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1.  Dialectical behavior therapy alters emotion regulation and amygdala activity in patients with borderline personality disorder 
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.
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.
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).
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.
PMCID: PMC4263347  PMID: 25038629
Borderline personality disorder; Emotion regulation; Amygdala; Habituation; fMRI
2.  Role of Standardized Grape Polyphenol Preparation as a novel treatment to improve synaptic plasticity through attenuation of features of metabolic syndrome in a mouse model 
Molecular nutrition & food research  2013;57(12):10.1002/mnfr.201300230.
Metabolic syndrome has become an epidemic and poses tremendous burden on the health system. People with metabolic syndrome are more likely to experience cognitive decline. As obesity and sedentary lifestyles become more common, the development of early prevention strategies are critical. In this study, we explore the potential beneficial effects of a combinatory polyphenol preparation composed of grape seed extract, Concord purple grape juice extract and resveratrol, referred to as Standardized Grape Polyphenol Preparation (SGP), on peripheral as well as brain dysfunction induced by metabolic syndrome.
We found dietary fat content had minimal effects on absorption and metabolites of major polyphenols derived from SGP. Using a diet-induced animal model of metabolic syndrome (DIM), we found that brain functional connectivity and synaptic plasticity are compromised in the DIM mice. Treatment with SGP not only prevented peripheral metabolic abnormality but also improved brain synaptic plasticity.
Our study demonstrated that SGP comprised of multiple bioavailable and bioactive components targeting a wide range of metabolic syndrome-related pathological features provides greater global protection against peripheral and central nervous system dysfunctions and can be potentially developed as novel prevention/treatment for improving brain connectivity and synaptic plasticity important for learning and memory.
PMCID: PMC3855562  PMID: 23963661
metabolic syndrome; polyphenols; Standardized Grape Polyphenol Preparation; synaptic plasticity
3.  Early-life stress, corpus callosum development, hippocampal volumetrics, and anxious behavior in male nonhuman primates 
Psychiatry research  2011;192(1):37-44.
Male bonnet monkeys (Macaca radiata) were subjected to the Variable Foraging Demand (VFD) early stress paradigm as infants, MRI scans were completed an average of four years later, and behavioral assessments of anxiety and ex-vivo corpus callosum (CC) measurements were made when animals were fully matured. VFD rearing was associated with smaller CC size, CC measurements were found to correlate with fearful behavior in adulthood, and ex-vivo CC assessments showed high consistency with earlier MRI measures. Region of Interest (ROI) hippocampus and whole brain voxel- based morphometry assessments were also completed and VFD rearing was associated with reduced hippocampus and inferior and middle temporal gyri volumes. Animals were also characterized according to serotonin transporter genotype (5-HTTLPR), and the effect of genotype on imaging parameters was explored. The current findings highlight the importance of future research to better understand the effects of stress on brain development in multiple regions, including the corpus callosum, hippocampus, and other regions involved in emotion processing. Nonhuman primates provide a powerful model to unravel the mechanisms by which early stress and genetic makeup interact to produce long-term changes in brain development, stress reactivity, and risk for psychiatric disorders.
PMCID: PMC4090111  PMID: 21377844
stress; monkeys; corpus callosum; hippocampus; brain abnormalities; 5-HTTLPR
4.  Early life stress and macaque amygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene 
Background: Children exposed to early life stress (ELS) exhibit enlarged amygdala volume in comparison to controls. The primary goal of this study was to examine amygdala volumes in bonnet macaques subjected to maternal variable foraging demand (VFD) rearing, a well-established model of ELS. Preliminary analyses examined the interaction of ELS and the serotonin transporter gene on amygdala volume. Secondary analyses were conducted to examine the association between amygdala volume and other stress-related variables previously found to distinguish VFD and non-VFD reared animals.
Methods: Twelve VFD-reared and nine normally reared monkeys completed MRI scans on a 3T system (mean age = 5.2 years).
Results: Left amygdala volume was larger in VFD vs. control macaques. Larger amygdala volume was associated with: “high” cerebrospinal fluid concentrations of corticotropin releasing-factor (CRF) determined when the animals were in adolescence (mean age = 2.7 years); reduced fractional anisotropy (FA) of the anterior limb of the internal capsule (ALIC) during young adulthood (mean age = 5.2 years) and timid anxiety-like responses to an intruder during full adulthood (mean age = 8.4 years). Right amygdala volume varied inversely with left hippocampal neurogenesis assessed in late adulthood (mean age = 8.7 years). Exploratory analyses also showed a gene-by-environment effect, with VFD-reared macaques with a single short allele of the serotonin transporter gene exhibiting larger amygdala volume compared to VFD-reared subjects with only the long allele and normally reared controls.
Conclusion: These data suggest that the left amygdala exhibits hypertrophy after ELS, particularly in association with the serotonin transporter gene, and that amygdala volume variation occurs in concert with other key stress-related behavioral and neurobiological parameters observed across the lifecycle. Future research is required to understand the mechanisms underlying these diverse and persistent changes associated with ELS and amygdala volume.
PMCID: PMC4186477  PMID: 25339875
amygdala; early life stress; non-human primates; MRI; stress; serotonin transporter gene
5.  Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders 
Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).
Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].
Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.
Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.
PMCID: PMC4274982  PMID: 25566007
variable foraging demand; MRI; cisternal tap; serotonin metabolite; monoamine metabolites
6.  Diagnostic value of diffusion-weighted MR imaging in thyroid disease: application in differentiating benign from malignant disease 
BMC Medical Imaging  2013;13:23.
Fine needle aspiration biopsy is usually performed to evaluate thyroid lesions. The purpose of this study was to evaluate the usefulness of diffusion weighted imaging to differentiate malignancy of thyroid lesions.
The study was approved by ethics committee of Shanghai Changzheng Hospital.Forty-two patients, 10 men and 32 women (range: 20–72 years, mean age 42.4 years) with thyroid lesions were included in the study. Routine neck MR and diffusion-weighted MR imaging was performed using multiple b-values. ADC values were computed for the different b-values. Histological results of the thyroidectomy samples were obtained for all the patients. ADC values of benign and malignant thyroid lesions were compared with the pathology results. Logistic regression analysis was used to detect independent parameters for differentiating benign and malignancy of lesions.
Based on the histology results there were 28 benign and 14 malignant cases. The difference of ADC value between benign and malignant thyroid lesions was significant for ADC values obtained using b-values of 0 and 300 s/mm2 (p < 0.001). The ADC values were significantly higher in benign lesions (benign ADC: 2.37 ± 0.47 × 10-3 mm2/s vs. malignant: 1.49 ± 0.60 × 10-3 mm2/s). ADC values obtained with b-values of 0 and 300 mm2/s and max nodular diameter was regarded as the two most discriminative parameters for differentiating malignancy. Using the pathology results as a standard reference, area under ROC curve was found to be 0.876 for an ADC cutoff value of 2.17 × 10-3 mm2/s that corresponded to an acquisition with b-values of 0 and 300 mm2/s.
Diffusion-weighted MR imaging is a promising non-invasive method to differentiate malignancy in thyroid lesions.
PMCID: PMC3750353  PMID: 23899414
Thyroid lesions; Diffusion weighted imaging; ADC mapping
7.  Predicting missing biomarker data in a longitudinal study of Alzheimer disease 
Lo, Raymond Y. | Jagust, William J. | Aisen, Paul | Jack, Clifford R. | Toga, Arthur W. | Beckett, Laurel | Gamst, Anthony | Soares, Holly | C. Green, Robert | Montine, Tom | Thomas, Ronald G. | Donohue, Michael | Walter, Sarah | Dale, Anders | Bernstein, Matthew | Felmlee, Joel | Fox, Nick | Thompson, Paul | Schuff, Norbert | Alexander, Gene | DeCarli, Charles | Bandy, Dan | Chen, Kewei | Morris, John | Lee, Virginia M.-Y. | Korecka, Magdalena | Crawford, Karen | Neu, Scott | Harvey, Danielle | Kornak, John | Saykin, Andrew J. | Foroud, Tatiana M. | Potkin, Steven | Shen, Li | Buckholtz, Neil | Kaye, Jeffrey | Dolen, Sara | Quinn, Joseph | Schneider, Lon | Pawluczyk, Sonia | Spann, Bryan M. | Brewer, James | Vanderswag, Helen | Heidebrink, Judith L. | Lord, Joanne L. | Petersen, Ronald | Johnson, Kris | Doody, Rachelle S. | Villanueva-Meyer, Javier | Chowdhury, Munir | Stern, Yaakov | Honig, Lawrence S. | Bell, Karen L. | Morris, John C. | Mintun, Mark A. | Schneider, Stacy | Marson, Daniel | Griffith, Randall | Clark, David | Grossman, Hillel | Tang, Cheuk | Marzloff, George | Toledo-Morrell, Leylade | Shah, Raj C. | Duara, Ranjan | Varon, Daniel | Roberts, Peggy | Albert, Marilyn S. | Pedroso, Julia | Toroney, Jaimie | Rusinek, Henry | de Leon, Mony J | De Santi, Susan M | Doraiswamy, P. Murali | Petrella, Jeffrey R. | Aiello, Marilyn | Clark, Christopher M. | Pham, Cassie | Nunez, Jessica | Smith, Charles D. | Given, Curtis A. | Hardy, Peter | Lopez, Oscar L. | Oakley, MaryAnn | Simpson, Donna M. | Ismail, M. Saleem | Brand, Connie | Richard, Jennifer | Mulnard, Ruth A. | Thai, Gaby | Mc-Adams-Ortiz, Catherine | Diaz-Arrastia, Ramon | Martin-Cook, Kristen | DeVous, Michael | Levey, Allan I. | Lah, James J. | Cellar, Janet S. | Burns, Jeffrey M. | Anderson, Heather S. | Laubinger, Mary M. | Bartzokis, George | Silverman, Daniel H.S. | Lu, Po H. | Graff-Radford MBBCH, Neill R | Parfitt, Francine | Johnson, Heather | Farlow, Martin | Herring, Scott | Hake, Ann M. | van Dyck, Christopher H. | MacAvoy, Martha G. | Benincasa, Amanda L. | Chertkow, Howard | Bergman, Howard | Hosein, Chris | Black, Sandra | Graham, Simon | Caldwell, Curtis | Hsiung, Ging-Yuek Robin | Feldman, Howard | Assaly, Michele | Kertesz, Andrew | Rogers, John | Trost, Dick | Bernick, Charles | Munic, Donna | Wu, Chuang-Kuo | Johnson, Nancy | Mesulam, Marsel | Sadowsky, Carl | Martinez, Walter | Villena, Teresa | Turner, Scott | Johnson, Kathleen B. | Behan, Kelly E. | Sperling, Reisa A. | Rentz, Dorene M. | Johnson, Keith A. | Rosen, Allyson | Tinklenberg, Jared | Ashford, Wes | Sabbagh, Marwan | Connor, Donald | Jacobson, Sandra | Killiany, Ronald | Norbash, Alexander | Nair, Anil | Obisesan, Thomas O. | Jayam-Trouth, Annapurni | Wang, Paul | Lerner, Alan | Hudson, Leon | Ogrocki, Paula | DeCarli, Charles | Fletcher, Evan | Carmichael, Owen | Kittur, Smita | Mirje, Seema | Borrie, Michael | Lee, T-Y | Bartha, Dr Rob | Johnson, Sterling | Asthana, Sanjay | Carlsson, Cynthia M. | Potkin, Steven G. | Preda, Adrian | Nguyen, Dana | Tariot, Pierre | Fleisher, Adam | Reeder, Stephanie | Bates, Vernice | Capote, Horacio | Rainka, Michelle | Hendin, Barry A. | Scharre, Douglas W. | Kataki, Maria | Zimmerman, Earl A. | Celmins, Dzintra | Brown, Alice D. | Gandy, Sam | Marenberg, Marjorie E. | Rovner, Barry W. | Pearlson, Godfrey | Anderson, Karen | Saykin, Andrew J. | Santulli, Robert B. | Englert, Jessica | Williamson, Jeff D. | Sink, Kaycee M. | Watkins, Franklin | Ott, Brian R. | Wu, Chuang-Kuo | Cohen, Ronald | Salloway, Stephen | Malloy, Paul | Correia, Stephen | Rosen, Howard J. | Miller, Bruce L. | Mintzer, Jacobo
Neurology  2012;78(18):1376-1382.
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.
CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.
The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
PMCID: PMC3345787  PMID: 22491869
8.  Diffuse Disconnectivity in tBi: a resting state fMri anD Dti stuDy 
Translational neuroscience  2012;3(1):9-14.
Diffuse axonal injury is a common pathological consequence of Traumatic Brain Injury (TBI). Diffusion Tensor Imaging is an ideal technique to study white matter integrity using the Fractional Anisotropy (FA) index which is a measure of axonal integrity and coherence. There have been several reports showing reduced FA in individuals with TBI, which suggest demyelination or reduced fiber density in white matter tracts secondary to injury. Individuals with TBI are usually diagnosed with cognitive deficits such as reduced attention span, memory and executive function. In this study we sought to investigate correlations between brain functional networks, white matter integrity, and TBI severity in individuals with TBI ranging from mild to severe. A resting state functional magnetic resonance imaging protocol was used to study the default mode network in subjects at rest. FA values were decreased throughout all white matter tracts in the mild to severe TBI subjects. FA values were also negatively correlated with TBI injury severity ratings. The default mode network showed several brain regions in which connectivity measures were higher among individuals with TBI relative to control subjects. These findings suggest that, subsequent to TBI, the brain may undergo adaptation responses at the cellular level to compensate for functional impairment due to axonal injury.
PMCID: PMC3583347  PMID: 23459252
Traumatic Brain Injury (TBI); Functional magnetic resonance imaging (fMRI); DTI; Cognitive Function
9.  Concomitant jejunal sarcomatoid carcinoma and gastric GIST in patient with polymyalgia rheumatica: A case report 
Sarcomatoid carcinoma (SCA) of the small bowel is an extremely rare tumor with only 21 cases reported in literature and GISTs are relatively rare gastrointestinal neoplasms.
We report a case of an 85 year-old female admitted with intestinal obstruction in June 2010. She suffered from polymyalgia rheumatica and was under surveillance for a presumed gastric GIST. A laparotomy was performed with resection of the jejunal obstruction and complete excision of the gastric mass. Histology confirmed a gastric GIST and sarcomatoid carcinoma of the small bowel. The patient was discharged 21 days after the operation and died on the 88th post-operative day.
Synchronous GISTs and other malignancies have been reported over the last years with increasing frequency.
Sarcomatoid carcinoma of the small bowel is an aggressive neoplasm with poor survival rates and surgery is the cornerstones of treatment. Given its unpredictable clinical behaviour and concomitant association with other malignancies, GISTs require adequate surgical resection with careful, long-term follow-up.
This is the first case of concomitant gastric GIST with Sarcomatoid carcinoma of the small bowel, and the first report of sarcomatoid small bowel carcinoma in association with polymyalgia rheumatica.
PMCID: PMC3731735  PMID: 23548706
GISTs; Sarcomatoid carcinoma; Polymyalgia rheumatica; Small bowel
10.  Elevated Plasma MCP-1 Concentration Following Traumatic Brain Injury as a Potential “Predisposition” Factor Associated with an Increased Risk for Subsequent Development of Alzheimer’s Disease 
We explored whether changes in the expression profile of peripheral blood plasma proteins may provide a clinical, readily accessible “window” into the brain, reflecting molecular alterations following traumatic brain injury (TBI) that might contribute to TBI complications. We recruited fourteen TBI and ten control civilian participants for the study, and also analyzed banked plasma specimens from 20 veterans with TBI and 20 control cases. Using antibody arrays and ELISA assays, we explored differentially-regulated protein species in the plasma of TBI compared to healthy controls from the two independent cohorts. We found three protein biomarker species, monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-binding protein-3, and epidermal growth factor receptor, that are differentially regulated in plasma specimens of the TBI cases. A three-biomarker panel using all three proteins provides the best potential criterion for separating TBI and control cases. Plasma MCP-1 contents are correlated with the severity of TBI and the index of compromised axonal fiber integrity in the frontal cortex. Based on these findings, we evaluated postmortem brain specimens from 7 mild cognitive impairment (MCI) and 7 neurologically normal cases. We found elevated MCP-1 expression in the frontal cortex of MCI cases that are at high risk for developing Alzheimer’s disease. Our findings suggest that additional application of the three-biomarker panel to current diagnostic criteria may lead to improved TBI detection and more sensitive outcome measures for clinical trials. Induction of MCP-1 in response to TBI might be a potential predisposing factor that may increase the risk for development of Alzheimer’s disease.
PMCID: PMC3576700  PMID: 22543850
Alzheimer’s disease; biomarker; long-term clinical TBI phenotypes; mild cognitive impairment; monocyte chemotactic protein-1; plasma; traumatic brain injury
11.  Real-time outcome monitoring following oesophagectomy using cumulative sum techniques 
AIM: To examine the feasibility of prospective, real-time outcome monitoring in a United Kingdom oesophago-gastric cancer surgery unit.
METHODS: The first 100 hybrid (laparoscopic abdominal phase, open thoracic phase) Ivor-Lewis oesophagectomies performed by a United Kingdom oesophago-gastric cancer surgery unit were assessed retrospectively using cumulative sum (CUSUM) techniques. The monitored outcome was 30-d post-operative mortality, with the accepted mortality risk defined as 5%. A variable life adjusted display (VLAD) was constructed by plotting a graph of cumulative mortality minus cumulative mortality risk on the y axis vs sequential case number on the x axis. This was modified to a zeroed VLAD by preventing the plot from crossing the y = 0 axis - essentially creating two plots, one examining trends where cumulative mortality was higher than mortality risk (i.e., worse than expected outcomes) where y > 0, and vice versa. Alert lines were set at y = ± 2. At any point where a plot breaches an alert line, it is felt that the 30-d post-operative mortality rate has deviated significantly from that expected and an internal review should be performed.
RESULTS: One hundred cases were assessed, with a mean age of 66.4 years, mean T stage of 2.1, and mean N stage of 0.48. Three cases were commenced using a laparoscopic technique and converted to open surgery due to technical factors. Median length of inpatient stay was 15 d. The crude 30 d mortality was 5% and the incidence of clinically significant anastomotic leak was 6%. The VLAD demonstrated a plot of cumulative mortality minus cumulative mortality risk (i.e., 5% per case) which remained in the range -1.4 to +0.5 excess mortalities. With the alert set at two greater or fewer than predicted mortalities, this method does not approach the point of triggering internal review. It is however arguable that a run of performance that is better than expected, causing the plot to be well below y = 0, would mask a subsequent run of poor performance by requiring a rise of greater than two excess mortalities to trigger the alert line. The zeroed VLAD removes this problem by preventing the plot that is examining above expected mortality from passing below y = 0, and vice versa. In this study period, no audit triggers were reached. It is therefore possible to independently assess runs of good, or poor performance and so target internal audit to the appropriate series of cases. It is important to note this technique allows targeted internal review, in response to both above and below average outcomes. This study has demonstrated the feasibility of prospective outcome monitoring using the above techniques, actual real-time implementation has the potential to pick up and reinforce good practices when performance is better than predicted, and provide an early warning system for when performance falls below that predicted. Further development is possible, including more patient specific risk adjustment using the oesophago-gastric surgery physiological and operative severity score for the enumeration of mortality and morbidity score.
CONCLUSION: CUSUM techniques provide a potential method of prospective, real-time outcome monitoring in oesophageal cancer surgery.
PMCID: PMC3582162  PMID: 23443533
Oesophagectomy; Cumulative sum; Variable life adjusted display; Outcome; Mortality
12.  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.
PMCID: PMC3139821  PMID: 21600737
Schizophrenia; White Matter; Diffusion Tensor Imaging; Anisotropy; Brodmann Areas; Age
13.  Regional gray matter correlates of vocational interests 
BMC Research Notes  2012;5:242.
Previous studies have identified brain areas related to cognitive abilities and personality, respectively. In this exploratory study, we extend the application of modern neuroimaging techniques to another area of individual differences, vocational interests, and relate the results to an earlier study of cognitive abilities salient for vocations.
First, we examined the psychometric relationships between vocational interests and abilities in a large sample. The primary relationships between those domains were between Investigative (scientific) interests and general intelligence and between Realistic (“blue-collar”) interests and spatial ability. Then, using MRI and voxel-based morphometry, we investigated the relationships between regional gray matter volume and vocational interests. Specific clusters of gray matter were found to be correlated with Investigative and Realistic interests. Overlap analyses indicated some common brain areas between the correlates of Investigative interests and general intelligence and between the correlates of Realistic interests and spatial ability.
Two of six vocational-interest scales show substantial relationships with regional gray matter volume. The overlap between the brain correlates of these scales and cognitive-ability factors suggest there are relationships between individual differences in brain structure and vocations.
PMCID: PMC3476449  PMID: 22591829
14.  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.
PMCID: PMC3049905  PMID: 21115066
working memory; borderline personality disorder; schizotypal personality disorder; dorsolateral prefrontal cortex; ventrolateral prefrontal cortex; MRI
15.  Involvement of the anterior cingulate and frontoinsular cortices in rapid processing of salient facial emotional information 
NeuroImage  2010;54(3):2539-2546.
The anterior cingulate cortex (ACC) and frontoinsular cortex (FI) have been implicated in processing information across a variety of domains, including those related to attention and emotion. However, their role in rapid information processing, for example, as required for timely processing of salient stimuli, is not well understood. Here, we designed an emotional face priming paradigm and employed functional magnetic resonance imaging to elucidate their role in these mechanisms. Target faces with either neutral or fearful emotion were briefly primed by either neutral or fearful faces, or by blank ovals. Activation in the pregenual ACC and the FI, together with other regions, such as the amygdala, were preferentially activated in response to fearful face priming, suggesting that these regions are involved in the rapid processing of salient facial emotional information.
PMCID: PMC3006498  PMID: 20937394
anterior cingulate cortex; emotion; fMRI; frontoinsular cortex; priming
16.  The role of early life stress in development of the anterior limb of the internal capsule in non-human primates 
Neuroscience letters  2010;480(2):93-96.
Deep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) may be effective in treating depression. Parental verbal abuse has been linked to decreased fractional anisotropy (FA) of white matter and reduced FA correlated with depression and anxiety scores. Utilizing a nonhuman primate model of mood and anxiety disorders following disrupted mother-infant attachment, we examined whether adverse rearing conditions lead to white matter impairment of the ALIC.
We examined white matter integrity using Diffusion Tensor Imaging (DTI) on a 3T-MRI. Twenty-one adult male Bonnet macaques participated in this study: 12 were reared under adverse [variable foraging demand (VFD)] conditions whereas 9 were reared under normative conditions. We examined ALIC, posterior limb of the internal capsule (PLIC) and occipital white matter.
VFD rearing was associated with significant reductions in FA in the ALIC with no changes evident in the PLIC or occipital cortex white matter.
Adverse rearing in monkeys persistently impaired frontal white matter tract integrity, a novel substrate for understanding affective susceptibility.
PMCID: PMC2951885  PMID: 20541590
Diffusion tensor imaging; fractional anisotropy; white matter integrity; variable foraging demand
17.  Occupational Solvent Exposure and Brain Function: An fMRI Study 
Environmental Health Perspectives  2011;119(7):908-913.
Background: Deficits in cognitive function have been demonstrated among workers chronically exposed to solvents, but the neural basis for these deficits has not been shown.
Objectives: We used functional magnetic resonance imaging (fMRI) to compare pathophysiological changes in brain function between solvent-exposed and control workers.
Methods: Painters, drywall tapers, and carpenters were recruited from the International Union of Painters and Allied Trades, District Council 9 in New York City and District Council 21 in Philadelphia, Pennsylvania, and from the Carpenters Union in New Jersey. Twenty-seven solvent-exposed and 27 control subjects of similar age, education, and occupational status completed the N-Back working memory test during fMRI. After controlling for confounders (age; lifetime marijuana, cocaine, and alcohol use; blood lead; symptoms of depression; verbal intelligence), voxelwise group analysis and regional activation levels were compared and then correlated with an index of lifetime solvent exposure.
Results: Solvent-exposed workers’ performance on the N-Back was significantly worse than that of controls. Activation of the anterior cingulate, prefrontal, and parietal cortices—areas serving working memory function and attention—was also significantly lower for solvent-exposed workers relative to controls. After controlling for confounders, we observed a negative correlation between lifetime solvent exposure and activation in these same regions among the solvent-exposed workers.
Conclusions: This study is one of the few to document neural structures affected by exposure to solvents. Our findings provide a biological mechanism for the neurobehavioral deficits in working memory and attention that have previously been reported by other groups studying the effects of chronic exposure to solvents. These imaging markers, which are consistent with the neurobehavioral measures in our subject population, are consistent with altered brain pathology caused by prolonged exposure to solvent mixtures during construction work.
PMCID: PMC3222975  PMID: 21296712
brain function; fMRI; solvent exposure
18.  Diffusion tensor imaging in studying white matter complexity: A gap junction hypothesis 
Neuroscience letters  2010;475(3):161-164.
The role of the prefrontal cortex as an executive oversight of posterior brain regions raises the question of the extent to which the anterior regions of the brain interconnect with the posterior regions. The aim of this study is to test the complexity of rostral white matter tracts, which connect anterior and posterior brain regions, in comparison to caudal white matter tracts and the corpus callosum. Diffusion tensor imaging (DTI) is a modality that measures fractional anisotropy (FA). Higher white matter complexity could result in a decrease of FA, possibly through denser intersection of fiber tracts. DTI was used to determine regional FA in 9 healthy bonnet macaques (Macaca radiata). Four regions of interest were included: anterior and posterior limbs of the internal capsule, the occipital lobe white matter, and the corpus callosum. FA of the anterior limbs of the internal capsule was lowest compared to all other regions of interest (Newman-Keuls (N-K); p < 0.0001), whereas FA of the corpus callosum was highest (N-K; p < 0.0001). The posterior limbs of the internal capsule and the occipital white matter were not distinguishable but exhibited intermediate FA in comparison to the former (N-K; p < 0.0001) and the latter (N-K; p < 0.0001). The current study demonstrates that FA, a measure of white matter complexity, can vary markedly as a function of region of interest. Moreover, validation of these findings using neurohistological studies and replication in human samples appears warranted.
PMCID: PMC2862850  PMID: 20371267
Diffusion tensor imaging; fractional anisotropy; white matter; gap junctions; nonhuman primates; neuroimaging; neurodevelopment
19.  Persistent Depressive Symptoms after Acute Coronary Syndrome Are Associated with Compromised White Matter Integrity in the Anterior Cingulate: A Pilot Study 
Psychotherapy and Psychosomatics  2010;79(3):149-155.
Persistent depressive symptoms after acute coronary syndrome (ACS) are common and increase the risk of recurrent cardiac events and mortality. However, the neurobiological correlates of post-ACS depressive symptoms have not yet been studied.
Three months after ACS, 22 patients were scanned for the presence of cerebral deep white matter changes and microstructural abnormalities in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. We used the Coffey Rating Scale of deep white matter changes and measures of fractional anisotropy derived from diffusion tensor imaging. Patients also completed the Beck Depression Inventory, and the number of cardiovascular comorbidities as well as modifiable cardiovascular risk factors were assessed.
Controlling for cardiovascular comorbidity, depressive symptom severity at 3 months was negatively related to fractional anisotropy in the ACC (r = −0.72, p < 0.001), but this association disappeared when controlling for cardiovascular risk factors (p = 0.21). In comparison to patients who were non-depressed at 3 months after hospitalization (n = 14), patients with persistent depressive symptoms (n = 8) exhibited more advanced deep white matter changes overall (p < 0.02), but not when controlling for cardiovascular comorbidity. Persistently depressed patients also had lower fractional anisotropy in the ACC (p < 0.05), but this effect disappeared when controlling for modifiable cardiovascular risk factors.
This study provides the first evidence that persistent depressive symptoms after ACS are associated with vascular brain changes. Longitudinal studies are needed to determine whether depressive symptoms precede these changes or vice versa.
PMCID: PMC2865399  PMID: 20185971
Depression; Acute coronary syndrome; White matter lesions; Diffusion tensor imaging
20.  Gray matter correlates of cognitive ability tests used for vocational guidance 
BMC Research Notes  2010;3:206.
Individual differences in cognitive abilities provide information that is valuable for vocational guidance, but there is an ongoing debate about the role of ability factors, including general intelligence (g), compared to individual tests. Neuroimaging can help identify brain parameters that may account for individual differences in both factors and tests. Here we investigate how eight tests used in vocational guidance correlate to regional gray matter. We compare brain networks identified by using scores for ability factors (general and specific) to those identified by using individual tests to determine whether these relatively broad and narrow approaches yield similar results.
Using MRI and voxel-based morphometry (VBM), we correlated gray matter with independent ability factors (general intelligence, speed of reasoning, numerical, spatial, memory) and individual test scores from a battery of cognitive tests completed by 40 individuals seeking vocational guidance. Patterns of gray matter correlations differed between group ability factors and individual tests. Moreover, tests within the same factor showed qualitatively different brain correlates to some degree.
The psychometric factor structure of cognitive tests can help identify brain networks related to cognitive abilities beyond a general intelligence factor (g). Correlates of individual ability tests with gray matter, however, appear to have some differences from the correlates for group factors.
PMCID: PMC2917438  PMID: 20649948
21.  Event-related fMRI of inhibitory control in the Predominantly Inattentive and Combined Subtypes of AD/HD 
Background and Purpose
To examine the neurophysiological basis for the pronounced differences in hyperactivity and impulsiveness that distinguish the Predominantly Inattentive type of Attention-Deficit/Hyperactivity Disorder (ADHD-PI) from the combined type of the disorder (ADHD-C).
Event-related brain responses to a go/no-go test of inhibitory control were measured with functional magnetic resonance imaging (fMRI) in 11 children with ADHD-C and nine children with ADHD-PI, aged 7 to 13 years, who were matched for age, sex, and intelligence.
There were no significant group differences in task performance. Children with ADHD-C and ADHD-PI activated overlapping regions of right inferior frontal gyrus, right superior temporal lobe, and left inferior parietal lobe during inhibitory control. However, the magnitude of the activation in the temporal and parietal regions, as well as in the bilateral middle frontal gyrus, was greater in children with ADHD-PI than those with ADHD-C. Conversely, children with ADHD-C activated bilateral medial occipital lobe to a greater extent than children with ADHD-PI.
The results provide preliminary evidence that phenotypic differences between the ADHD-C and ADHD-PI subtypes are associated with differential activation of regions that have previously been implicated in the pathophysiology of ADHD and are thought to mediate executive and attentional processes.
PMCID: PMC2711513  PMID: 19594667
22.  Smaller superior temporal gyrus volume specificity in schizotypal personality disorder 
Schizophrenia research  2009;112(1-3):14-23.
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.
PMCID: PMC2782902  PMID: 19473820
Schizotypal personality disorder; Borderline personality disorder; Schizophrenia; MRI; Brodmann area 22; Auditory cortex
23.  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.
PMCID: PMC2677993  PMID: 19168139
24.  Dissociable Neural Effects of Stimulus Valence and Preceding Context during the Inhibition of Responses to Emotional Faces 
Human brain mapping  2009;30(9):2821-2833.
Socially appropriate behavior requires the concurrent inhibition of actions that are inappropriate in the context. This self-regulatory function requires an interaction of inhibitory and emotional processes that recruits brain regions beyond those engaged by either process alone. In this study, we isolated brain activity associated with response inhibition and emotional processing in 24 healthy adults using event-related functional magnetic resonance imaging (fMRI) and a go/no-go task that independently manipulated the context preceding no-go trials (i.e., number of go trials) and the valence (i.e., happy, sad, and neutral) of the face stimuli used as trial cues. Parallel quadratic trends were seen in correct inhibitions on no-go trials preceded by increasing numbers of go trials and associated activation for correct no-go trials in inferior frontal gyrus pars opercularis, pars triangularis, and pars orbitalis, temporoparietal junction, superior parietal lobule, and temporal sensory association cortices. Conversely, the comparison of happy versus neutral faces and sad versus neutral faces revealed valence-dependent activation in the amygdala, anterior insula cortex, and posterior midcingulate cortex. Further, an interaction between inhibition and emotion was seen in valence-dependent variations in the quadratic trend in no-go activation in the right inferior frontal gyrus and left posterior insula cortex. These results suggest that the inhibition of response to emotional cues involves the interaction of partly dissociable limbic and frontoparietal networks that encode emotional cues and use these cues to exert inhibitory control over the motor, attention, and sensory functions needed to perform the task, respectively.
PMCID: PMC2733937  PMID: 19086020
fMRI; motor inhibition; emotion; response context; prefrontal cortex; amygdala
25.  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.
PMCID: PMC2806688  PMID: 17587876
Age; White matter; Magnetic resonance imaging

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