonstrated disproportionately greater deterioration with increased task difficulty from 0-back to 1-back working memory demands as compared to Met/Met, while Val/Met did not differ from either genotypes. No differences were found on processing speed or verbal working memory. Both context processing and working memory appear related to COMT genotype and the AX-CPT and N-back may be most sensitive to the effects of COMT variation.
COMT; dopamine; context processing; working memory; schizotypal personality disorder
The identification of endophenotypes in the personality disorders may provide a basis for the identification of underlying genotypes that influence the traits and dimensions of the personality disorders, as well as susceptibility to major psychiatric illnesses. Clinical dimensions of personality disorders that lend themselves to the study of corresponding endophenotypes include affective instability impulsiwity aggression, emotional information processing, cognitive disorganization, social deficits, and psychosis. For example, the propensity to aggression can be evaluated by psychometric measures, interview, laboratory paradigms, neurochemical imaging, and pharmacological studies. These suggest that aggression is a measurable trait that may be related to reduced serotonergic activity. Hyperresponsiveness of amygdala and other limbic structures may be related to affective instability, while structural and functional brain alterations underlie the cognitive disorganization in psychoticlike symptoms of schizotypal personality disorder. Thus, an endophenotypic approach not only provides clues to underlying candidate genes contributing to these behavioral dimensions, but may also point the way to a better understanding of pathophysiological mechanisms.
endophenotype; borderline personality disorder; schizotypal personality disorder; psychosis; candidate gene