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1.  Neurophysiological Evidence of Corollary Discharge Function During Vocalization in Psychotic Patients and Their Nonpsychotic First-Degree Relatives 
Schizophrenia Bulletin  2012;39(6):1272-1280.
Predictions about sensations resulting from motor acts are instantiated through neural mechanisms such as the corollary discharge. With each action, the corollary discharge provides an unconscious comparison between predicted and actual sensations resulting from the action; closer matches result in greater suppression of sensation. This mechanism is disrupted in schizophrenia (SZ) and may contribute to, or reflect a failure to, distinguish self- from externally generated experiences, a hallmark of psychosis. We asked whether disruption is specific to SZ or is seen in other psychotic illnesses and in first-degree relatives of psychotic patients. Corollary discharge function was assessed in SZ patients (n = 30), schizoaffective (SA) patients (n = 19), bipolar patients with a history of psychosis (BPP; n = 39), nonpsychotic relatives of SZ (n = 30), SA (n = 23), and BPP (n = 50) patients, and healthy controls (n = 43). The N1 component of the event-related potential, reflecting auditory cortical responses to sounds, was elicited by speech sound onset as subjects talked and later when they listened to a recording of those sounds. N1 was suppressed during talking compared to N1 during listening, consistent with the suppressive action of the corollary discharge mechanism. Suppression was significantly reduced in SZ and BPP patients, with a similar trend in the smaller SA group. Patient groups did not differ, and unaffected relatives did not differ from controls or probands. The failure to monitor sensations resulting from self-generated actions, implicating corollary discharge dysfunction, may be a common feature across affective and nonaffective psychosis. Data from unaffected family members do not indicate that this is a marker of psychosis risk.
PMCID: PMC3796076  PMID: 23155183
psychosis; corollary discharge; ERP; N1; first-degree relatives
2.  Are Structural Brain Abnormalities Associated With Suicidal Behavior In Patients With Psychotic Disorders? 
Journal of psychiatric research  2013;47(10):1389-1395.
Suicide represents a major health problem world-wide. Nevertheless, the understanding of the neurobiological underpinnings of suicidal behavior remains far from complete. We compared suicide attempters to non-attempters, and high vs. low lethality attempters, to identify brain regions associated with suicidal behavior in patients with psychotic disorders. 489 individuals with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder I and 262 healthy controls enrolled in the B-SNIP study were studied. Groups were compared by attempt history and the highest medical lethality of previous suicide attempts. 97 patients had a history of a high lethality attempt, 51 of a low lethality attempt and 341 had no attempt history. Gray matter volumes were obtained from 3T structural MRI scans using FreeSurfer. ANCOVAs were used to examine differences between groups, followed by Hochberg multiple comparison correction. Compared to non-attempters, attempters had significantly less gray matter volume in bilateral inferior temporal and superior temporal cortices, left superior parietal, thalamus and supramarginal regions, right insula, superior frontal and rostral middle frontal regions. Among attempters, a history of high lethality attempts was associated with significantly smaller volumes in the left lingual gyrus and right cuneus. Compared to non-attempters, low lethality attempters had significant decreases in the left supramarginal gyrus, thalamus and the right insula. Structural brain abnormalities may distinguish suicide attempters from non-attempters and high from low lethality attempters among individuals with psychotic disorders. Regions in which differences were observed are part of neural circuitries that mediate inhibition, impulsivity and emotion, visceral, visual and auditory perception.
PMCID: PMC4075042  PMID: 23866739
imaging; suicide; schizophrenia
3.  Saccadic eye movement abnormalities in autism spectrum disorder indicate dysfunctions in cerebellum and brainstem 
Molecular Autism  2014;5(1):47.
Individuals with autism spectrum disorder (ASD) show atypical scan paths during social interaction and when viewing faces, and recent evidence suggests that they also show abnormal saccadic eye movement dynamics and accuracy when viewing less complex and non-social stimuli. Eye movements are a uniquely promising target for studies of ASD as their spatial and temporal characteristics can be measured precisely and the brain circuits supporting them are well-defined. Control of saccade metrics is supported by discrete circuits within the cerebellum and brainstem - two brain regions implicated in magnetic resonance (MR) morphometry and histopathological studies of ASD. The functional integrity of these distinct brain systems can be examined by evaluating different parameters of visually-guided saccades.
A total of 65 participants with ASD and 43 healthy controls, matched on age (between 6 and 44-years-old), gender and nonverbal IQ made saccades to peripheral targets. To examine the influence of attentional processes, blocked gap and overlap trials were presented. We examined saccade latency, accuracy and dynamics, as well as the trial-to-trial variability of participants’ performance.
Saccades of individuals with ASD were characterized by reduced accuracy, elevated variability in accuracy across trials, and reduced peak velocity and prolonged duration. In addition, their saccades took longer to accelerate to peak velocity, with no alteration in the duration of saccade deceleration. Gap/overlap effects on saccade latencies were similar across groups, suggesting that visual orienting and attention systems are relatively spared in ASD. Age-related changes did not differ across groups.
Deficits precisely and consistently directing eye movements suggest impairment in the error-reducing function of the cerebellum in ASD. Atypical increases in the duration of movement acceleration combined with lower peak saccade velocities implicate pontine nuclei, specifically suggesting reduced excitatory activity in burst cells that drive saccades relative to inhibitory activity in omnipause cells that maintain stable fixation. Thus, our findings suggest that both cerebellar and brainstem abnormalities contribute to altered sensorimotor control in ASD.
Electronic supplementary material
The online version of this article (doi:10.1186/2040-2392-5-47) contains supplementary material, which is available to authorized users.
PMCID: PMC4233053  PMID: 25400899
Autism spectrum disorder (ASD); Sensorimotor; Eye movement; Saccade; Cerebellum; Brainstem
4.  Is Aberrant Functional Connectivity A Psychosis Endophenotype? A Resting State Functional Magnetic Resonance Imaging Study 
Biological psychiatry  2013;74(6):458-466.
Schizophrenia and bipolar disorder share overlapping symptoms and risk genes. Shared aberrant functional connectivity is hypothesized in both disorders and in relatives.
We investigated resting state functional MRI (fMRI) in 70 schizophrenia and 64 psychotic bipolar probands, their respective first-degree relatives (N = 70 and 52) and 118 healthy subjects. We used independent component analysis (ICA) to identify components representing various resting state networks and assessed spatial aspects of functional connectivity within all networks. We first investigated group differences using five-level, one-way analysis of covariance (ANCOVA), followed by post-hoc t-tests within regions displaying ANCOVA group differences and correlation of such functional connectivity measures with symptom ratings to examine clinical relationships.
Seven different networks revealed abnormalities (five-level one-way ANCOVA, family-wise error correction p < 0.05): (A) fronto-occipital, (B) midbrain/cerebellum, (C) frontal/thalamic/basal ganglia, (D) meso/paralimbic, (E) posterior default mode network, (F) fronto-temporal/paralimbic and (G) sensorimotor networks. Abnormalities in networks B and F were unique to schizophrenia probands only. Furthermore, abnormalities in networks D and E were common to both patient groups. Finally, networks A, C and G showed abnormalities shared by probands and their relative groups. Negative correlation with Positive and Negative Syndrome Scale (PANSS) negative and positive scores were found in regions within network C and F respectively, and positive correlation with PANSS negative scores was found in regions in network D among schizophrenia probands only.
Schizophrenia, psychotic bipolar probands and their relatives share both unique and overlapping within-network brain connectivity abnormalities, revealing potential psychosis endophenotypes.
PMCID: PMC3752322  PMID: 23746539
Bipolar; endophenotype; relatives; resting state; schizophrenia; within-network connectivity
5.  Assessing clinical discharge data preferences among practicing surgeons 
The Journal of surgical research  2013;184(1):42-48.e3.
It is believed that many postoperative patient readmissions can be curbed via optimization of a patient’s discharge from hospital, but little is known about how surgeons make the decision to discharge a patient. This study explored the criteria that surgeons preferentially value in their discharge decision-making process.
Materials and Methods
All surgical faculty and residents at a U.S. academic medical center were surveyed about the relative importance of specific criteria regularly used to make a discharge decision. Demographic and professional information was collected about each surgeon as well. A Kruskal-Wallis and Fisher’s exact test were used to describe one-way analysis of variance between groupings of surgeons. Ordered logit regressions were used to analyze variations across multiple different subgroups. Factor analysis was used to further characterize statistically relevant groupings of criteria.
88 (49%) of the invited surgeons responded to the survey. Respondents reported statistically less reliance on common laboratory tests and patient demographics when making discharge decisions preferring vital signs, perioperative factors, and functional criteria. Surgeon-specific factors that influenced discharge criteria preferences included years of clinical education and gender. Factor analysis further identified subtle variations in preferences for specific criteria groupings based on clinical education, gender, and race.
Surgeons use a wide-range of clinical data when making discharge decisions. Typical measures of patient condition also appear to be used heterogeneously with a preference for binary rather than continuous measures. Further understanding the nature of these preferences may suggest novel ways of presenting discharge-relevant information to the clinical decision-makers to optimize discharge outcomes.
PMCID: PMC3758431  PMID: 23706559
discharge; clinical decision-making; ordered logit regression; decision support; hospital readmission; surgical outcomes
6.  Corticosteroid therapy in regressive autism: Preliminary findings from a retrospective study 
BMC Medicine  2014;12:79.
Some children with autism spectrum disorders (ASD; 15% to 30% of patients) show a significant and persistent regression in speech and social function during early childhood. There are no established treatments for the regressive symptoms. However, there are some known causes of this type of regression, such as Rett syndrome and Landau-Kleffner syndrome (LKS). In LKS, steroids have been used as a treatment. Some evidence suggests an autoimmune contribution to the pathophysiology of autism (Chez MG, Guido-Estrada N: Immune therapy in autism: historical experience and future directions with immunomodulatory therapy. Neurotherapeutics 2010, 7:293–301, Wasilewska J, Kaczmarski M, Stasiak-Barmuta A, Tobolczyk J, Kowalewska E: Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Arch Med Sci 2012, 8:324–331, Stefanatos G: Changing perspectives on Landau-Kleffner syndrome. Clin Neuropsychol 2011, 25:963–988), raising the possibility that steroids might be a useful therapy for regression in ASD. A retrospective study published in BMC Neurology by Duffy et al. (Duffy, et al: Corticosteroid therapy in regressive autism: A retrospective study of effects on the Frequency Modulated Auditory Evoked Response (FMAER), language, and behavior. BMC Neurol 2014, 14:70) reviewed 20 steroid treated R-ASD (STAR) patients and 24 ASD control patients not treated with steroids (NSA). Improvements in clinical function and in a neurophysiological biomarker were seen in the steroid-treated children pre- to post-prednisolone treatment. This research provides a rationale for a randomized trial with steroid therapy to determine the longer term benefits and complications of steroids in this population.
Please see related article
PMCID: PMC4022409  PMID: 24884537
Autism; Regression; Corticosteroids; FMAER; Language; Behavior
7.  Translational Neuroimaging of the Mood and Anxiety Disorders 
BioMed Research International  2014;2014:240769.
PMCID: PMC4036418  PMID: 24900956
8.  Peripheral vasopressin but not oxytocin relates to severity of acute psychosis in women with acutely-ill untreated first-episode psychosis 
Schizophrenia research  2013;146(0):138-143.
In women with chronic schizophrenia, higher levels of peripheral oxytocin have been associated with lower levels of positive but not negative symptoms. Sex-specific associations between endogenous levels of oxytocin (OT) and arginine-vasopressin (AVP) with clinical symptoms and cognition in untreated early course patients have not been examined.
Clinical ratings and neuropsychological testing were performed in thirty-eight acutely ill, unmedicated first-episode schizophrenia patients (14 women, 24 men). Serum hormone assays were obtained in patients and thirty-eight demographically similar healthy controls.
Patients demonstrated increased AVP levels compared to controls (p=0.01). Higher AVP levels were associated with greater positive symptoms (r=0.58, p=0.03) and worse verbal learning (r=−0.63, p=0.02) in female, but not male, patients. OT levels did not statistically differ between patients and controls, and were unrelated to clinical symptoms or cognition in patients.
Results suggest an association of endogenous AVP with increased positive symptom severity and worse cognition in untreated female, but not male, schizophrenia patients. Findings support the role of neuroendocrine alterations in acute psychosis and the importance of examining sex-specific neuroendocrine alterations early in the course of schizophrenia.
PMCID: PMC3622845  PMID: 23465965
oxytocin; vasopressin; symptoms; verbal learning; schizophrenia; sex differences
9.  Impaired frontothalamic circuitry in suicidal patients with depression revealed by diffusion tensor imaging at 3.0 T 
The neurobiology of suicide is largely unknown. Studies of white matter tracts in patients with a history of suicidal behaviour have shown alteration in the left anterior limb of the internal capsule (ALIC). Our aim was to determine whether particular target fields of fibre projections through the ALIC are affected in depressed patients who recently attempted suicide.
We studied patients with major depressive disorder (MDD) with and without a history of suicide attempts and healthy controls using diffusion tensor imaging (DTI) and deterministic tractography to generate fibre tract maps for each participant. Tract voxels were coded as being unique to the left ALIC. We compared the mean percentage of fibres projecting to relevant brain regions in the 3 groups using analysis of covariance.
We included 63 patients with MDD (23 with and 40 without a history of suicide attempts) and 46 controls in our study. Both groups of depressed patients had reduced fibre projections through the ALIC to the left medial frontal cortex, orbitofrontal cortex and thalamus. Those with a history of suicide attempts had greater abnormalities than those without suicide attempts in the left orbitofrontal cortex and thalamus.
Diffusion tensor imaging deterministic tracking is unable to distinguish between afferent and efferent pathways, limiting our ability to distinguish the directionality of altered fibre tracts.
Frontothalamic loops passing through the ALIC are abnormal in patients with depression and significantly more abnormal in depressed patients with a history of suicide attempts than in those without a history of suicide attempts. Abnormal projections to the orbitofrontal cortex and thalamus may disrupt affective and cognitive functions to confer a heightened vulnerability for suicidal behaviour.
PMCID: PMC3997602  PMID: 24119793
10.  Differences in resting-state fMRI functional network connectivity between schizophrenia and psychotic bipolar probands and their unaffected first-degree relatives 
Biological psychiatry  2012;71(10):881-889.
Schizophrenia and bipolar disorder share overlapping symptoms and genetic etiology. Functional brain dysconnectivity is seen in both disorders.
We compared 70 schizophrenia and 64 psychotic bipolar probands, their respective unaffected first-degree relatives (N= 70 and 52) and 118 healthy subjects, all group age-, sex- and ethnicity-matched. We used functional network connectivity (FNC) analysis to measure differential connectivity among 16 fMRI RSNs. First, we examined connectivity differences between probands and controls. Next, we probed these dysfunctional connections in relatives for potential endophenotypes. Network connectivity was then correlated with PANSS scores to reveal clinical relationships.
Three different network pairs were differentially connected in probands (FDR-corrected q<0.05) involving 5 individual resting-state networks: (A) Fronto/Occipital, (B) anterior Default Mode/Prefrontal, (C) Meso/Paralimbic, (D) Fronto-Temporal/Paralimbic & (E) Sensory-motor. One abnormal pair was unique to schizophrenia, (C-E), one unique to bipolar, (C-D) and one (A-B) shared. Two of these 3 combinations (A-B, C-E) were also abnormal in bipolar relatives, but none in schizophrenia relatives (non-significant trend for C-E). The Paralimbic circuit (C-D), that uniquely distinguished bipolar probands, contained multiple mood-relevant regions. Network relationship C-D correlated significantly with PANSS negative scores in bipolar probands and A-B was correlated to PANSS positive and general scores in schizophrenia.
Schizophrenia and psychotic bipolar probands share several abnormal RSN connections, but there are also unique neural network underpinnings between disorders. We identified specific connections and clinical relationships that may also be candidate psychosis endophenotypes, although these do not segregate straightforwardly with conventional diagnoses.
PMCID: PMC3968680  PMID: 22401986
resting state; default mode; schizophrenia; bipolar; functional connectivity; gene; relatives
11.  Reduced Behavioral Flexibility in Autism Spectrum Disorders 
Neuropsychology  2013;27(2):152-160.
Restricted and repetitive behaviors, and a pronounced preference for behavioral and environmental consistency, are distinctive characteristics of autism spectrum disorders (ASD). Whether these clinical features of ASD are related to fundamental neuropsychological impairments in behavioral flexibility remains to be clarified.
Forty-one individuals with ASD and 37 matched controls performed a probabilistic reversal learning task to assess behavioral flexibility. Participants learned to choose the correct stimulus location from a pair of locations to win points (acquisition). After making the correct choice over multiple trials, the rewarded stimulus location changed without warning (reversal). Feedback was provided on an 80:20 probabilistic schedule, with 80% of correct choices and 20% of incorrect choices randomly reinforced.
ASD and control participants performed comparably during acquisition. At reversal, ASD participants initially chose the new correct location as quickly as controls, but then more frequently reverted back to the previously preferred response. The ASD group also more frequently shifted back to the previous response choice immediately following intermittent non-reinforcement of the new correct response. The number of regressive errors was positively correlated with independently ascertained clinical ratings of restricted and repetitive behaviors, but not other core features of ASD.
Restricted and repetitive behaviors in ASD are associated with neurocognitive deficits in flexible choice behavior. Preclinical research has established that frontostriatal circuitry supports flexibility on reversal learning tasks. Thus, alterations in this circuitry may contribute to behavioral rigidity in ASD and represent a target for therapeutic intervention.
PMCID: PMC3740947  PMID: 23527643
autism; behavioral flexibility; reversal learning; restricted and repetitive behaviors
12.  Postoperative Complications and Hospital Readmissions in Surgical Patients 
Annals of surgery  2013;258(1):19-20.
PMCID: PMC3914403  PMID: 23728280
13.  Oxotremorine treatment reduces repetitive behaviors in BTBR T+ tf/J mice 
Repetitive behaviors with restricted interests is one of the core criteria for the diagnosis of autism spectrum disorder (ASD). Current pharmacotherapies that target the dopaminergic or serotonergic systems have limited effectiveness in treating repetitive behaviors. Previous research has demonstrated that administration of muscarinic cholinergic receptor (mAChR) antagonists can exacerbate motor stereotypies while mAChR agonists reduce stereotypies. The present study determined whether the mAChR agonist, oxotremorine affected repetitive behaviors in the BTBR T+ tf/J (BTBR) mouse model of autism. To test the effects of oxotremorine on repetitive behaviors, marble burying and grooming behavior were measured in BTBR mice and compared to that in C57BL/6J (B6) mice. The effects of oxotremorine on locomotor activity was also measured. Thirty minutes before each test, mice received an intraperitoneal (ip) injection of saline, 0.001 mg or 0.01 mg of oxotremorine methiodide. Saline- treated BTBR mice exhibited increased marble burying and self-grooming behavior compared to that of saline-treated B6 mice. Oxotremorine significantly reduced marble burying and self-grooming behavior in BTBR mice, but had no significant effect in B6 mice. In addition, oxotremorine did not affect locomotor activity in BTBR mice, but significantly reduced locomotor activity in B6 mice at the 0.01 mg dose. These findings demonstrate that activation of mAChRs reduces repetitive behavior in the BTBR mouse and suggest that treatment with a mAChR agonist may be effective in reducing repetitive behaviors in ASD.
PMCID: PMC4131251  PMID: 25165445
acetylcholine; muscarinic receptors; autism; repetitive behaviors; marble burying; grooming
14.  Neural Activations During Auditory Oddball Processing Discriminating Schizophrenia and Psychotic Bipolar Disorder 
Biological psychiatry  2012;72(9):766-774.
Reduced amplitude of the P300 event-related potential in auditory oddball tasks may characterize schizophrenia (SZ), but is also reported in bipolar disorder. Similarity of auditory processing abnormalities between these diagnoses is uncertain given the frequent combination of both psychotic and nonpsychotic patients in bipolar samples; abnormalities may be restricted to psychosis. In addition, typically only latency and amplitude of brain responses at selected sensors and singular time-points are used to characterize neural responses. Comprehensive quantification of brain activations involving both spatio-temporal and time-frequency analyses could better identify unique auditory oddball responses among patients with different psychotic disorders.
Sixty SZ, 60 bipolar I with psychosis (BPP), and 60 healthy subjects (H) were compared on neural responses during an auditory oddball task using multi-sensor electroencephalography. Principal components analysis was used to reduce multi-sensor data prior to evaluating group differences on voltage and frequency of neural responses over time.
Linear discriminant analysis revealed five variables that best differentiated groups: (i) late beta activity to standard stimuli and (ii) late beta/gamma activity to targets discriminated BPP from other groups; (iii) mid-latency theta/alpha activity to standards and (iv) target-related voltage at the late N2 response discriminated both psychosis groups from H; and (v) target-related voltage during early N2 discriminated BPP from H.
Although the P300 significantly differentiated psychotic groups from H, it did not uniquely discriminate groups beyond the above variables. No variable uniquely discriminated SZ, perhaps indicating utility of this task for studying psychosis-associated neurophysiology generally and BPP specifically.
PMCID: PMC3465513  PMID: 22572033
ERP; auditory oddball; psychosis; time-frequency; P300; PCA
15.  Brain structural plasticity in survivors of a major earthquake 
Stress responses have been studied extensively in animal models, but effects of major life stress on the human brain remain poorly understood. The aim of this study was to determine whether survivors of a major earthquake, who were presumed to have experienced extreme emotional stress during the disaster, demonstrate differences in brain anatomy relative to individuals who have not experienced such stressors.
Healthy survivors living in an area devastated by a major earthquake and matched healthy controls underwent 3-dimentional high-resolution magnetic resonance imaging (MRI). Survivors were scanned 13–25 days after the earthquake; controls had undergone MRI for other studies not long before the earthquake. We used optimized voxel-based morphometry analysis to identify regional differences of grey matter volume between the survivors and controls.
We included 44 survivors (17 female, mean age 37 [standard deviation (SD) 10.6] yr) and 38 controls (14 female, mean age 35.3 [SD 11.2] yr) in our analysis. Compared with controls, the survivors showed significantly lower grey matter volume in the bilateral insula, hippocampus, left caudate and putamen, and greater grey matter volume in the bilateral orbitofrontal cortex and the parietal lobe (all p < 0.05, corrected for multiple comparison).
Differences in the variance of survivor and control data could impact study findings.
Acute anatomic alterations could be observed in earthquake survivors in brain regions where functional alterations after stress have been described. Anatomic changes in the present study were observed earlier than previously reported and were seen in prefrontal–limbic, parietal and striatal brain systems. Together with the results of previous functional imaging studies, our observations suggest a complex pattern of human brain response to major life stress affecting brain systems that modulate and respond to heightened affective arousal.
PMCID: PMC3819151  PMID: 23710694
16.  Risk Factors for 30-Day Hospital Readmission among General Surgery Patients 
Hospital readmission within 30-days of an index hospitalization is receiving increased scrutiny as a marker of poor quality patient care. This study identifies factors associated with 30-day readmission following General Surgery procedures.
Study Design
Using standard National Surgical Quality Improvement Project (NSQIP) protocol, preoperative, intraoperative, and postoperative outcomes were collected on patients undergoing inpatient General Surgery procedures at a single academic center between 2009 and 2011. Data were merged with our institutional clinical data warehouse to identify unplanned 30-day readmissions. Demographics, comorbidities, type of procedure, postoperative complications, and ICD-9 coding data were reviewed for patients who were readmitted. Univariate and multivariate analysis was utilized to identify risk factors associated with 30-day readmission.
1442 General Surgery patients were reviewed. 163 (11.3%) were readmitted within 30 days of discharge. The most common reasons for readmission were gastrointestinal complaint/complication (27.6%), surgical infection (22.1%), and failure to thrive/malnutrition (10.4%). Comorbidities associated with risk of readmission included disseminated cancer, dyspnea, and preoperative open wound (p<0.05 for all variables). Surgical procedures associated with higher rates of readmission included pancreatectomy, colectomy, and liver resection. Postoperative occurrences leading to increased risk of readmission were blood transfusion, postoperative pulmonary complication, wound complication, sepsis/shock, urinary tract infection, and vascular complications. Multivariable analysis demonstrates that the most significant independent risk factor for readmission is the occurrence of any postoperative complication (OR 4.20, 95% CI 2.89–6.13).
Risk factors for readmission after General Surgery procedures are multi-factorial; however, postoperative complications appear to drive readmissions in surgical patients. Taking appropriate steps to minimize postoperative complications will decrease postoperative readmissions.
PMCID: PMC3423490  PMID: 22726893
Postoperative Readmission; Complications; Risk Factors; General Surgery
17.  Microstructural abnormalities of white matter differentiate pediatric and adult onset bipolar disorder 
Bipolar disorders  2012;14(6):597-606.
White matter microstructure, known to undergo significant developmental transformation, is abnormal in bipolar disorder (BD). Available evidence suggests that white matter deviation may be more pronounced in pediatric than adult onset BD. This study aimed to examine how white matter microstructure deviates from a typical maturational trajectory in BD.
Fractional anisotropy (FA) was measured in 35 individuals presenting with first episode BD (type I) and 46 healthy controls (HC) (aged 9–42) using diffusion tensor imaging (DTI). Patients were medication free and close to illness onset at the time of DTI scans. Tract based spatial statistics were used to examine the center of white matter tracts, and FA was extracted from nine tracts of interest. Axial, radial, and mean diffusivity were examined in post-hoc analyses.
The left anterior limb of the internal capsule (ALIC) showed significantly lower FA in pediatric than adult onset BD. The lower FA in BD was due primarily to greater radial rather than a decrease in axial diffusivity.
ALIC connects the frontal lobes with archistriatum, thalamus, and medial temporal regions, and alteration in these pathways may contribute to mood dysregulation in BD. Abnormalities in this pathway appear to be associated with an earlier onset of illness and thus may reflect a greater liability for illness.
PMCID: PMC3612992  PMID: 22882719
diffusion tensor imaging; development; limbic system; anterior limb of internal capsule; affect network
18.  Cognitive Dysfunction is Worse Among Pediatric Patients with Bipolar Disorder Type I than Type II 
Impaired profiles of neurocognitive function have been consistently demonstrated among pediatric patients with bipolar disorder (BD), and may aid in the identification of endophenotypes across subtypes of the disorder. This study aims to determine phenotypic cognitive profiles of patients with BD Type I and II.
Subjects (N=79) consisted of BD I (n=27) and BD II (n=19) patients and demographic and intellectually matched healthy controls (HC; n=33) that completed a battery of neurocognitive tasks.
BD I patients performed significantly more poorly compared to HC on all domains of cognitive function including attention, executive function, working memory, visual memory, and verbal learning and memory. BD I patients also performed more poorly compared to BD II patients on all domains of cognitive functioning with the exception of working memory, whereas BD II patients did poorly relative to HC only on verbal learning and memory.
Findings from the current study indicate that BD I patients are characterized by more severe cognitive impairment relative to BD II patients who show an intermediate pattern of performance between BD I patients and HC. Verbal learning and memory may effectively differentiate pediatric BD patients and controls, regardless of the subtype of BD, and may serve as a cognitive endophenotype for the disorder. Additionally, these findings move us closer to developing effective cognitive interventions tailored to specific subtypes of pediatric BD patients.
PMCID: PMC3415381  PMID: 22339488
Pediatric bipolar disorder; neurocognitive function; bipolar I disorder; bipolar II disorder; clinical subtypes
19.  Consensus Paper: Pathological Role of the Cerebellum in Autism 
Cerebellum (London, England)  2012;11(3):777-807.
There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.
PMCID: PMC3677555  PMID: 22370873
cerebellum; autism
20.  Saccade Adaptation Abnormalities Implicate Dysfunction of Cerebellar-Dependent Learning Mechanisms in Autism Spectrum Disorders (ASD) 
PLoS ONE  2013;8(5):e63709.
The cerebellar vermis (lobules VI-VII) has been implicated in both postmortem and neuroimaging studies of autism spectrum disorders (ASD). This region maintains the consistent accuracy of saccadic eye movements and plays an especially important role in correcting systematic errors in saccade amplitudes such as those induced by adaptation paradigms. Saccade adaptation paradigms have not yet been used to study ASD. Fifty-six individuals with ASD and 53 age-matched healthy controls performed an intrasaccadic target displacement task known to elicit saccadic adaptation reflected in an amplitude reduction. The rate of amplitude reduction and the variability of saccade amplitude across 180 adaptation trials were examined. Individuals with ASD adapted slower than healthy controls, and demonstrated more variability of their saccade amplitudes across trials prior to, during and after adaptation. Thirty percent of individuals with ASD did not significantly adapt, whereas only 6% of healthy controls failed to adapt. Adaptation rate and amplitude variability impairments were related to performance on a traditional neuropsychological test of manual motor control. The profile of impaired adaptation and reduced consistency of saccade accuracy indicates reduced neural plasticity within learning circuits of the oculomotor vermis that impedes the fine-tuning of motor behavior in ASD. These data provide functional evidence of abnormality in the cerebellar vermis that converges with previous reports of cellular and gross anatomic dysmorphology of this brain region in ASD.
PMCID: PMC3660571  PMID: 23704934
21.  Negative Emotion Impairs Working Memory in Pediatric Patients with Bipolar Disorder Type I 
Psychological medicine  2012;42(12):2567-2577.
We investigated affect recognition and the impact of emotional valence on working memory (using happy, angry, and neutral faces) in pediatric patients with bipolar disorder (BD) and healthy controls (HC).
Subjects (N=70) consisted of unmedicated patients with BD type I (n=23) and type II (n=16) and matched HC (n=31). All subjects completed tasks of emotion recognition (Chicago Pediatric Emotional Acuity Task; Chicago PEAT) and working memory for happy, angry, and neutral faces (Affective N-Back Memory Task; ANMT).
Compared to HC, BD patients performed significantly more poorly when identifying the intensity of happy and angry expressions on the Chicago PEAT, and demonstrated working memory impairments regardless of the type of facial emotional stimuli. Pediatric BD patients displayed the most impaired accuracy and reaction time performance with negative facial stimuli relative to neutral stimuli, but did not display this pattern with positive stimuli. Only BD type I patients displayed working memory deficits, while both type I and type II patients displayed emotion identification impairments. Results remained significant after controlling for comorbid ADHD and mood state.
Both type I and type II BD youth demonstrate emotion identification deficits. BD youth also demonstrate working memory impairments for facial stimuli irrespective of emotional valence, however, working memory deficits were the most pronounced with negative emotional stimuli. These deficits appear to be specific to BD type I patients, and suggest therefore that a more severe form of illness is characterized by more severe social-cognitive impairment.
PMCID: PMC3652422  PMID: 22564881
Pediatric bipolar disorder; ADHD; emotion identification; attention; working memory
22.  Spatio-temporal and Frequency Domain Analysis of Auditory Paired Stimuli Processing in Schizophrenia and Psychotic Bipolar Disorder 
Psychophysiology  2011;49(4):522-530.
Individuals with schizophrenia (SZ) or psychotic bipolar disorder (BPP) may share neurophysiological abnormalities as measured in auditory paired-stimuli paradigms with electroencephalography (EEG). Such investigations have been limited, however, by quantifying only event-related potential peaks and/or broad frequency bands at limited scalp locations without considering possible mediating factors (e.g., baseline differences). Results from 64-sensor EEG collected in 180 age- and gender-matched participants reveal (i) accentuated pre-stimulus gamma oscillations and (ii) reduced P2 amplitudes and theta/alpha oscillations to S1 among both SZ and BPP. Conversely (iii) N1s in SZ to S1 were reduced compared to healthy and BPP, while (iv) beta range oscillations 200–300 ms following S2 were accentuated in BPP but not SZ. Results reveal a pattern of both unique and shared neurophysiological phenotypes occurring within major psychotic diagnoses.
PMCID: PMC3309114  PMID: 22176721
23.  White matter microstructure in untreated first episode bipolar disorder with psychosis: comparison with schizophrenia 
Bipolar disorders  2011;13(0):604-613.
White matter abnormalities have been reported in bipolar disorder. The present study aimed to investigate white matter integrity in untreated first episode patients with psychotic bipolar disorder using diffusion tensor imaging, and to compare observations with those from untreated first episode schizophrenia patients.
Fractional anisotropy and mean diffusivity were measured in first episode psychotic patients with bipolar disorder (n = 13) or schizophrenia (n = 21) and healthy individuals (n = 18). Group differences were evaluated using voxel based morphometry. Axial and radial diffusivity were examined in regions with altered fractional anisotropy in post-hoc analyses.
Patients with bipolar disorder showed lower fractional anisotropy than healthy controls in several white matter tracts. Compared with schizophrenia patients, bipolar disorder patients showed lower fractional anisotropy in the cingulum, internal capsule, posterior corpus callosum, tapetum, and occipital white matter including posterior thalamic radiation and inferior longitudinal fasciculus/inferior fronto-occipital fasciculus. Lower fractional anisotropy in bipolar disorder was characterized by increased radial diffusion rather than axial diffusion along the orientation of fiber tracts. Across several white matter tracts, both patient groups showed greater mean diffusivity than healthy individuals.
Selectively increased radial diffusivity in bipolar disorder patients suggests structural disorganization in fiber tract coherence of neurodevelopmental origin or alterations in myelin sheaths along fiber tracts. In contrast, increased isotropic diffusion along white matter tracts in schizophrenia patients with alterations in both radial and axial diffusivity suggests increased water content outside of axonal space. Thus, the present results suggest that different pathophysiological mechanisms may underlie white matter microstructural abnormalities in bipolar disorder and schizophrenia.
PMCID: PMC3612986  PMID: 22085473
diffusion tensor imaging; first episode psychosis; radial diffusivity; fractional anisotropy; mean diffusivity
24.  Risperidone and Divalproex Differentially Engage the Fronto-Striato-Temporal Circuitry in Pediatric Mania: A Pharmacological fMRI Study 
The current study examined the impact of risperidone and divalproex on affective and working memory circuitry in patients with pediatric bipolar disorder (PBD).
This was a six-week double blind randomized trial of risperidone plus placebo vs. divalproex plus placebo for patients with mania (n=21; 13.6±2.5 years). The fMRI outcomes were measured using a block design affective N-back task with angry, happy and neutral face stimuli at baseline and at 6-week follow-up. Matched healthy controls (HC; n=15, 14.5±2.8 years) were also scanned twice.
Post hoc analyses on the significant interaction in a 3×2×2 ANOVA which included patient groups and HC revealed that the risperidone group showed greater activation after treatment in response to the angry face condition in the left subgenual anterior cingulate cortex (ACC) and striatum relative to the divalproex group. The divalproex group showed greater activation relative to the risperidone group in left inferior frontal gyrus and right middle temporal gyrus. Over the treatment course, the risperidone group showed greater change in activation in the left ventral striatum than the divalproex group, and the divalproex group showed greater activation change in left inferior frontal gyrus and right middle temporal gyrus than the risperidone group. Furthermore, each patient group showed increased activation relative to HC in fronto-striato-temporal regions over time. The happy face condition was potentially less emotionally challenging in this study and did not elicit notable findings.
When patients performed a working memory task under emotional duress inherent in the paradigm, divalproex enhanced activation in a fronto-temporal circuit while risperidone increased activation in the dopamine (D2) receptor-rich ventral striatum.
PMCID: PMC3357915  PMID: 22265362
risperidone; divalproex; pediatric bipolar disorder; fMRI
25.  Resting state EEG abnormalities in autism spectrum disorders 
Autism spectrum disorders (ASD) are a group of complex and heterogeneous developmental disorders involving multiple neural system dysfunctions. In an effort to understand neurophysiological substrates, identify etiopathophysiologically distinct subgroups of patients, and track outcomes of novel treatments with translational biomarkers, EEG (electroencephalography) studies offer a promising research strategy in ASD. Resting-state EEG studies of ASD suggest a U-shaped profile of electrophysiological power alterations, with excessive power in low-frequency and high-frequency bands, abnormal functional connectivity, and enhanced power in the left hemisphere of the brain. In this review, we provide a summary of recent findings, discuss limitations in available research that may contribute to inconsistencies in the literature, and offer suggestions for future research in this area for advancing the understanding of ASD.
PMCID: PMC3847481  PMID: 24040879
Autism; Resting-state; EEG; Electroencephalography

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