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Military service members are at increased risk for mental health issues and comorbidity with mild traumatic brain injury (mTBI) is common. Largely overlapping symptoms between conditions suggest a shared pathophysiology. The present work investigates the associations between white matter microstructure, psychological functioning, and serum neuroactive steroids that are part of the stress-response system.Diffusion-weighted brain imaging was acquired from 163 participants (with and without military affiliation) and free-water-corrected fractional anisotropy (FAT) was extracted. Associations between serum neurosteroid levels of allopregnanolone (ALLO) and pregnenolone (PREGNE), psychological functioning, and whole-brain white matter microstructure were assessed using regression models. Moderation models tested the effect of mTBI and comorbid post-traumatic stress disorder (PTSD) and mTBI on these associations.ALLO is associated with whole-brain white matter FAT (β=.24, t=3.00, p= .006). This association is significantly modulated by PTSD+mTBI comorbidity (β=.01, t=3.07, p=.003) while an mTBI diagnosis alone did not significantly impact this association (p=.183). There was no significant association between PREGNE and FAT (p=.380). Importantly, lower FAT is associated with poor psychological functioning (β=-.19, t=-2.35, p=.020).This study provides novel insight into a potential common pathophysiological mechanism of neurosteroid dysregulation underlying the high risk for mental health issues in military service members. Further, comorbidity of PTSD and mTBI may bring the compensatory effects of the brain's stress response to their limit. Future research is needed to investigate whether neurosteroid regulation may be a promising tool for restoring brain health and improving psychological functioning.

Background: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations. Objective: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players. Methods: Individual-level proxies (e.g., education) defined reserve. We additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined. Results: Higher reading ability was associated with better attention/information processing (β=0.25; 95% CI, 0.05–0.46), episodic memory (β=0.27; 95% CI, 0.06–0.48), semantic and phonemic fluency (β=0.24; 95% CI, 0.02–0.46; β=0.38; 95% CI, 0.17–0.59), and behavioral regulation (β=–0.26; 95% CI, –0.48, –0.03) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95% CI, 0.25, 0.65), executive functioning (β=0.36; 95% CI, 0.15, 0.57), and semantic fluency (β=0.38; 95% CI, 0.17, 0.59) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95% CI, 0.24, 0.64) and episodic memory (β=0.37; 95% CI, 0.16, 0.58) performance. Conclusion: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population.

Background Exposure to repetitive head impacts (RHI) is associated with an increased risk of later‐life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown. Purpose To investigate whether RHI exposure is associated with later‐life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning. Study Type Retrospective cohort study. Population Seventy‐five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms. Field Strength/Sequence Diffusion‐weighted echo‐planar MRI at 3 T. Assessment Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self‐report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free‐water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1‐7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT‐A) and Part B (TMT‐B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF‐A). Statistical Tests Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures. Results RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT‐A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT‐B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT‐A (FA, r = 0.36; AD, r = 0.28), TMT‐B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29). Data Conclusion These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players. Level of Evidence: 3 Technical Efficacy Stage: 1, publishedVersion

Younger age at first exposure (AFE) to repetitive head impacts while playing American football increases the risk for later-life neuropsychological symptoms and brain alterations. However, it is not known whether AFE is associated with cortical thickness in American football players. Sixty-three former professional National Football League players (55.5 ± 7.7 years) with cognitive, behavioral, and mood symptoms underwent neuroimaging and neuropsychological testing. First, the association between cortical thickness and AFE was tested. Second, the relationship between clusters of decreased cortical thickness and verbal and visual memory, and composite measures of mood/behavior and attention/psychomotor speed was assessed. AFE was positively correlated with cortical thickness in the right superior frontal cortex (cluster-wise P value [CWP] = 0.0006), the left parietal cortex (CWP = 0.0003), and the occipital cortices (right: CWP = 0.0023; left: CWP = 0.0008). A positive correlation was found between cortical thickness of the right superior frontal cortex and verbal memory (R = 0.333, P = 0.019), and the right occipital cortex and visual memory (R = 0.360, P = 0.012). In conclusion, our results suggest an association between younger AFE and decreased cortical thickness, which in turn is associated with worse neuropsychological performance. Furthermore, an association between younger AFE and signs of neurodegeneration later in life in symptomatic former American football players seems likely.

The US Naval Research Laboratory (NRL) has developed clock ensembles for a number of vital GNSS projects and services throughout the US and international community. Some efforts include algorithms for local realization of Coordinated Universal Time; participation in the upgrade of the Global Positioning System (GPS) system time; the initial implementation of a coherent geophysical reference time known as IGS Time (IGST); and development of various Department of Defense (DoD) capabilities for the dissemination and transfer of precise time. This paper will cover the major algorithm components that compute and maintain a robust and stable time reference for the most stringent applications mentioned here. These components include automated alert and response to clock anomalies and reduction of measurement weight in response to large clock measurement residuals. Both real and simulated data have been used to validate the ensemble algorithm and its products for reliable and robust usage in these environments.

The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players.A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60.In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function.In older former football players, WMH may have unique presentations, risk factors, and etiologies.Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n= 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q&nbsp

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells (r = −0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes (r = −0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.

Objectives To determine whether or not automated FreeSurfer segmentation of brain regions considered important in repetitive head trauma can be analyzed accurately without manual correction. Materials and methods 3 T MR neuroimaging was performed with automated FreeSurfer segmentation and manual correction of 11 brain regions in former National Football League (NFL) players with neurobehavioral symptoms and in control subjects. Automated segmentation and manually-corrected volumes were compared using an intraclass correlation coefficient (ICC). Linear mixed effects regression models were also used to estimate between-group mean volume comparisons and to correlate former NFL player brain volumes with neurobehavioral factors. Results Eighty-six former NFL players (55.2 ± 8.0 years) and 22 control subjects (57.0 ± 6.6 years) were evaluated. ICC was highly correlated between automated and manually-corrected corpus callosum volumes (0.911), lateral ventricular volumes (right 0.980, left 0.967), and amygdala-hippocampal complex volumes (right 0.713, left 0.731), but less correlated when amygdalae (right −0.170, left −0.090) and hippocampi (right 0.539, left 0.637) volumes were separately delineated and also less correlated for cingulate gyri volumes (right 0.639, left 0.351). Statistically significant differences between former NFL player and controls were identified in 8 of 11 regions with manual correction but in only 4 of 11 regions without such correction. Within NFL players, manually corrected brain volumes were significantly associated with 3 neurobehavioral factors, but a different set of 3 brain regions and neurobehavioral factor correlations was observed for brain region volumes segmented without manual correction. Conclusions Automated FreeSurfer segmentation of the corpus callosum, lateral ventricles, and amygdala-hippocampus complex may be appropriate for analysis without manual correction. However, FreeSurfer segmentation of the amygdala, hippocampus, and cingulate gyrus need further manual correction prior to performing group comparisons and correlations with neurobehavioral measures., Highlights • Statistical outcomes vary with/without manual correction of FreeSurfer segmentation. • Manual correction of amygdala and hippocampus FreeSurfer segmentation is necessary. • Amygdala-hippocampus complex FreeSurfer segmentation appears adequate. • Corpus callosum and lateral ventricle FreeSurfer segmentation also appears adequate. • Manual correction of cingulate gyrus FreeSurfer segmentation is necessary.

Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume (p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory (p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms (p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life.

The next generation Global Positioning System (GPS) ground control segment will entail a number of GPS ground system upgrades from the existing ground control segment. One of these upgrades is the inclusion of a new modernized timescale algorithm used to generate GPS Time. The timescale is currently being designed as a separate modular unit (given the acronym ETF, or Ensemble Timescale Filter) within the ground system navigation package and is based upon a U-D Kalman Filter implementation that utilizes measurements of all clocks in the ground network and satellite constellation. The new ETF module will include a number of features that improve the stability of the GPS Time timescale and provide more user/operator autonomy to include: multi-weight clock weighting for better handling of mixed clock types in the same filter; automated clock break detection and handling; robust outlier and anomalous clock behavior mitigation; admission of multiple external timescale solutions, including alternate ETF realizations; and adaptive clock parameter estimation. The preliminary results presented in this paper demonstrate some of the performance capabilities and robustness characteristics of the ETF.

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

Posttraumatic stress disorder (PTSD) co-occurring with mild traumatic brain injury (mTBI) is common in veterans. Worse clinical outcome in those with PTSD has been associated with decreased serum neurosteroid levels. Furthermore, decreased cortical thickness has been associated with both PTSD and mTBI. However, it is not known whether decreased neurosteroids are associated with decreased cortical thickness in PTSD co-occurring with mTBI. This study included 141 individuals divided into the following groups: ( a) mTBI group (n = 32 [10 female, 22 male] veterans with a history of mTBI); ( b) PTSD + mTBI group (n = 41 [6 female, 35 male] veterans with current PTSD with a history of mTBI); and ( c) control group (n = 68 [35 female, 33 male] control participants), which were acquired through the Injury and Traumatic Stress (INTRuST) Clinical Consortium. Subjects underwent clinical assessment, magnetic resonance imaging at 3 T, and serum neurosteroid quantifications of allopregnanolone (ALLO) and pregnenolone (PREGN). Group differences in cortical thickness and associations between serum neurosteroid levels and cortical thickness were investigated. Cortical thickness was decreased in the PTSD + mTBI group compared with the other groups. In the PTSD + mTBI group, decreased cortical thickness was also associated with lower serum ALLO (right superior frontal cortex) and lower serum PREGN (left middle temporal and right orbitofrontal cortex). Cortical thickness in the middle temporal and orbitofrontal cortex was associated with PTSD symptom severity. There were no significant associations between neurosteroids and cortical thickness in the mTBI or control groups. Decreased cortical thickness in individuals with PTSD + mTBI is associated with decreased serum neurosteroid levels and greater PTSD symptom severity. Causality is unclear. However, future studies might investigate whether treatment with neurosteroids could counteract stress-induced neural atrophy in PTSD + mTBI by potentially preserving cortical thickness.

Traumatic brain injury (TBI) results from blunt trauma, acceleration–deceleration forces, rotational forces, or blast exposure to the head. The injury involves a heterogenous pattern of focal and/or diffuse axonal injury, leading to a wide range of symptoms. The severity of the injury covers the spectrum from mild to moderate to severe, with severe injury leading to possible coma and even death. The range of symptoms, the variability in treatment options, and the prognosis of TBI, as well as the psychosocial implications, make it a complex injury that often calls upon the services of neurosurgeons, neurologists, psychiatrists, psychologists, and rehabilitation specialists to help patients achieve the best possible outcome. This chapter aims to provide an overview of TBI that includes the classification, epidemiology, aetiology, pathophysiology, clinical symptoms, long-term outcome, diagnostic implications, and differential diagnosis, as well as possible treatment options and future directions for research.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes – the amygdala, hippocampus, and cingulate gyrus – between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 ± 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 ± 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p

To date, few studies have evaluated the contribution of early life experiences to neurocognitive abnormalities observed in posttraumatic stress disorder (PTSD). Childhood maltreatment is common among individuals with PTSD and is thought to catalyze stress-related biobehavioral changes that might impact both brain structure and function in adulthood. The current study examined differences in brain morphology (brain volume, cortical thickness) and neuropsychological performance in individuals with PTSD characterized by low or high self-reported childhood maltreatment, compared with healthy comparison participants. Data were drawn from the INjury and TRaUmatic STress (INTRuST) Clinical Consortium imaging repository, which contains MRI and self-report data for individuals classified as PTSD positive (with and without a history of mild traumatic brain injury [mTBI]), individuals with mTBI only, and healthy comparison participants. The final sample included 36 individuals with PTSD without childhood maltreatment exposure (PTSD, n = 30 with mTBI), 31 individuals with PTSD and childhood maltreatment exposure (PTSD + M, n = 26 with mTBI), and 114 healthy comparison participants without history of childhood maltreatment exposure (HC). The PTSD + M and PTSD groups demonstrated cortical thinning in prefrontal and occipital regions, and poorer verbal memory and processing speed compared to the HC group. PTSD + M participants demonstrated cortical thinning in frontal and cingulate regions, and poorer executive functioning relative to the PTSD and HC groups. Thus, neurocognitive features varied between individuals with PTSD who did versus did not have exposure to childhood maltreatment, highlighting the need to assess developmental history of maltreatment when examining biomarkers in PTSD.

The US Naval Research Laboratory (NRL) has been active in the development of clock ensembling technology over the past decades that has become part of a number of vital GNSS projects and services throughout the US and international community. Some of the efforts include: algorithms and systems for local realization of Coordinated Universal Time designated UTC(k), that designates the site performing the realization; participation in the upgrade of the Global Positioning System (GPS) system time, known as GPS Time (GPST); the initial implementation of a coherent geophysical reference time known as IGS Time (IGST) and its later upgrade; support in the IGS clock product working group’s maintenance of IGST and its viability for the geophysical community; and development of various Department of Defense (DoD) capabilities for the dissemination and transfer of precise time. This paper will cover the major algorithm components that compute and maintain a robust and stable time reference for the most stringent applications mentioned here. These components include: automatic adaptation of clock spectral density parameters to real-time data feed; automated alert and response to adapt to clock anomalies with a latency of hours (dependent upon break severity); and, reduction of measurement weight in response to large clock measurement residuals. Both real and simulated data have been used to validate the timescale algorithm and its products for reliable and robust usage in these environments.

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.

The objective of this study was to examine the contribution of procedural memory to grammar and numeracy skills, which both involve the manipulation of abstract patterns. Seventy-six typically developing children between 5 and 7 years of age were assessed on grammar with a past tense production task and a sentence comprehension task, on numeracy with a counting task and a calculation task, and on procedural memory with a serial reaction time task. Moderate correlations were found between the measures of grammar and numeracy. Moreover, 4 hierarchical linear regressions indicated that procedural memory was associated with calculation but not with counting or grammar skills when age and working memory were taken into account. These novel findings suggest that procedural memory may have a role to play in the development of some numeracy skills. Several possible explanations for the absence of contribution to grammar are considered.

BACKGROUND: Cognitive dysfunction is a fundamental component of serious mental illness (SMI). One key feature of cognitive dysfunction is thought disorder (TD). Although TD is a transdiagnostic feature of SMI, certain TD profiles are strongly associated with individual disorders. The TD phenotypes in clinically unaffected relatives of schizophrenia patients (RelSZ) and relatives of bipolar disorder patients (RelBPD) are qualitatively similar to (but milder than) that found in the respective proband groups. METHODS: Here we examine the heritability, as measured by relative risk, of TD in the largest patient and relatives’ samples studied to date. RESULTS: We report significant heritability of schizophrenia-related TD in SZ and RelSZ (but not in BPD and RelBPD) and of BPD-related TD in BPD and RelBPD (but not in RelSZ). Among RelSZ, 34% (91/268) show the same distinct form of TD seen in schizophrenia (SZ) probands. Among RelBPD, 37% (14/38) show the same distinct form of TD seen in bipolar disorder (BPD) probands. DISCUSSION: These results are consistent with the relative specificity of each TD phenotype and meet the heritability criterion for an endophenotype. The significant heritability and high recurrence rate of TD in unaffected relatives strengthen the rationale for incorporating TD in genetic studies of SMI.

BACKGROUND: Although thought disorder (TD) is a fundamental component of serious mental illness (SMI), qualitatively and quantitatively distinct TD phenotypes are associated with schizophrenia and bipolar disorder, both in patients and in their clinically unaffected biological relatives. Each TD phenotype shows relative specificity in relation to each disorder and with respect to familial aggregation. TD does occur in the general population, even one that has been screened for a personal or family history of psychosis, psychiatric hospitalization and suicide. METHODS: The Thought disorder Index (TDI) was administered to 242 individuals with a diagnosis of schizophrenia (SZ), 272 of their first-degree relatives (RelSZ), 79 individuals with a diagnosis of bipolar disorder (BPD) with psychotic features, 40 of their first-degree relatives, and 184 nonpsychiatric controls (NC). All patients were outpatients at the time of participation. All relatives were clinically unaffected. RESULTS: When TD occurs in nonpsychiatric controls, total TD scores are significantly lower in NC than in SZ patients and RelSZ and the proportion of NC with no TD is significantly higher than it is in SZ and RelSZ. Similarly, TD with “SZ features” (SZTD) and deviant verbalizations (the hallmark of SZTD) are also present in the general population, but at a significantly lower rate and in lower amounts than in SZ patients and RelSZ. Importantly, the SZTD phenotype shows significant heritability (higher relative risk) for SZ but not for bipolar disorder, both in patients and in clinically unaffected relatives, relative to NC despite the fact that some controls have TD. DISCUSSION: The presence of TD in NC is not sufficient to obscure the significant associations of TD phenotypes with SZ and BPD, biological risk for SZ and BPD, or their heritability.

Post-mortem studies reveal a high rate of cavum septi pellucidi (CSP) in chronic traumatic encephalopathy (CTE). It remains, however, to be determined whether or not the presence of CSP may be a potential in vivo imaging marker in populations at high risk to develop CTE. The aim of this study was to evaluate CSP in former professional American football players presenting with cognitive and behavioral symptoms compared with noncontact sports athletes. Seventy-two symptomatic former professional football players (mean age 54.53 years, standard deviation [SD] 7.97) as well as 14 former professional noncontact sports athletes (mean age 57.14 years, SD 7.35) underwent high-resolution structural 3T magnetic resonance imaging. Two raters independently evaluated the CSP, and interrater reliability was calculated. Within National Football League players, an association of CSP measures with cognitive and behavioral functioning was evaluated using a multivariate mixed effects model. The measurements of the two raters were highly correlated (CSP length: rho = 0.98; Intraclass Correlation Coefficient [ICC] 0.99; p

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease confirmed at postmortem. Those at highest risk are professional athletes who participate in contact sports and military personnel who are exposed to repetitive blast events. All neuropathologically confirmed CTE cases, to date, have had a history of repetitive head impacts. This suggests that repetitive head impacts may be necessary for the initiation of the pathogenetic cascade that, in some cases, leads to CTE. Importantly, while all CTE appears to result from repetitive brain trauma, not all repetitive brain trauma results in CTE. Magnetic resonance imaging has great potential for understanding better the underlying mechanisms of repetitive brain trauma. In this review, we provide an overview of advanced imaging techniques currently used to investigate brain anomalies. We also provide an overview of neuroimaging findings in those exposed to repetitive head impacts in the acute/subacute and chronic phase of injury and in more neurodegenerative phases of injury, as well as in military personnel exposed to repetitive head impacts. Finally, we discuss future directions for research that will likely lead to a better understanding of the underlying mechanisms separating those who recover from repetitive brain trauma vs. those who go on to develop CTE.

Several laboratories, including ours, have reported an overrepresentation of craniofacial (CF) anomalies in schizophrenia (SZ). How might this dysmorphology arise in a brain-based disorder? Because the brain and face derive from shared embryologic primordia and morphogenetic forces, maldevelopmental processes may result in both CF and brain dysmorphology.Our approach is 2-pronged. First, we have employed, for the first time in the study of psychiatric disorders, objective measures of CF morphology that utilize an extensive normative database, permitting computation of standardized scores for each subject. Second, we have rendered these findings biologically interpretable by adopting principles of embryology in the analysis of dysmorphology.Dependent measures in this investigation focused on derivatives of specific embryonic primordia and were contrasted among probands with psychotic disorders, their first-degree relatives, and normal controls (NC). Subject groups included patients with a diagnosis of SZ (N = 39) or bipolar (BP) disorder with psychotic features (N = 32), their clinically unaffected relatives (N = 82 and N = 41, respectively), and NC (N = 95) subjects.Anomalies involving derivatives of frontonasal and mandibular embryonic primordia showed a clear association with psychotic illness, as well as familial aggregation in relatives in both diagnostic groups. In contrast, one class of CF anomalies emerged only among SZ probands and their first-degree relatives: dysmorphology arising along the junction of the frontonasal and maxillary prominence derivatives, manifested as marked asymmetries. This class was not overrepresented among the BP patients nor among their relatives, indicating that this dysmorphology appears to be specific to SZ and not a generalized feature of psychosis. We discuss these findings in light of embryologic models that relate brain regions to specific CF areas.

Improvements in cataract surgery and ophthalmic lens technology have turned cataract surgery into a refractive procedure. Patients are expecting that they will no longer require contact lens or glasses for excellent vision. In order to meet the patient’s expectations, the surgeon must be meticulous with preoperative measurements and precise with the intraoperative alignment of the implanted toric lens. Technological advances in intraoperative aberrometry and image guidance software will improve intraoperative alignment of astigmatism correcting lens. Despite the improvements in measurements, unforeseen refractive outcomes will occur and it is critical that the cataract surgeon is equipped to correct any problems. A systematic evaluation should be undertaken to find the source of the error. Complete ocular exam with lens axis measurement, manifest refraction and repeat corneal measurements should be done. Treatment options to correct residual refractive error include toric lens rotation, laser vision corre...

Thought disorder (TD) has long been associated with schizophrenia (SZ) and is now widely recognized as a symptom of mania and other psychotic disorders as well. Previous studies have suggested that the TD found in the clinically unaffected relatives of SZ, schizoaffective and bipolar probands is qualitatively similar to that found in the probands themselves. Here, we examine which quantitative measures of TD optimize the distinction between patients with diagnoses of SZ and bipolar disorder with psychotic features (BP) from nonpsychiatric controls (NC) and from each other. In addition, we investigate whether these same TD measures also distinguish their respective clinically unaffected relatives (RelSZ, RelBP) from controls as well as from each other. We find that deviant verbalizations are significantly associated with SZ and are co-familial in clinically unaffected RelSZ, but are dissociated from, and are not co-familial for, BP disorder. In contrast, combinatory thinking was nonspecifically associated with psychosis, but did not aggregate in either group of relatives. These results provide further support for the usefulness of TD for identifying potential non-penetrant carriers of SZ-risk genes, in turn enhancing the power of genetic analyses. These findings also suggest that further refinement of the TD phenotype may be needed in order to be suitable for use in genetic studies of bipolar disorder.

For parabolic antennas with sufficient surface accuracy, more power can be radiated with a larger aperture size. This paper explores the performance of antennas of various size and reflector depth. The particular focus is on a large inflatable elastic antenna reflector that is supported about its perimeter by a set of elastic tendons and is subjected to a constant hydrostatic pressure. The surface accuracy of the antenna is measured by an RMS calculation, while the reflector phase error component of the efficiency is determined by computing the power density at boresight. In the analysis, the calculation of antenna efficiency is not based on the Ruze Equation. Hence, no assumption regarding the distribution of the reflector surface distortions is presumed. The reflector surface is modeled as an isotropic elastic membrane using a linear stress-strain constitutive relation. Three types of antenna reflector construction are considered: one molded to an ideal parabolic form and two different flat panel design patterns. The flat panel surfaces are constructed by seaming together panels in a manner that the desired parabolic shape is approximately attained after pressurization. Numerical solutions of the model problem are calculated under a variety of conditions in order to estimate the accuracy and efficiency of these antenna systems. In the case of the flat panel constructions, several different cutting patterns are analyzed in order to determine an optimal cutting strategy.

Deficits in the visual working memory (WM) system have been consistently reported in schizophrenia patients, but the relative contribution of initial perceptual encoding to these deficits remains unsettled. We assessed the role of visual perceptual encoding on performance on an object WM task. Schizophrenia patients (N=37) and nonpsychiatric control subjects (N=33) were tested on an object WM task involving three delay periods: 200 msec, 3 sec, and 10 sec. Schizophrenia patients performed significantly less accurately than controls on all three conditions. However, after controlling for the effect of perceptual encoding (accuracy on the 200 msec delay condition) on performance in the two memory load conditions, schizophrenia patients demonstrated intact WM in the 3 sec delay condition, and showed a weak trend for decreased accuracy on the 10 sec delay compared with controls. Analysis of individual differences in pattern of performance revealed that a distinct subgroup of poor encoder patients had a significantly greater reduction in accuracy at 3 sec than the other patient subgroups and controls. In contrast, among schizophrenia patients who performed poorly on the 10 sec delay, accuracy was equivalently reduced independent of encoding ability. WM deficits in controls were independent of encoding ability at both delay intervals. These results indicate that encoding ability titrates the magnitude of WM impairment in schizophrenia patients but not in controls, and that heterogeneity has to be taken into account to correctly estimate the effects of perceptual encoding on visual object WM deficits in schizophrenia.

Preferential attention to biological motion can be seen in typically developing infants in the first few days of life and is thought to be an important precursor in the development of social communication. We examined whether children with autism spectrum disorder (ASD) aged 3-7 years preferentially attend to point-light displays depicting biological motion. We found that children with ASD did not preferentially attend to biological motion over phase-scrambled motion, but did preferentially attend to a point-light display of a spinning top rather than a human walker. In contrast a neurotypical matched control group preferentially attended to the human, biological motion in both conditions. The results suggest a core deficit in attending to biological motion in ASD.

We discuss the dynamics and stability of a rigid rimless spoked wheel, or regular polygon, confined to ‘rolling’ in a vertical plane uphill or downhill. The wheel has smooth inverted pendulum motions punctuated by repeated dissipative spoke impacts. It is a simple mechanical analogue to legged locomotion. The problem is completely soluble in closed form. We derive a return map for the full nonlinear system. The map has two asymptotically stable fixed points whose existence depends on slope angle: (1) standing still on two spokes and (2) limit cycle motion. For small slopes, only standing still exists; for intermediate slopes, the fixed points coexist; and, for large slopes, only limit cycles exist. We also completely define their basins of attraction. The rimless wheel's dynamical behaviour is analogous to two other dissipative systems, one smooth (a constantly forced, damped pendulum) and the other non-smooth (a 2D discrete skate).

The delineation of schizophrenia-related symptomatology is critical to informative clinical phenotyping in linkage studies. A minority of first-degree relatives of schizophrenia and schizoaffective probands (RelSZSA) qualifies for a clinical diagnosis in the schizophrenia spectrum. Schizotypal personality disorder (SPD) is a key component of this spectrum, largely because of its relatively specific familial aggregation in relatives. The criteria for SPD were not developed for the purpose of identifying RelSZSA, however, and SPD is not a homogeneous clinical disorder, potentially introducing false positives and false negatives into affectedness classifications. In this study we used logistic regression (LR) to identify the combination of clinical signs and symptoms that maximized the discrimination between nonpsychotic first-degree RelSZSA (n=241) and controls (n=161). Three variables contributed significantly to optimizing this distinction: no close friends or confidants other than family members, social isolation and irritability. The combination of deviant LR scores and schizophrenia-spectrum psychotic disorders had greater sensitivity for identifying RelSZSA, 23.7%, than SPD and schizophrenia-spectrum psychotic disorders, 16%. Importantly, the diagnosis of SPD and deviant LR scores were not significantly correlated. Most individuals with deviant LR scores did not meet criteria for a diagnosis of SPD and only a minority of those who were diagnosed with SPD had deviant LR scores. Since misclassification of gene carriers as non-gene carriers in linkage analyses increases the risk of false negatives, it may be advantageous to tailor the definition of the clinical phenotype to those aspects of social-interpersonal dysfunction that optimize the discrimination of RelSZSA from controls.

Recent findings suggest that children with autism may be impaired in the perception of biological motion from moving point-light displays. Some children with autism also have abnormally high motion coherence thresholds. In the current study we tested a group of children with autism and a group of typically developing children aged 5 to 12 years of age on several motion perception tasks, in order to establish the specificity of the biological motion deficit in relation to other visual discrimination skills. The first task required the recognition of biological from scrambled motion. Three quasi-psychophysical tasks then established individual thresholds for the detection of biological motion in dynamic noise, of motion coherence and of form-from-motion. Lastly, individual thresholds for a task of static perception--contour integration (Gabor displays)--were also obtained. Compared to controls, children with autism were particularly impaired in processing biological motion in relation to any developmental measure (chronological or mental age). In contrast, there was some developmental overlap in ability to process other types of visual motion between typically developing children and the children with autism, and evidence of developmental change in both groups. Finally, Gabor display thresholds appeared to develop typically in children with autism.

Few materials are available to assess speech perceptual skills in young children without hearing impairments. However, children with a range of developmental conditions are at risk of speech discrimination deficits. Tasks that reliably assess speech perception skills are thus necessary for research and clinical practice. The development and application of two speech perception tests are described. Data were collected from 105 children, aged 4-5 years, attending mainstream schools, on two tasks, mispronunciation detection and non-word XAB, in quiet and in a background of multi-talker babble. Children's receptive language skills were also measured. Performance on mispronunciation detection was significantly better than on the XAB non-word task, and significantly better in quiet than in babble. Performance significantly improved with age, and speech discrimination was significantly related to receptive language abilities. Scores obtained in quiet and in babble were highly correlated and findings suggest there may be no advantage to testing in noise, except to avoid ceiling effects on performance. These tasks prove useful in the assessment of young children who may have speech discrimination deficits.

This study was designed to test three competing hypotheses (impaired configural processing; impaired Theory of Mind; atypical amygdala functioning) to explain the basic facial expression recognition profile of adults with autism spectrum disorders (ASD). In Experiment 1 the Ekman and Friesen (1976) series were presented upright and inverted. Individuals with ASD were significantly less accurate than controls at recognising upright facial expressions of fear, sadness and disgust and their pattern of errors suggested some configural processing difficulties. Impaired recognition of inverted facial expressions suggested some additional difficulties processing the facial features. Unexpectedly, the clinical group misidentified fear as anger. In Experiment 2 feature processing of facial expressions was investigated by presenting stimuli in a piecemeal fashion, starting with either just the eyes or the mouth. Individuals with ASD were impaired at recognising fear from the eyes and disgust from the mouth; they al...

The nature and extent of face-processing impairments in individuals with autism spectrum disorder (ASD) remain contentious. The aim of this research study is to assess the face- and object-processing performance of individuals with ASD compared with typically developing controls. Our hypothesis was that individuals with ASD would be significantly impaired on tests of face processing but show intact object processing. More specifically, we tested two competing hypotheses to explain face-processing deficits: holistic hypothesis; second-order configural hypothesis. Twenty-six able adults with ASD and 26 intelligence quotient-matched typically developing controls completed two computerized tests of face and object discrimination. In task 1, the first picture (faces or cars) in a pair was presented as quickly as 40 msec to test holistic processing. In task 2, the decision was whether pairs of faces or houses had been altered in terms of the features or the distance between the features (the second-order configural properties). Individuals with ASD were impaired on all tests of face processing but showed intact object processing and the pattern of findings favored the holistic hypothesis. The heterogeneous pattern of performance in the clinical group showed that some individuals with ASD perform similarly to typically developing individuals in their face-processing skills, whereas others are more accurate in object processing compared with face processing.

The purpose of this study was to examine whether individuals with autism spectrum disorders (ASD) use the same cognitive strategies as typically developing individuals when processing eye-gaze direction. Subjects viewed pictures of whole faces, the eye region alone, and pairs of arrows presented for 40, 70, or 100 ms, and responded according to the direction the eyes were looking or the arrows pointing (left, right, or straight ahead). Experiment 1 demonstrated that typically developing adults ( n = 41) were more accurate and showed shorter reaction times when judging direction of averted eye gaze in the context of the whole face than when only the eyes were visible (eye-region-alone condition). Furthermore, in the eye-region-alone condition participants were more accurate and faster at judging direct eye gaze than averted eye gaze. The same task was used in experiment 2 to compare the performance of a group of individuals with ASD ( n = 24) with that of a group of IQ-matched typically developing individuals ( n = 26). The performance of the control participants was identical to that observed in experiment 1. Individuals with ASD were able to judge eye-gaze direction accurately at short exposure duration; however, they failed to show the typical advantage for judging averted gaze in whole faces and the increased sensitivity to direct gaze in the eye-region-alone condition. The findings are discussed in terms of impairments to discrete gaze-processing and face-processing mechanisms, and the connectivity between these mechanisms.

Reading and speechreading are both visual skills based on speech and language processing. Here we explore individual differences in speechreading in profoundly prelingually deaf adults, hearing adults with a history of dyslexia, and hearing adults with no history of a literacy disorder. Speechreading skill distinguished the three groups: the deaf group were better speechreaders than hearing controls, who were better than the group with a history of dyslexia. The dyslexic group, while within range of hearing controls in terms of reading, nevertheless showed a residual deficit in speech/language processing when tested with silent speech. Within-group correlations suggested different associations between speechreading subtasks, reading and language skills. In particular, in the deaf and dyslexic groups, but not in the hearing controls, speechreading skill correlated with reading ability.

Background: The identification of mutations in specific genes could enable personalized, “medically actionable” treatment interventions. We identified a potentially informative mutation, a rare structural rearrangement that includes a triplication of the glycine decarboxylase gene (GLDC). GLDC is the enzyme that catabolizes glycine, a precursor of d-serine, both of which are coagonists at the NMDA receptor (NMDAR). Four copies of GLDC would be expected to increase the degradation of glycine, resulting in low levels of brain glycine and NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of psychotic disorders. Carriers of this mutation may especially benefit from augmentation of psychotropic drug treatment with NMDAR coagonists. Methods: We carried out a double-blind placebo-controlled clinical trial (6 weeks per arm) of d-cycloserine (DCS), a partial agonist at the NMDAR glycine site, followed by 24 weeks of open-label DCS, in 2 related individuals who are carriers of the GLDC mutation, one with a diagnosis of bipolar disorder with psychotic features and the other with a diagnosis of schizo-affective disorder. Clinical assessments were carried out every 2 weeks using the PANSS, BPRS, YMRS, HAM-D, and CGI. The same individuals previously completed trials of acute and chronic glycine augmentation, which produced significant symptom improvement but caused problematic GI side effects. Results: Full trial results are still pending as the blind has not yet been broken. However, blinded analyses show significant changes in severity of clinical symptoms, indicating that DCS either produced dramatic clinical improvements or worsened symptom severity. Complete, unblinded results will be available and presented at the meeting. Conclusion: DCS may be an effective augmentation in psychotic individuals selected for being carriers of duplications or triplications of GLDC, or who are carriers of other genetic variants resulting in NMDAR hypofunction. If DCS reduced symptom severity, it is a preferable alternative to glycine as a targeted treatment in light of its clinical efficacy, ease of administration, and favorable side effect profile.

Existing data demonstrate a developmental trend in the way in which highly familiar faces are recognized, such that young children rely more on the outer facial features (the hairline, chin and ears) than the inner facial features (the eyes, nose and mouth) and adults demonstrate the reverse pattern. However, little is known about the developmental pattern of importance of inner and outer facial features for recognizing people who are not highly familiar. Here we report a study which attempts to describe this pattern. Using a two-alternative forced-choice procedure, we presented 5-, 7-, and 9-year-olds and adults (N = 22 in each group) with the task of recognizing an experimentally familiarized face (initially seen in a short video) from a still picture of either the whole face, just the inner, or just the outer parts. The results showed that, for all ages, recognition was faster (and in most cases, more accurate) for outer features alone than for inner features alone (and was fastest for whole faces). These data demonstrate the importance of outer facial features for the recognition of relatively unfamiliar faces. Taken together with previous findings, they enhance our picture of the effects of age and experience with individual faces on recognition and configural processing.

Face recognition is thought to rely on configural visual processing, Where face recognition impairments have been identified, qualitatively delayed or anomalous configural processing has also been found. A group of women with Turner syndrome (TS) with monosomy for a single maternal X chromosome (45, X-super(m)) showed an impairment in face recognition skills compared with normally developing women. However, normal configural face-processing abilities were apparent. The ability to recognize facial expressions of emotion, particularly fear, was also impaired in this TS subgroup. Face recognition and fear recognition accuracy were significantly correlated in the female control group but not in women with TS. The authors therefore suggest that anomalies in amygdala function may be a neurological feature of TS of this karyotype.