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1.  Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder 
Objective
Siever and Davis’ (1991) psychobiological framework of borderline personality disorder (BPD) identifies affective instability (AI) as a core dimension characterized by prolonged and intense emotional reactivity. Recently, deficient amygdala habituation, defined as a change in response to repeated relative to novel unpleasant pictures within a session, has emerged as a biological correlate of AI in BPD. Dialectical behavior therapy (DBT), an evidence-based treatment, targets AI by teaching emotion-regulation skills. This study tested the hypothesis that BPD patients would exhibit decreased amygdala activation and improved habituation, as well as improved emotion regulation with standard 12-month DBT.
Methods
Event-related fMRI was obtained pre- and post-12-months of standard-DBT in unmedicated BPD patients. Healthy controls (HCs) were studied as a benchmark for normal amygdala activity and change over time (n = 11 per diagnostic-group). During each scan, participants viewed an intermixed series of unpleasant, neutral and pleasant pictures presented twice (novel, repeat). Change in emotion regulation was measured with the Difficulty in Emotion Regulation (DERS) scale.
Results
fMRI results showed the predicted Group × Time interaction: compared with HCs, BPD patients exhibited decreased amygdala activation with treatment. This post-treatment amygdala reduction in BPD was observed for all three pictures types, but particularly marked in the left hemisphere and during repeated-emotional pictures. Emotion regulation measured with the DERS significantly improved with DBT in BPD patients. Improved amygdala habituation to repeated-unpleasant pictures in patients was associated with improved overall emotional regulation measured by the DERS (total score and emotion regulation strategy use subscale).
Conclusion
These findings have promising treatment implications and support the notion that DBT targets amygdala hyperactivity—part of the disturbed neural circuitry underlying emotional dysregulation in BPD. Future work includes examining how DBT-induced amygdala changes interact with frontal-lobe regions implicated in emotion regulation.
doi:10.1016/j.jpsychires.2014.06.020
PMCID: PMC4263347  PMID: 25038629
Borderline personality disorder; Emotion regulation; Amygdala; Habituation; fMRI
3.  Developmental Differences in Diffusion-Tensor Imaging Parameters in Borderline Personality Disorder 
Journal of psychiatric research  2013;47(8):1101-1109.
Background
Borderline personality disorder (BPD) often presents during adolescence. Early detection and intervention decreases its subsequent severity. However, little is known about early predictors and biological underpinnings of BPD. The observed abnormal functional connectivity among brain regions in BPD led to studies of white matter, as the neural substrate of connectivity. However, diffusion tensor imaging (DTI) studies in adult BPD have been inconclusive, and, as yet, there are no published DTI studies in borderline adolescents.
Methods
We conducted DTI tractography in 38 BPD patients (14-adolescents,24-adults) and 32 healthy controls (13-adolescents,19-adults).
Results
We found bilateral tract-specific decreased fractional anisotropy (FA) in inferior longitudinal fasciculus (ILF) in BPD adolescents compared to adolescent controls. ILF FA was significantly higher in adolescent controls compared to BPD adolescents, BPD adults and adult controls (WilksF(3,57)=3.55, p<0.02). Follow-up voxelwise TBSS analysis demonstrated lower FA in BPD adolescents compared to adolescent controls also in uncinate and occipitofrontal fasciculi.
Discussion
FA generally develops along an inverted U-shape curve, increasing through adolescence, and slowly decreasing in adulthood. Our findings suggest that, in adolescent BPD, this normal developmental “peak” in FA, which is seen in healthy controls, is not achieved. This suggests a possible neural substrate for the previously reported OFC-amygdala disconnect in adults with BPD. It raises the possibility that a white matter tract abnormality in BPD present in adolescence may not be appreciable in adulthood, but a functional abnormality in the coordination among brain regions persists. Our finding represents a possible biological marker to identify those at risk for developing BPD.
doi:10.1016/j.jpsychires.2013.03.021
PMCID: PMC3725738  PMID: 23628384
4.  Larger putamen size in antipsychotic-naïve individuals with schizotypal personality disorder 
Schizophrenia research  2012;143(1):158-164.
Objective
To (a) compare the size of the dorsal and ventral striatum(caudate and putamen) in a large sample of antipsychotic-naïve individuals with schizotypal personality disorder (SPD) and healthy control participants; (b) examine symptom correlates of striatal size in SPD.
Methods
The left and right caudate and putamen were hand-traced on structural MRI at five dorsal to ventral slice levels in 76 SPD and 148 healthy control participants. A Group × Region (caudate, putamen) × Slice (1–5: ventral, 2, 3, 4, dorsal) × Hemisphere (left, right) mixed-model MANOVA was conducted on size relative to whole brain.
Results
Primary results showed that compared with the controls, the SPD group showed (a) larger bilateral putamen size overall and this enlargement was more pronounced at the most ventral and dorsal levels; in contrast, there were no between-group differences in caudate volume; (b) larger bilateral size of the striatum ventrally, averaged across the caudate and putamen. Among the SPD group, larger striatal size ventrally, particularly in the left hemisphere was associated with less severe paranoid symptoms.
Conclusions
Striatal size is abnormal in SPD and resembles that of patients with schizophrenia who respond well to antipsychotic treatment. The results suggest that striatal size may be an important endophenotype to consider when developing new pharmacological treatments and when studying factors mitigating psychosis.
doi:10.1016/j.schres.2012.11.003
PMCID: PMC3634353  PMID: 23187070
Schizotypal personality disorder; Putamen; Caudate; Striatum; Schizophrenia; MRI; Striatal size
5.  Anterior limb of the internal capsule in schizotypal personality disorder: Fiber-tract counting, volume, and anisotropy 
Schizophrenia research  2012;141(0):119-127.
Mounting evidence suggests that white matter abnormalities and altered subcortical–cortical connectivity may be central to the pathology of schizophrenia (SZ). The anterior limb of the internal capsule (ALIC) is an important thalamo-frontal white-matter tract shown to have volume reductions in SZ and to a lesser degree in schizotypal personality disorder (SPD). While fractional anisotropy (FA) and connectivity abnormalities in the ALIC have been reported in SZ, they have not been examined in SPD. In the current study, magnetic resonance (MRI) and diffusion tensor imaging (DTI) were obtained in age- and sex-matched individuals with SPD (n=33) and healthy controls (HCs; n=38). The ALIC was traced bilaterally on five equally spaced dorsal-to-ventral axial slices from each participant’s MRI scan and co-registered to DTI for the calculation of FA. Tractography was used to examine tracts between the ALIC and two key Brodmann areas (BAs; BA10, BA45) within the dorsolateral prefrontal cortex (DLPFC). Compared with HCs, the SPD participants exhibited (a) smaller relative volume at the mid-ventral ALIC slice level but not the other levels; (b) normal FA within the ALIC; (c) fewer relative number of tracts between the most-dorsal ALIC levels and BA10 but not BA45 and (d) fewer dorsal ALIC–DLPFC tracts were associated with greater symptom severity in SPD. In contrast to prior SZ studies that report lower FA, individuals with SPD show sparing. Our findings are consistent with a pattern of milder thalamo-frontal dysconnectivity in SPD than schizophrenia.
doi:10.1016/j.schres.2012.08.022
PMCID: PMC3742803  PMID: 22995934
Schizotypal personality disorder; Diffusion tensor imaging; Tractography; Magnetic resonance imaging; Anisotropy; Internal capsule
6.  Potentiated amygdala response to repeated emotional pictures in borderline personality disorder 
Biological psychiatry  2012;72(6):448-456.
Background
Borderline personality disorder (BPD) is characterized by an inability to regulate emotional responses. The amygdala is important in learning about the valence (goodness and badness) of stimuli and has been reported to function abnormally in BPD.
Methods
Event-related functional MRI (fMRI) was employed in three groups: unmedicated BPD (n=33) and schizotypal personality disorder (SPD;n=28) participants and healthy controls (n=32) during a task involving an intermixed series of unpleasant, neutral, and pleasant pictures each presented twice within their respective trial block/run. The amygdala was hand-traced on each participant’s structural-MRI scan which was co-registered to their BOLD-scan. Amygdala responses were examined with a mixed-model MANOVA with repeated measures.
Results
Compared with both control groups, BPD patients showed greater amygdala activation, particularly to the repeated emotional but not neutral pictures and a prolonged return to baseline for the overall BOLD response averaged across all pictures. Despite amygdala overactivation, BPD patients showed a blunted response on the self-report ratings of emotional but not neutral pictures. Fewer dissociative symptoms in both patient groups were associated with greater amygdala activation to repeated unpleasant pictures.
Conclusions
The increased amygdala response to the repeated emotional pictures observed in BPD was not observed in SPD patients suggesting diagnostic specificity. This BPD-related abnormality is consistent with the well-documented clinical feature of high sensitivity to emotional stimuli with unusually strong and long-lasting reactions. The finding of a mismatch between physiological and self-report measures of emotion reactivity in BPD patients suggests they may benefit from treatments which help them recognize emotions.
doi:10.1016/j.biopsych.2012.03.027
PMCID: PMC3415575  PMID: 22560044
borderline personality disorder; schizotypal personality disorder; amygdala; emotion; fMRI; arousal; valence
7.  Striatal Activity in Borderline Personality Disorder with Comorbid Intermittent Explosive Disorder: Sex Differences 
Journal of psychiatric research  2012;46(6):797-804.
Borderline Personality Disorder (BPD) is associated with behavioral and emotional dysregulation, particularly in social contexts; however, the underlying pathophysiology at the level of brain function is not well understood. Previous studies found abnormalities in frontal cortical and limbic areas suggestive of poor frontal regulation of downstream brain regions. However, the striatum, which is closely connected with the medial frontal cortices and plays an important role in motivated behaviors and processing of rewarding stimuli, has been understudied in BPD. Here we hypothesized that, in addition to frontal dysfunction, BPD patients may show abnormal striatal function. In this study, 38 BPD patients with intermittent explosive disorder (BPD-IED) and 36 healthy controls (HC) participated in the Point Subtraction Aggression Paradigm (PSAP), a computer game played with a fictitious other player. 18Fluoro-deoxyglucose positron emission tomography (FDG-PET) measured relative glucose metabolism (rGMR) within caudate and putamen in response to aggression-provoking and non-provoking versions of the PSAP. Male BPD-IED patients had significantly lower striatal rGMR than all other groups during both conditions, although male and female BPD-IED patients did not differ in clinical or behavioral measures. These sex differences suggest differential involvement of frontal-striatal circuits in BPD-IED, and are discussed in relation to striatal involvement in affective learning and social decision-making.
doi:10.1016/j.jpsychires.2012.02.014
PMCID: PMC3645307  PMID: 22464337
Borderline personality disorder; intermittent explosive disorder; striatum; aggression; positron emission tomography
8.  Brodmann Area Analysis of White Matter Anisotropy and Age in Schizophrenia 
Schizophrenia research  2011;130(1-3):57-67.
Diffusion tensor and structural MRI images were acquired on ninety-six patients with schizophrenia (69 men and 27 women between the ages of 18 and 79 (mean = 39.83, SD = 15.16 DSM-IV diagnosis of schizophrenia according to the Comprehensive Assessment of Symptoms and History). The patients reported a mean age of onset of 23 years (range = 13–38, SD = 6). Patients were divided into an acute subgroup (duration ≤ 3 years, n = 25), and a chronic subgroup (duration > 3 years, n = 64). Ninety-three mentally normal comparison subjects were recruited; 55 men and 38 women between the ages of 18 and 82 (mean = 35.77, SD = 18.12). The MRI images were segmented by Brodmann area, and the fractional anisotropy (FA) for the white matter within each Brodmann area was calculated. The FA in white matter was decreased in patients with schizophrenia broadly across the entire brain, but to a greater extent in white matter underneath frontal, temporal and cingulate cortical areas. Both normals and patients with schizophrenia showed a decrease in anisotropy with age but patients with schizophrenia showed a significantly greater rate of decrease in FA in Brodmann area 10 bilaterally, 11 in the left hemisphere and 34 in the right hemisphere. When the effect of age was removed, patients ill more than three years showed lower anisotropy in frontal motor and cingulate white matter in comparison to acute patients ill three years or less, consistent with an ongoing progression of the illness.
doi:10.1016/j.schres.2011.04.027
PMCID: PMC3139821  PMID: 21600737
Schizophrenia; White Matter; Diffusion Tensor Imaging; Anisotropy; Brodmann Areas; Age
9.  Anterior and Posterior Cingulate Cortex Volume in Healthy Adults: Effects of Aging and Gender Differences 
Brain research  2011;1401:18-29.
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.
doi:10.1016/j.brainres.2011.05.050
PMCID: PMC3134959  PMID: 21669408
Cingulate cortex; aging; gender differences; MRI; gray matter; morphometry
10.  Dorso- and Ventro-lateral Prefrontal Volume and Spatial Working Memory in Schizotypal Personality Disorder 
Behavioural brain research  2010;218(2):335-340.
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.
doi:10.1016/j.bbr.2010.11.042
PMCID: PMC3049905  PMID: 21115066
working memory; borderline personality disorder; schizotypal personality disorder; dorsolateral prefrontal cortex; ventrolateral prefrontal cortex; MRI
11.  Cingulate and Temporal Lobe Fractional Anisotropy in Schizotypal Personality Disorder 
Neuroimage  2011;55(3):900-908.
Background
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.
Aims
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.
Method
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.
Results
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).
Conclusions
Similar to schizophrenia, our results indicate cingulum-temporal lobe FA abnormalities in SPD and suggest that cingulum abnormalities are associated with negative symptoms.
doi:10.1016/j.neuroimage.2010.12.082
PMCID: PMC3262398  PMID: 21223999
Diffusion tensor imaging; schizotypal personality disorder; dorsolateral prefrontal cortex; temporal lobe; cingulum; fractional anisotropy
12.  A Review of Structural MRI and Diffusion Tensor Imaging in Schizotypal Personality Disorder 
Current Psychiatry Reports  2011;14(1):70-78.
Individuals with schizotypal personality disorder (SPD) share genetic, phenomenologic, and cognitive abnormalities with people diagnosed with schizophrenia. To date, 15 structural MRI studies of the brain have examined size, and 3 diffusion tensor imaging studies have examined white matter connectivity in SPD. Overall, both types of structural neuroimaging modalities have shown temporal lobe abnormalities similar to those observed in schizophrenia, while frontal lobe regions appear to show more sparing. This intriguing pattern suggests that frontal lobe sparing may suppress psychosis, which is consistent with the idea of a possible neuroprotective factor. In this paper, we review these 18 studies and discuss whether individuals with SPD who both resemble and differ from schizophrenia patients in their phenomenology, share some or all of the structural brain imaging characteristics of schizophrenia. We attempt to group the MRI abnormalities in SPD into three patterns: 1) a spectrum of severity—abnormalities are similar to those observed in schizophrenia but not so severe; 2) a spectrum of region—abnormalities affecting some, but not all, brain regions affected in schizophrenia; and 3) a spectrum of compensation—abnormalities reflecting greater-than-normal white matter volume, possibly serving as a buffer or compensatory mechanism protecting the individual with SPD from the frank psychosis observed in schizophrenia.
doi:10.1007/s11920-011-0241-z
PMCID: PMC3256320  PMID: 22006127
Schizotypal personality disorder; Schizotypy; MRI; Diffusion tensor; Diffusion tensor imaging; Fractional anisotropy; DTI; White matter; Gray matter; Morphometry; Schizophrenia; Schizophrenia spectrum; Brain volume; Frontal lobe; Temporal lobe; Superior temporal gyrus; Cingulate; Cingulum
13.  Effects of sex and normal aging on regional brain activation during verbal memory performance 
Neurobiology of aging  2008;31(5):826-838.
This study examined the main and interactive effects of age and sex on relative glucose metabolic rate (rGMR) within gray matter of 39 cortical Brodmann areas (BAs) and the cingulate gyrus using 18FDG-PET during a verbal memory task in 70 healthy normal adults, aged 20–87 years. Women showed significantly greater age-related rGMR decline in left cingulate gyrus than men (BAs 25, 24, 23, 31, 29). Both groups showed a decline in the anterior cingulate—a neuroanatomical structure that mediates effective cognitive-emotional interactions (BAs 32, 24, 25), while the other frontal regions did not show substantial decline. No sex differences in rGMR were identified within temporal, parietal and occipital lobes. Sex differences were observed for rGMR within subcomponents of the cingulate gyrus with men higher in BA25 and BA29, but lower in BA24 and BA 23 compared to women. For men, better memory performance was associated with greater rGMR in BA24, whereas in women better performance was associated with orbitofrontal-BA12. These results suggest that both age-related metabolic decline and sex differences within frontal regions are more marked in medial frontal and cingulate areas, consistent with some age-related patterns of affective and cognitive change.
doi:10.1016/j.neurobiolaging.2008.10.005
PMCID: PMC2871327  PMID: 19027195
Aging; healthy adults; sex differences; 18FDG PET; cingulate; prefrontal cortex
14.  Correlations between ventricular enlargement and gray and white matter volumes of cortex, thalamus, striatum, and internal capsule in schizophrenia 
Ventricular enlargement is one of the most consistent abnormal structural brain findings in schizophrenia and has been used to infer brain shrinkage. However, whether ventricular enlargement is related to local overlying cortex and/or adjacent subcortical structures or whether it is related to brain volume change globally has not been assessed. We systematically assessed interrelations of ventricular volumes with gray and white matter volumes of 40 Brodmann areas (BAs), the thalamus and its medial dorsal nucleus and pulvinar, the internal capsule, caudate and putamen. We acquired structural MRI ( patients with schizophrenia (n = 64) and healthy controls (n = 56)) and diffusion tensor fractional anisotropy (FA) (untreated schizophrenia n = 19, controls n = 32). Volumes were assessed by manual tracing of central structures and a semi-automated parcellation of BAs. Patients with schizophrenia had increased ventricular size associated with decreased cortical gray matter volumes widely across the brain; a similar but less pronounced pattern was seen in normal controls; local correlations (e.g. temporal horn with temporal lobe volume) were not appreciably higher than non-local correlations (e.g. temporal horn with prefrontal volume). White matter regions adjacent to the ventricles similarly did not reveal strong regional relationships. FA and center of mass of the anterior limb of the internal capsule also appeared differentially influenced by ventricular volume but findings were similarly not regional. Taken together, these findings indicate that ventricular enlargement is globally interrelated with gray matter volume diminution but not directly correlated with volume loss in the immediately adjacent caudate, putamen, or internal capsule.
Electronic supplementary material
The online version of this article (doi:10.1007/s00406-011-0202-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00406-011-0202-x
PMCID: PMC3182327  PMID: 21431919
Cerebral spinal fluid; Sulcal enlargement; Myelin; Fronto-thalamic connectivity
15.  Laboratory Induced Aggression: A PET Study of Aggressive Individuals with Borderline Personality Disorder 
Biological psychiatry  2009;66(12):1107-1114.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2009.07.015
PMCID: PMC2788117  PMID: 19748078
brain imaging; Point Subtraction Aggression Paradigm; PSAP; emotion
16.  A longitudinal study of the corpus callosum in chronic schizophrenia 
Schizophrenia research  2009;114(1-3):144-153.
Background
Decreased callosal size and anisotropy have been described in schizophrenia patients but their longitudinal progression remains poorly understood.
Methods
We performed diffusion-tensor and structural magnetic resonance imaging at baseline and at follow-up four years later in 49 chronic schizophrenia patients and 16 healthy comparison subjects. Schizophrenia patients were subdivided into good-outcome (n=23) and poor-outcome (n=26) groups. Baseline-to-follow-up changes in size, shape, position and fractional anisotropy of the corpus callosum, divided into five sagittal sections and five rostro-caudal segments, were assessed.
Results
At baseline scan and in comparison to healthy subjects, schizophrenia patients displayed 1) smaller callosal size, 2) lower average anisotropy in all sagittal sections except the midline, 3) more dorsal average coordinate position. During the four years after the baseline scan, patients with schizophrenia exhibited a more pronounced decline in absolute size of the corpus callosum than healthy comparison subjects. As compared with the good-outcome group, the corpus callosum in poor-outcome patients at baseline was of smaller size and lower average anisotropy, more elongated and posteriorly positioned. During the follow-up interval, poor-outcome patients displayed a more pronounced decline in size but less pronounced decline in anisotropy of the corpus callosum than patients with good outcomes.
Conclusions
Differences in callosal size between schizophrenia patients and healthy subjects seen at baseline continue to widen in the chronic phase of the illness, especially in patients with poor functional outcome. Baseline differences in callosal anisotropy among patients with different outcomes, however, diminish over time.
doi:10.1016/j.schres.2009.07.021
PMCID: PMC2763416  PMID: 19713080
Corpus callosum; MRI; Kraepelinian schizophrenia; poor outcome; longitudinal course; follow-up
17.  Poor outcome in chronic schizophrenia is associated with progressive loss of volume of the putamen 
Schizophrenia research  2009;113(2-3):241-245.
Background
We have previously demonstrated that putaminal but not caudate volumes are associated with poor outcome in patients with chronic schizophrenia. Present longitudinal study was designed to investigate progressive differences in striatal volumes among chronic schizophrenia patients with different outcomes and healthy subjects.
Method
Structural MRI scans were acquired at baseline and at follow-up four years later to evaluate volumetric changes in 26 poor-outcome schizophrenia patients, 23 good-outcome patients and 16 healthy subjects.
Results
Schizophrenia patients with different outcomes entered the study with similar volumes of the caudate nucleus and putamen. The rate of decline in volumes of the putamen was greater in patients with poor outcome than in the good-outcome group, so that their putaminal but not caudate volumes were significantly smaller at the time of follow-up. There were no differences in baseline and follow-up volumes of the putamen or in the rate of their progression among patients with schizophrenia and healthy comparison subjects. The caudate volumes were lower in schizophrenia patients than healthy subjects at baseline and follow-up, but showed no differential patterns of progression between the groups.
Conclusions
Volumes of the putamen may represent a longitudinal marker of treatment responsiveness and outcome in patients with chronic schizophrenia.
doi:10.1016/j.schres.2009.06.022
PMCID: PMC2763420  PMID: 19616411
Chronic schizophrenia; caudate nucleus; putamen; poor outcome; Kraepelinian; striatum
18.  Smaller superior temporal gyrus volume specificity in schizotypal personality disorder 
Schizophrenia research  2009;112(1-3):14-23.
Background
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.
Methods
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.
Results
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.
doi:10.1016/j.schres.2009.04.027
PMCID: PMC2782902  PMID: 19473820
Schizotypal personality disorder; Borderline personality disorder; Schizophrenia; MRI; Brodmann area 22; Auditory cortex
19.  Age and diffusion tensor anisotropy in adolescent and adult patients with schizophrenia 
NeuroImage  2009;45(3):662-671.
Findings of white matter pathology as indicated by diffusion tensor anisotropy values in schizophrenia are well established, but the differences in this measure between the onset of the disease and the chronic state are not well known. To investigate the differences between these states in the progression of the disease of schizophrenia we acquired 1.5 T diffusion tensor anisotropy images on 35 adult patients with schizophrenia and schizoaffective disorder, 23 adolescents having their first psychotic episode, and age and sex matched controls (33 adults and 15 adolescents). Regions of interest in major cortical white matter tracts chosen as salient to the prefrontal executive deficit in schizophrenia were assessed using stereotaxic coordinates from the Talairach and Tournoux atlas. Regions of each tract along anterior-posterior and/or inferior-superior directions in both hemispheres were evaluated in multiway ANOVA. Tracts between the frontal lobe and other brain regions, but not temporal, occipital and interhemispheric tracts, showed a differential aging pattern in normals and patients indicating that the white matter pathology in these regions is not stable between the onset and the chronic state in schizophrenia. This suggests that tracts involved in the connectivity of the temporal lobe white matter deficits were already well in place in adolescent patients, while frontal lobe pathology continues to develop from adolescence to adulthood.
doi:10.1016/j.neuroimage.2008.12.057
PMCID: PMC2677993  PMID: 19168139
20.  Diffusion Tensor Anisotropy in Adolescents and Adults 
Neuropsychobiology  2007;55(2):96-111.
We acquired diffusion tensor images on 33 normal adults aged 22–64 and 15 adolescents aged 14–21. We assessed relative anisotropy in stereotaxically located regions of interest in the internal capsule, corpus callosum, anterior thalamic radiations, frontal anterior fasciculus, fronto-occipital fasciculus, temporal lobe white matter, cingulum bundle, frontal inferior longitudinal fasciculus, frontal superior longitudinal fasciculus, and optic radiations. All of these structures except the optic radiations, corpus callosum, and frontal inferior longitudinal fasciculus exhibited differences in anisotropy between adolescents and adults. Areas with anisotropy increasing with age included the anterior limb of the internal capsule, superior levels of the frontal superior longitudinal fasciculus and the inferior portion of the temporal white matter. Areas with anisotropy decreasing with age included the posterior limb of the internal capsule, anterior thalamic radiations, fronto-occipital fasciculus, anterior portion of the frontal anterior fasciculus, inferior portion of the frontal superior longitudinal fasciculus, cingulum bundle and superior portion of the temporal axis. Sex differences were found in the majority of areas but were most marked in the cingulum bundle and internal capsule. These results suggest continuing white matter development between adolescence and adulthood.
doi:10.1159/000104277
PMCID: PMC2806688  PMID: 17587876
Age; White matter; Magnetic resonance imaging
21.  Frontal-striatal-thalamic mediodorsal nucleus dysfunction in schizophrenia-spectrum patients during sensorimotor gating 
NeuroImage  2008;42(3):1164-1177.
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.
doi:10.1016/j.neuroimage.2008.05.039
PMCID: PMC2548278  PMID: 18588988
dorsolateral prefrontal cortex; caudate nucleus; putamen; thalamus; mediodorsal nucleus; fMRI; schizophrenia; schizotypal personality disorder; startle; prepulse inhibition; attention; sensorimotor gating
22.  Cortical Gray and White Matter Volume in Unmedicated Schizotypal and Schizophrenia Patients 
Schizophrenia research  2008;101(1-3):111-123.
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.
doi:10.1016/j.schres.2007.12.472
PMCID: PMC2672563  PMID: 18272348
MRI; schizophrenia; schizotypal personality disorder; frontal lobe volume; temporal lobe volume; cingulate gyrus; negative symptoms; gray matter volume; white matter volume
23.  Longitudinal Assessment of Gray and White Matter in Chronic Schizophrenia: A Combined Diffusion-Tensor and Structural Magnetic Resonance Imaging Study 
Previous studies have reported continued focal gray matter loss after the clinical onset of schizophrenia. Longitudinal assessments in chronic illness, of white matter in particular, have been less conclusive.
We used diffusion-tensor and structural magnetic resonance imaging in 16 healthy subjects and 49 chronic schizophrenia patients, subdivided into good-outcome (n=23) and poor-outcome (n=26) groups, scanned twice 4 years apart. Fractional anisotropy, gray matter and white matter volumes were parcellated into the Brodmann’s areas and entered into multiway ANCOVAs.
At baseline, schizophrenia patients had 1) lower anisotropy in frontoparietal white matter, 2) larger posterior frontal white matter volumes, and 3) smaller frontal, temporal, and parietal gray matter volumes. On follow-up, healthy subjects showed a more pronounced 1) decline in anisotropy, 2) expansion of regional white matter volumes, and 3) reduction in regional gray matter volumes than schizophrenia patients. Good-outcome patients showed a more pronounced decline in white matter anisotropy and a less pronounced increase in white matter volumes than poor-outcome patients. Poor-outcome patients displayed a greater gray matter loss throughout the brain than good-outcome patients.
In the chronic phase of the illness, longitudinal changes in both gray and white matter are in the direction of an effacement of between-group differences among schizophrenia patients and healthy subjects. Similarly, preexisting white matter differences between good-outcome and poor-outcome patients diminish over time. In contrast, gray matter volumes in poor-outcome patients continue to decline more rapidly than in patients with good outcome. These patterns are consistent with earlier onset of aging-associated changes in schizophrenia.
doi:10.2174/1874440000903010031
PMCID: PMC2700015  PMID: 19547667
Kraepelinian schizophrenia; poor outcome; anisotropy; white matter; illness progression.
24.  A comprehensive assessment of gray and white matter volumes and their relationship to outcome and severity in schizophrenia 
NeuroImage  2007;37(2):449-462.
Preliminary data suggest an association of posterior cortical gray matter reduction with poor outcome in schizophrenia. We made a systematic MRI assessment of regional gray and white matter volumes, parcellated into 40 Brodmann’s areas, in 104 patients with schizophrenia (51 with good outcomes, 53 with poor outcomes) and 41 normal comparison subjects, and investigated correlations of regional morphometry with outcome and severity of the illness. Schizophrenia patients displayed differential reductions in frontal and to a lesser degree temporal gray matter volumes in both hemispheres, most pronounced in the frontal pole and lateral temporal cortex. White matter volumes in schizophrenia patients were bilaterally increased, primarily in the frontal, parietal, and isolated temporal regions, with volume reductions confined to anterior cingulate gyrus. In patients with schizophrenia as a group, higher illness severity was associated with reduced temporal gray matter volumes and expanded frontal white matter volumes in both hemispheres. In comparison to good-outcome group, patients with poor outcomes had lower temporal, occipital, and to a lesser degree parietal gray matter volumes in both hemispheres and temporal, parietal, occipital, and posterior cingulate white matter volumes in the right hemisphere. While gray matter deficits in the granular cortex were observed in all schizophrenia patients, agranular cortical deficits in the left hemisphere were peculiar to patients with poor outcomes. These results provide support for frontotemporal gray matter reduction and frontoparietal white matter expansion in schizophrenia. Poor outcome is associated with more posterior distribution (posteriorization) of both gray and white matter changes, and with preferential impairment in the unimodal visual and paralimbic cortical regions.
doi:10.1016/j.neuroimage.2007.04.070
PMCID: PMC1994089  PMID: 17587598
Schizophrenia; Poor outcome; Gray matter; White matter; Illness severity; MRI
25.  Diffusion tensor imaging of frontal lobe white matter tracts in schizophrenia 
We acquired diffusion tensor and structural MRI images on 103 patients with schizophrenia and 41 age-matched normal controls. The vector data was used to trace tracts from a region of interest in the anterior limb of the internal capsule to the prefrontal cortex. Patients with schizophrenia had tract paths that were significantly shorter in length from the center of internal capsule to prefrontal white matter. These tracts, the anterior thalamic radiations, are important in frontal-striatal-thalamic pathways. These results are consistent with findings of smaller size of the anterior limb of the internal capsule in patients with schizophrenia, diffusion tensor anisotropy decreases in frontal white matter in schizophrenia and hypothesized disruption of the frontal-striatal-thalamic pathway system.
doi:10.1186/1744-859X-5-19
PMCID: PMC1687182  PMID: 17132158

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