Showing papers by "Martha E. Shenton published in 2018"

Widespread white matter microstructural differences in schizophrenia across 4322 individuals : results from the ENIGMA Schizophrenia DTI Working Group

Abstract: The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Multi-site harmonization of diffusion MRI data in a registration framework

Abstract: Diffusion MRI (dMRI) data acquired on different scanners varies significantly in its content throughout the brain even if the acquisition parameters are nearly identical. Thus, proper harmonization of such data sets is necessary to increase the sample size and thereby the statistical power of neuroimaging studies. In this paper, we present a novel approach to harmonize dMRI data (the raw signal, instead of dMRI derived measures such as fractional anisotropy) using rotation invariant spherical harmonic (RISH) features embedded within a multi-modal image registration framework. All dMRI data sets from all sites are registered to a common template and voxel-wise differences in RISH features between sites at a group level are used to harmonize the signal in a subject-specific manner. We validate our method on diffusion data acquired from seven different sites (two GE, three Philips, and two Siemens scanners) on a group of age-matched healthy subjects. We demonstrate the efficacy of our method by statistically comparing diffusion measures such as fractional anisotropy, mean diffusivity and generalized fractional anisotropy across these sites before and after data harmonization. Validation was also done on a group oftest subjects, which were not used to "learn" the harmonization parameters. We also show results using TBSS before and after harmonization for independent validation of the proposed methodology. Using synthetic data, we show that any abnormality in diffusion measures due to disease is preserved during the harmonization process. Our experimental results demonstrate that, for nearly identical acquisition protocol across sites, scanner-specific differences in the signal can be removed using the proposed method in a model independent manner.

Validating the Predictive Accuracy of the NAPLS-2 Psychosis Risk Calculator in a Clinical High-Risk Sample From the SHARP (Shanghai At Risk for Psychosis) Program

Abstract: s for the Sixth Biennial SIRS Conference S366 Poster Session III research. The SCIP is a valid and reliable tool and was tested in an international multisite study in three countries (USA, Canada and Egypt) between 2000 and 2012 (Aboraya, El-Missiry et al. 2014, Aboraya 2015, Aboraya 2016, Aboraya, Nasrallah et al. 2016). A total of 700 patients were interviewed at William R. Sharpe Jr. Hospital in Weston, West Virginia (670 patients) and Chestnut Ridge Center in Morgantown, West Virginia (30 patients). Mean patient age was 34, 59% male, 95% White and 34% had less than 12 years of education. The SCIP includes 38 items covering subtypes of delusions, hallucinations and disorganization. The 38 items were shortened by removing items with low prevalence, low sensitivity or low item-rest correlation (< 0.4). The reliability and validity of the remaining items was recalculated with repetitive iterations. The final model was developed with input from experts. The result is the Core Schizophrenia Symptoms (CSS) Scale which has 18 items: 6 items measuring hallucinations, 8 items measuring delusions and 4 items measuring disorganization. The items were scored with binary and Likert-type scales ranging from 0 to 3. The reliability of the CSS scale was measured using the kappa coefficient for inter-rater reliability of the CSS individual items and Cronbach’s alpha for internal consistency of the CSS dimension. The validity of the CSS scale was assessed using Receiver Operating Characteristic (ROC) curves to determine the best clinical cut-off point for the CSS scale that maximizes sensitivity and specificity of the scale against the SCIP diagnosis of schizophrenia (the reference standard). Results: Table (1) shows stable kappa values and standard error of 15 CSS items. Nine items have good reliability (kappa > 0.7), three items have fair reliability (kappa values range from 0.5 to 0.7) and three items have poor reliability (kappa < 0.5). Table (2) shows the internal consistency of the CSS dimension using Cronbach’s alpha and one-sided 95% confidence interval. The Cronbach’s alpha is 0.8317, indicating excellent internal consistency. Table (3) shows the sensitivity and specificity of the Core Schizophrenia Symptoms (CSS) scale. At a cut-off of one or more positive items, sensitivity is 95.06% and specificity is 88.94%; at a cut-off of two or more positive items, sensitivity is 90.12% and specificity is 89.39%. Discussion: The Core Schizophrenia Symptoms (CSS) Scale is reliable at the level of individual items and at the dimensional level. In addition, the CSS scale is a valid scale that differentiates between schizophrenia and nonschizophrenia cases in a clinical population. S105. VALIDATING THE PREDICTIVE ACCURACY OF THE NAPLS-2 PSYCHOSIS RISK CALCULATOR IN A CLINICAL HIGH-RISK SAMPLE FROM THE SHARP (SHANGHAI AT RISK FOR PSYCHOSIS) PROGRAM TianHong Zhang*,1, HuiJun Li2, LiHua Xu1, YingYing Tang1, HuiRu Cui1, Junjie Wang1, Chunbo Li1, Kristen Woodberry3, Daniel I. Shapiro3, Margaret Niznikiewicz3, Martha E. Shenton4, Matcheri S. Keshavan5, William S. Stone3, JiJun Wang1, Robert W. McCarley6, Larry J. Seidman7 1Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine; 2Florida A & M University; 3Beth Israel Deaconess Medical Center, Harvard Medical Center; 4Brigham and Women’s Hospital, Harvard Medical School, Veterans Affairs Boston Healthcare System; 5Massachusetts Mental Health Center, Beth Israel Deaconess Medical Center, Harvard Medical School; 6Harvard Medical School, Veterans Affairs Boston Healthcare System; 7Harvard Medical School Background: The present study aims to validate the predictive accuracy of the NAPLS-2 psychosis risk calculator in a clinical high-risk (CHR) sample from the SHARP (ShangHai At Risk for Psychosis) program in Shanghai, China using comparable inclusion/exclusion criteria and assessments. Methods: Three hundred CHR individuals were identified by the Chinese version of the Structured Interview for Prodromal Symptoms. Of these, 228 (76.0%) completed neuro-cognitive assessments at baseline and 199 (66.3%) had at least a one-year follow-up assessment. The latter group was used in risk calculation. Six key predictors (baseline age, unusual thoughts and suspiciousness, symbol coding and verbal learning test performance, functional decline and family history of psychosis) were entered into the NAPLS-2 model to generate a psychosis risk estimate for each case. The area under the receiver operating characteristic curve (AUC) was used to test the effectiveness of this discrimination. Results: The NAPLS risk calculator showed moderate discrimination of subsequent transition to psychosis in the SHARP sample with an AUC of 0.631 (p = 0.007). Whether discriminating either transition or poor treatment/clinical outcomes, the AUC of the model increased to 0.754 (p < 0.001). A risk estimate of 30% or higher had moderate sensitivity (53%) and excellent specificity (86%) for prediction of poor treatment/clinical outcome. Discussion: The NAPLS-2 risk calculator largely generalizes to a Shanghai CHR sample but is meaningfully improved when predicting an individual’s poor clinical outcome as well as conversion. Our findings provide a critical step in the implementation of CHR risk calculation in China. S106. SUBMISSION WITHDRAWN S107. HEALTHCARE UTILIZATION AND COST IN SCHIZOPHRENIA AND BIPOLAR DISORDER: REAL-WORLD EVIDENCE FROM US CLAIMS DATABASES Mallik Greene1, Tingjian Yan2, Eunice Chang2, Ann Hartry*,3, Jennifer Munday4, Michael S. Broder4 1Otsuka Pharmaceutical Development & Commercialization, Inc.; 2Partnership for Health Analytic Research, LLC; 3Lundbeck; 4Phar, LLC Background: Schizophrenia (SCZ) and bipolar disorder (BD) are distinct psychiatric disorders, but patients may be diagnosed with both. The objective of this study was to explore healthcare resource utilization (HCRU) and cost in patients with claims-based diagnoses of SCZ, type 1 BD (BD-I), and both in a real-world setting. Methods: This retrospective study used (1/1/12–6/30/16) Truven MarketScan® Commercial, Medicaid, and Medicare Supplemental databases. SCZ was defined as 1 inpatient or 2 outpatient claims for SCZ; BD-I was defined analogously. Three mutually exclusive groups were included: 1) SCZ alone: new episode with SCZ (e.g., met the claims-based diagnostic criteria for SCZ, but not for BD-I), 2) BD-I alone: new episode with BD-I (e.g., met the claims-based diagnostic criteria for BD-I, but not for SCZ), and 3) a diagnosis of both SCZ and BD-I: new episodes with both SCZ and BD-I (e.g., met the claims-based diagnostic criteria for both SCZ and BD-I). Descriptive statistics were reported; costs were adjusted to 2016 US$. Results: Of the 63,725 patients in the final sample, 11.5% had SCZ alone, 80.8% had BD-I alone, and 7.7% had a diagnosis of both SCZ and BD. In the year following diagnosis, the group having a diagnosis of both SCZ and BD-I had the highest all-cause hospitalization rates (67.4% versus 39.5% in SCZ alone and 33.7% in BD-I alone) and the highest mean (SD) number of emergency room visits [3.44 (7.1] versus 1.39 (3.5) in SCZ alone and 1.29 (3.2) in BD-I alone]. All-cause total healthcare costs were highest in the group having a diagnosis of both SCZ and BD-I [mean (SD): $51,085 (62,759)], followed by the SCZ alone group [$34,204 (52,995)], and the BD-I alone group [$26,393 (48,294)].

White matter alterations in college football players: a longitudinal diffusion tensor imaging study

Abstract: The aim of this study was to evaluate longitudinal changes in the diffusion characteristics of brain white matter (WM) in collegiate athletes at three time points: prior to the start of the football season (T1), after one season of football (T2), followed by six months of no-contact rest (T3). Fifteen male collegiate football players and 5 male non-athlete student controls underwent diffusion MR imaging and computerized cognitive testing at all three timepoints. Whole-brain tract-based spatial statistics (TBSS) were used to compare fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and trace between all timepoints. Average diffusion values were obtained from statistically significant clusters for each individual. No athlete suffered a concussion during the study period. After one season of play (T1 to T2), we observed a significant increase in trace in a cluster located in the brainstem and left temporal lobe, and a significant increase in FA in the left parietal lobe. After six months of no-contact rest (T2 to T3), there was a significant decrease in trace and FA in clusters that were partially overlapping or in close proximity with the initial clusters (T1 to T2), with no significant changes from T1 to T3. Repetitive head impacts (RHI) sustained during a single football season may result in alterations of the brain’s WM in collegiate football players. These changes appear to return to baseline after 6 months of no-contact rest, suggesting remission of WM alterations. Our preliminary results suggest that collegiate football players might benefit from periods without exposure to RHI.

White matter abnormalities in mild traumatic brain injury with and without post-traumatic stress disorder: a subject-specific diffusion tensor imaging study

Abstract: Mild traumatic brain injuries (mTBIs) are often associated with posttraumatic stress disorder (PTSD). In cases of chronic mTBI, accurate diagnosis can be challenging due to the overlapping symptoms this condition shares with PTSD. Furthermore, mTBIs are heterogeneous and not easily observed using conventional neuroimaging tools, despite the fact that diffuse axonal injuries are the most common injury. Diffusion tensor imaging (DTI) is sensitive to diffuse axonal injuries and is thus more likely to detect mTBIs, especially when analyses account for the inter-individual variability of these injuries. Using a subject-specific approach, we compared fractional anisotropy (FA) abnormalities between groups with a history of mTBI (n = 35), comorbid mTBI and PTSD (mTBI + PTSD; n = 22), and healthy controls (n = 37). We compared all three groups on the number of abnormal FA clusters derived from subject-specific injury profiles (i.e., individual z-score maps) along a common white matter skeleton. The mTBI + PTSD group evinced a greater number of abnormally low FA clusters relative to both the healthy controls and the mTBI group without PTSD (p < .05). Across the groups with a history of mTBI, increased numbers of abnormally low FA clusters were significantly associated with PTSD symptom severity, depression, post-concussion symptoms, and reduced information processing speed (p < .05). These findings highlight the utility of subject-specific microstructural analyses when searching for mTBI-related brain abnormalities, particularly in patients with PTSD. This study also suggests that patients with a history of mTBI and comorbid PTSD, relative to those without PTSD, are at increased risk of FA abnormalities.

Childhood adversity associated with white matter alteration in the corpus callosum, corona radiata, and uncinate fasciculus of psychiatrically healthy adults

Abstract: Diffusion tensor imaging studies report childhood adversity (CA) is associated with reduced fractional anisotropy (FA) in multiple white matter tracts in adults. Reduced FA may result from changes in tissue, suggesting myelin/axonal damage, and/or from increased levels of extracellular free-water, suggesting atrophy or neuroinflammation. Free-water imaging can separately identify FA in tissue (FAT) and the fractional volume of free-water (FW). We tested whether CA was associated with altered FA, FAT, and FW in seven white matter regions of interest (ROI), in which FA changes had been previously linked to CA (corona radiata, corpus callosum, fornix, cingulum bundle: hippocampal projection, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus). Tract-based spatial statistics were performed in 147 psychiatrically healthy adults who had completed a self-report questionnaire on CA primarily stemming from parental maltreatment. ROI were extracted according to the protocol provided by the ENIGMA-DTI working group. Analyses were performed both treating CA as a continuous and a categorical variable. CA was associated with reduced FA in all ROI (although categorical analyses failed to find an association in the fornix). In contrast, CA was only associated with reduced FAT in the corona radiata, corpus callosum, and uncinate fasciculus (with the continuous measure of CA finding evidence of a negative relation between CA and FAT in the fornix). There was no association between CA on FW in any ROI. These results provide preliminary evidence that childhood adversity is associated with changes to the microstructure of white matter itself in adulthood. However, these results should be treated with caution until they can be replicated by future studies which address the limitations of the present study.

Retrospective harmonization of multi-site diffusion MRI data acquired with different acquisition parameters

Abstract: A joint and integrated analysis of multi-site diffusion MRI (dMRI) datasets can dramatically increase the statistical power of neuroimaging studies and enable comparative studies pertaining to several brain disorders. However, dMRI data sets acquired on multiple scanners cannot be naively pooled for joint analysis due to scanner specific nonlinear effects as well as differences in acquisition parameters. Consequently, for joint analysis, the dMRI data has to be harmonized, which involves removing scanner-specific differences from the raw dMRI signal. In this work, we present a dMRI harmonization method that, when applied to multi-site data, is capable of removing scanner-specific effects, while accounting for minor differences in acquisition parameters such as b-value, spatial resolution and number of gradient directions in the dMRI data (typical for multi-site clinical research scans). We validate our algorithm on dMRI data acquired from two sites: Philadelphia Neurodevelopmental Cohort (PNC) with 800 healthy adolescents (ages 8 to 22 years) and Brigham and Women9s Hospital (BWH) with 70 healthy subjects (ages 14 to 54 years). In particular, we show that gender differences and maturation in different age groups are preserved after harmonization, as measured using effect sizes (small, medium and large), irrespective of the test sample size. Further, because we use matched control subjects from different scanners to estimate scanner-specific effects, we tested how many subjects are needed from each site to achieve best harmonization results. Our results indicate that at-least 16 to 18 well-matched healthy controls from each site are needed to reliably capture scanner related differences. The proposed method can thus be used for retrospective harmonization of raw dMRI data across sites despite differences in acquisition parameters, while preserving inter-subject anatomical variability.

Impaired white matter connectivity between regions containing mirror neurons, and relationship to negative symptoms and social cognition, in patients with first-episode schizophrenia.

Abstract: In schizophrenia, abnormalities in structural connectivity between brain regions known to contain mirror neurons and their relationship to negative symptoms related to a domain of social cognition are not well understood. Diffusion tensor imaging (DTI) scans were acquired in 16 patients with first episode schizophrenia and 16 matched healthy controls. FA and Trace of the tracts interconnecting regions known to be rich in mirror neurons, i.e., anterior cingulate cortex (ACC), inferior parietal lobe (IPL) and premotor cortex (PMC) were evaluated. A significant group effect for Trace was observed in IPL-PMC white matter fiber tract (F (1, 28) = 7.13, p = .012), as well as in the PMC-ACC white matter fiber tract (F (1, 28) = 4.64, p = .040). There were no group differences in FA. In addition, patients with schizophrenia showed a significant positive correlation between the Trace of the left IPL-PMC white matter fiber tract, and the Ability to Feel Intimacy and Closeness score (rho = .57, p = 0.034), and a negative correlation between the Trace of the left PMC-ACC and the Relationships with Friends and Peers score (rho = remove -.54, p = 0.049). We have demonstrated disrupted white mater microstructure within the white matter tracts subserving brain regions containing mirror neurons. We further showed that such structural disruptions might impact negative symptoms and, more specifically, contribute to the inability to feel intimacy (a measure conceptually related to theory of mind) in first episode schizophrenia. Further studies are needed to understand the potential of our results for diagnosis, prognosis and therapeutic interventions.

Neuro-Metabolite Changes in a Single Season of University Ice Hockey Using Magnetic Resonance Spectroscopy.

Abstract: Background: Previous research has shown evidence for transient neuronal loss after repetitive head impacts (RHI) as demonstrated by a decrease in N-acetylaspartate (NAA) However, few studies have investigated other neuro-metabolites that may be altered in the presence of RHI; furthermore, the relationship of neuro-metabolite changes to neurocognitive outcome and potential sex differences remain largely unknown Objective: The aim of this study was to identify alterations in brain metabolites and their potential association with neurocognitive performance over time as well as to characterize sex-specific differences in response to RHI Methods: 33 collegiate ice hockey players (17 males and 16 females) underwent 3T magnetic resonance spectroscopy (MRS) and neurocognitive evaluation before and after the Canadian Interuniversity Sports (CIS) ice hockey season 2011-2012 The MRS voxel was placed in the corpus callosum Pre- and postseason neurocognitive performances were assessed using the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) Absolute neuro-metabolite concentrations were then compared between pre- and postseason MRS were (level of statistical significance after correction for multiple comparisons: p < 0007) and correlated to ImPACT scores for both sexes Results: A significant decrease in NAA was observed from preseason to postseason (p = 0001) Furthermore, a trend toward a decrease in total choline (Cho) was observed (p = 0044) Although no overall effect was observed for glutamate (Glu) over the season, a difference was observed with females showing a decrease in Glu and males showing an increase in Glu, though this was not statistically significant (p = 0039) In both males and females, a negative correlation was observed between changes in Glu and changes in verbal memory (p = 0008) Conclusion: The results of this study demonstrate changes in absolute concentrations of neuro-metabolites following exposure to RHI Results suggest that changes in Glu are correlated with changes in verbal memory Future studies need to investigate further the association between brain metabolites and clinical outcome as well as sex-specific differences in the brain's response to RHI

Progressive symptom-associated prefrontal volume loss occurs in first-episode schizophrenia but not in affective psychosis.

Abstract: Although smaller gray matter volumes (GMV) in the prefrontal cortex (PFC) in schizophrenia and bipolar disorder have been reported cross-sectionally, there are, to our knowledge, no reports of longitudinal comparisons using manually drawn, gyrally based ROI, and their associations with symptoms. The object of this study was to determine whether first-episode schizophrenia (FESZ) and first-episode affective psychosis (FEAFF) patients show initial and progressive PFC GMV reduction in bilateral frontal pole, superior frontal gyrus (SFG), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG) and examine their symptom associations. Twenty-one FESZ, 24 FEAFF and 23 healthy control subjects (HC) underwent 1.5T MRI with follow-up imaging on the same scanner ~ 1.5 years later. Groups were strikingly different in progressive GMV loss. FESZ showed significant progressive GMV loss in the left SFG, bilateral MFG, and bilateral IFG. In addition, left MFG and/or IFG GMV loss was associated with worsening of withdrawal–retardation and total BPRS symptoms scores. In contrast, FEAFF showed no significant difference in GMV compared with HC, either cross-sectionally or longitudinally. Of note, FreeSurfer run on the same images showed no significant changes longitudinally.

Alteration of gray matter microstructure in schizophrenia

Abstract: Neuroimaging studies demonstrate gray matter (GM) macrostructural abnormalities in patients with schizophrenia (SCZ). While ex-vivo and genetic studies suggest cellular pathology associated with abnormal neurodevelopmental processes in SCZ, few in-vivo measures have been proposed to target microstructural GM organization. Here, we use diffusion heterogeneity- to study GM microstructure in SCZ. Structural and diffusion magnetic resonance imaging (MRI) were acquired on a 3 Tesla scanner in 46 patients with SCZ and 37 matched healthy controls (HC). After correction for free water, diffusion heterogeneity as well as commonly used diffusion measures FA and MD and volume were calculated for the four cortical lobes on each hemisphere, and compared between groups. Patients with early course SCZ exhibited higher diffusion heterogeneity in the GM of the frontal lobes compared to controls. Diffusion heterogeneity of the frontal lobe showed excellent discrimination between patients and HC, while none of the commonly used diffusion measures such as FA or MD did. Higher diffusion heterogeneity in the frontal lobes in early SCZ may be due to abnormal brain maturation (migration, pruning) before and during adolescence and early adulthood. Further studies are needed to investigate the role of heterogeneity as potential biomarker for SCZ risk.

Chronic traumatic encephalopathy: neuroimaging biomarkers.

Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with repetitive head impact exposure, such as that resulting from sports-related concussive and subconcussive brain trauma. Currently, the only way to diagnose CTE is by using neuropathologic markers obtained postmortem. To diagnose CTE earlier, so that possible treatment interventions may be employed, there is a need to develop noninvasive in vivo biomarkers of CTE. Neuroimaging provides promising biomarkers for the diagnosis of CTE and may also help elucidate pathophysiologic changes that occur with chronic sports-related brain injury. To describe the use of neuroimaging as presumed biomarkers of CTE, this chapter focuses on only those studies that report the chronic stages of sports-related brain injury, as opposed to previous chapters that described neuroimaging in the context of acute and subacute injury. Studies using positron emission tomography and magnetic resonance imaging and spectroscopy will be discussed for contact/collision sports such as American football, boxing, mixed martial arts, rugby, and soccer, in which repetitive head impacts are common.

Abnormal relationships between local and global brain measures in subjects at clinical high risk for psychosis: a pilot study.

Abstract: We examined whether abnormal volumes of several brain regions as well as their mutual associations that have been observed in patients with schizophrenia, are also present in individuals at clinical high-risk (CHR) for developing psychosis. 3T magnetic resonance imaging was acquired in 19 CHR and 20 age- and handedness-matched controls. Volumes were measured for the body and temporal horns of the lateral ventricles, hippocampus and amygdala as well as total brain, cortical gray matter, white matter, and subcortical gray matter volumes. Relationships between volumes as well as correlations between volumes and cognitive and clinical measures were explored. Ratios of lateral ventricular volume to total brain volume and temporal horn volume to total brain volume were calculated. Volumetric abnormalities were lateralized to the left hemisphere. Volumes of the left temporal horn, and marginally, of the body of the left lateral ventricle were larger, while left amygdala but not hippocampal volume was significantly smaller in CHR participants compared to controls. Total brain volume was also significantly smaller and the ratio of the temporal horn/total brain volume was significantly higher in CHR than in controls. White matter volume correlated positively with higher verbal fluency score while temporal horn volume correlated positively with a greater number of perseverative errors. Together with the finding of larger temporal horns and smaller amygdala volumes in the left hemisphere, these results indicate that the ratio of temporal horns volume to brain volume is abnormal in CHR compared to controls. These abnormalities present in CHR individuals may constitute the biological basis for at least some of the CHR syndrome.

T13. progressive spontaneous and synchrony gamma-band oscillation deficits in first episode schizophrenia

Abstract: Abstract Background Deficits in the gamma-band (30–100 Hz) auditory steady-state response (ASSR) and progressive volumetric decreases in the primary auditory cortex have been detected shortly after the onset of schizophrenia (SZ), and may be associated with symptoms such as auditory hallucinations. Disruption of gamma-band oscillation has received considerable interest, as the basic mechanisms underlying these oscillations are understood and are conserved across species. Despite the importance of abnormal gamma-band oscillations in SZ, it remains unclear whether the gamma-band ASSR deficit shows progressive change over time during the early stages of the disease. Moreover, animal models based on NMDA receptor hypofunction demonstrate an increase in spontaneous gamma power, which has been reported in chronic SZ (Hirano et al., JAMA Psychiatry 2015), yet it still remains unclear in first-episode schizophrenia (FESZ). Hence, a longitudinal electroencephalogram study of the spontaneous and synchrony gamma-band oscillation in FESZ is important to better understand the pathophysiology and trajectory of early-stage schizophrenia. Methods Subjects were 23 FESZ (14 treated and 9 untreated with antipsychotics), and 39 matched healthy controls (HC). Dipole source localization of dense electrode EEG data was used to examine oscillatory activities in auditory cortices during auditory steady-state stimulation (20/30/40-Hz rates). ICA was used to remove artifacts. Phase locking factor (PLF) and induced power (not phase-locked) were calculated from artifact-free single trial source estimates. Clinical symptoms were assessed by SAPS and SANS. Subjects were recruited as part of the Boston CIDAR Center (www.bostoncidar.org). Test sessions (Time-1/Time-2) were 11.9 months apart. Results Compared to HC, FESZ showed reduced 40-Hz ASSR PLF (synchrony gamma) and increased induced gamma power (spontaneous gamma) during continuous auditory stimuli at time-1. Longitudinally, FESZ showed overall progressive reductions in 40-Hz ASSR PLF and progressive increases in induced gamma power, especially within the left auditory cortex. These progressive deficits were not related to antipsychotic medication. Progressive increase of induced gamma power was correlated with increased positive symptoms. Discussion We found coincide disruptions of auditory gamma-band oscillation, which showed progressive increase in spontaneous gamma (cortical excitability) and progressive decrease in synchrony gamma (cortical synchrony failure) during continuous auditory stimuli in FESZ. These two apparently distinctive circuit progressive abnormalities already occurred in the very early stage of the disease. We propose that assessing ASSR-PLF and spontaneous gamma in FESZ may provide a sensitive translatable biomarker for the integrity of neural networks that are fundamentally altered in the very early stage of SZ.

Toward Imaging Chronic Traumatic Encephalopathy

Abstract: This chapter is based on a presentation given at Boston University School of Medicine in a symposium entitled “Chronic Traumatic Encephalopathy,” on Nov. 4, 2016. Neuroimaging findings were presented from those at risk for developing chronic traumatic encephalopathy (CTE), including retired National Football League players, university hockey players, and retired professional soccer players. Currently the diagnosis of CTE can be made only post mortem. What is known, however, is that repetitive brain trauma, including both concussive and subconcussive trauma, is a necessary but not sufficient predictor of those who are later diagnosed with CTE at postmortem examination. Of note, although not all those who experience repetitive brain trauma develop CTE, this is nonetheless an important group to study to learn more about possible precursors to CTE in living players, with the goal of developing imaging biomarkers that are associated both with postmortem findings in CTE and with symptoms associated with presumed CTE. In addition, the development of surrogate biomarkers of CTE may then be used to stage the disease while those who are at risk are still living, and when we can intervene as treatments become available in the future. Thus, understanding the antecedents of CTE and working toward developing biomarkers of early changes in the brain, before neurodegeneration, and perhaps even before the appearance of symptoms, would set the stage for intervention with disease-modifying or neuroprotective compounds. Finally, although we are far from our goals, understanding brain changes in those at risk for CTE is an important start.