Assessment of Spaceflight Medical Conditions' and Treatments' Potential Impacts on Behavioral Health and Performance.

Long-duration space exploration missions will pose significant risks to the physical and behavioral health and performance of the crew. We documented the presence and frequency of (1) behavioral health and performance (BHP)-relevant symptoms for each condition in NASA's Exploration Medical Conditions List (EMCL), (2) the BHP-relevant effects of applicable medical treatments in the current International Space Station (ISS) On-Orbit Medication List, (3) the breadth of potential BHP impacts of spaceflight medical treatments, and (4) the likelihood of adverse BHP effects of treating spaceflight medical conditions. BHP symptoms and effects were categorized by the six neurobehavioral domains of the National Institute of Mental Health's Research Domain Criteria (RDoC) framework. Including the cognitive effects of acute and chronic pain (e.g., attention, memory), 94% of spaceflight medical conditions include symptoms relevant to Cognitive Systems (e.g., attention deficits, confusion, psychosis), 36% include symptoms relevant to Negative Valence Systems (e.g., anxiety), 32% include symptoms relevant to Arousal and Regulatory Systems (e.g., sleep disturbances), 22% include symptoms relevant to Sensorimotor Systems (e.g., dizziness), 19% include symptoms relevant to Positive Valence Systems (e.g., mania), and 11% include symptoms relevant to Social Processes (e.g., social withdrawal). Only 2% of spaceflight medical conditions have no documented BHP symptoms. Of the spaceflight medical treatments, 63% affect Arousal and Regulatory Systems, 60% affect Sensorimotor Systems, 59% affect Cognitive Systems, 53% affect Negative Valence Systems, 38% affect Positive Valence Systems, and 31% affect Social Processes. The breadth of potential BHP impacts was bimodal, in that 27% of spaceflight medical treatments had no documented BHP effects; however, 27% of treatments may produce adverse effects across all six neurobehavioral domains. Historical prevalence data on medical conditions, symptoms, and complaints from 14 years of International Space Station operations coupled with documented BHP effects of recommended treatments indicates the potential for up to 481 adverse BHP effects of spaceflight medical treatments per person-year. Assessing the potential BHP impacts of spaceflight medical conditions and their treatments highlights the interactive nature of operational risks, and can provide an enhanced evidence base to support integrated research and countermeasure development strategies for long-duration exploration missions.

Corpus callosum size and diffusion tensor anisotropy in adolescents and adults with schizophrenia.

The corpus callosum has been implicated as a region of dysfunctional connectivity in schizophrenia, but the association between age and callosal pathology is unclear. Magnetic resonance imaging (MRI) and diffusion-tensor imaging (DTI) were performed on adults (n=34) and adolescents (n=17) with schizophrenia and adult (n=33) and adolescent (n=15) age- and sex-matched healthy controls. The corpus callosum was manually traced on each participant׳s MRI, and the DTI scan was co-registered to the MRI. The corpus callosum was divided into five anteroposterior segments. Area and anisotropy were calculated for each segment. Both patient groups demonstrated reduced callosal anisotropy; however, the adolescents exhibited reductions mostly in anterior regions while the reductions were more prominent in posterior regions of the adults. The adolescent patients showed greater decreases in absolute area as compared with the adult patients, particularly in the anterior segments. However, the adults showed greater reductions when area was considered relative to whole brain white matter volume. Our results suggest that the initial stages of the illness are characterized by deficiencies in frontal connections, and the chronic phase is characterized by deficits in the posterior corpus callosum; or, alternatively, adolescent-onset schizophrenia may represent a different or more severe form of the illness.

Cingulum bundle integrity associated with delusions of control in schizophrenia: Preliminary evidence from diffusion-tensor tractography.

BACKGROUND: Delusions of control are among the most distinctive and characteristic symptoms of schizophrenia. Several theories have been proposed that implicate aberrant communication between spatially disparate brain regions in the etiology of this symptom. Given that white matter fasciculi represent the anatomical infrastructure for long-distance communication in the brain, the present study investigated whether delusions of control were associated with structural abnormalities in four major white matter fasciculi. METHODS: Ten schizophrenia patients with current delusions of control, 13 patients with no clinical history of delusions of control, and 12 healthy controls underwent a Diffusion-Tensor Imaging (DTI) scan. Deterministic tractography was used to extract the corpus callosum, superior longitudinal fasciculus, arcuate fasciculus, and cingulum bundle. The structural integrity of these four fasciculi was quantified with fractional anisotropy (FA) and compared between groups. RESULTS: The patients with delusions of control exhibited significantly lower FA in all four fasciculi, relative to the healthy controls. Furthermore, the patients with delusions of control also exhibited significantly lower FA in the cingulum bundle relative to patients without a history of this symptom, and this difference remained significant when controlling for between-group differences in global SAPS score and medication dosage. CONCLUSIONS: The results suggest that structural damage to the cingulum bundle may be involved in the etiology of delusions of control, possibly because of its role in connecting the action initiation areas of the premotor cortex with the cingulate gyrus.

Cingulum bundle diffusivity and delusions of reference in first episode and chronic schizophrenia.

The goal of this study was to assess integrity of the cingulum bundle in patients diagnosed with first episode schizophrenia, chronic schizophrenia, and matched controls as well as to determine the relationship between diffusion measures of cingulum bundle integrity and severity of patients' delusions of reference. Participants, who comprised 18 first episode patients, 20 chronic patients, and two groups of matched controls (20 subjects in each), underwent 3 T MRI diffusion tensor imaging. Patients diagnosed with schizophrenia (chronic+first episode) showed decreased fractional anisotropy in the right cingulum bundle compared with controls. First episode patients exhibited higher trace bilaterally, compared with matched controls, and on the left compared with chronic patients. Axial diffusivity was increased in first episode patients, bilaterally, compared with matched controls and chronic patients. Radial diffusivity was also higher, bilaterally, in first episode patients compared with matched controls, and on the right compared with chronic patients. Trace diffusity and radial diffusivity in first episode patients were significantly correlated with increased severity of delusions of reference. Given that the abnormalities were present only in first episode patients and were not observed in chronic cases, it appears that they normalize over time. These abnormalities in first episode patients involved diffusivity measures in all directions (trace, radial and axial), suggesting a likely acute, partially reversible process in which there is an increase in brain water content, i.e., swelling, edema, or inflammation, that may reflect an early neuroinflammatory response in first episode patients.

Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes.

Early detection of brain abnormalities at the preclinical stage can be useful for developing preventive interventions to abate cognitive decline. We examined whether middle-aged type 2 diabetic patients show reduced white matter integrity in fiber tracts important for cognition and whether this abnormality is related to preestablished altered resting-state functional connectivity in the default mode network (DMN). Diabetic and nondiabetic participants underwent diffusion tensor imaging, functional magnetic resonance imaging, and cognitive assessment. Multiple diffusion measures were calculated using streamline tractography, and correlations with DMN functional connectivity were determined. Diabetic patients showed lower fractional anisotropy (FA) (a measure of white matter integrity) in the cingulum bundle and uncinate fasciculus. Control subjects showed stronger functional connectivity than patients between the posterior cingulate and both left fusiform and medial frontal gyri. FA of the cingulum bundle was correlated with functional connectivity between the posterior cingulate and medial frontal gyrus for combined groups. Thus, middle-aged patients with type 2 diabetes show white matter abnormalities that correlate with disrupted functional connectivity in the DMN, suggesting that common mechanisms may underlie structural and functional connectivity. Detecting brain abnormalities in middle age enables implementation of therapies to slow progression of neuropathology.

Fiber geometry in the corpus callosum in schizophrenia: evidence for transcallosal misconnection.

BACKGROUND: Structural abnormalities in the callosal fibers connecting the heteromodal association areas of the prefrontal and temporoparietal cortices bilaterally have been suggested to play a role in the etiology of schizophrenia. AIMS: To investigate for geometric abnormalities in these callosal fibers in schizophrenia patients by using a novel Diffusion-Tensor Imaging (DTI) metric of fiber geometry named Shape-Normalized Dispersion (SHD). METHODS: DTIs (3T, 51 gradient directions, 1.7mm isotropic voxels) were acquired from 26 schizophrenia patients and 23 matched healthy controls. The prefrontal and temporoparietal fibers of the corpus callosum were extracted by means of whole-brain tractography, and their mean SHD calculated. RESULTS: The schizophrenia patients exhibited subnormal levels of SHD in the prefrontal callosal fibers when controlling for between-group differences in Fractional Anisotropy. Reduced SHD could reflect either irregularly turbulent or inhomogeneously distributed fiber trajectories in the corpus callosum. CONCLUSIONS: The results suggest that the transcallosal misconnectivity thought to be associated with schizophrenia could reflect abnormalities in fiber geometry. These abnormalities in fiber geometry could potentially be underpinned by neurodevelopmental irregularities.

Brodmann area analysis of white matter anisotropy and age in schizophrenia.

Diffusion tensor and structural MRI images were acquired on ninety-six patients with schizophrenia (69 men and 27 women) between the ages of 18 and 79 (mean=39.83, SD=15.16 DSM-IV diagnosis of schizophrenia according to the Comprehensive Assessment of Symptoms and History). The patients reported a mean age of onset of 23 years (range=13-38, SD=6). Patients were divided into an acute subgroup (duration ≤3 years, n=25), and a chronic subgroup (duration >3 years, n=64). Ninety-three mentally normal comparison subjects were recruited; 55 men and 38 women between the ages of 18 and 82 (mean=35.77, SD=18.12). The MRI images were segmented by Brodmann area, and the fractional anisotropy (FA) for the white matter within each Brodmann area was calculated. The FA in white matter was decreased in patients with schizophrenia broadly across the entire brain, but to a greater extent in white matter underneath frontal, temporal and cingulate cortical areas. Both normals and patients with schizophrenia showed a decrease in anisotropy with age but patients with schizophrenia showed a significantly greater rate of decrease in FA in Brodmann area 10 bilaterally, 11 in the left hemisphere and 34 in the right hemisphere. When the effect of age was removed, patients ill more than three years showed lower anisotropy in frontal motor and cingulate white matter in comparison to acute patients ill three years or less, consistent with an ongoing progression of the illness.

Predicting inter-hemispheric transfer time from the diffusion properties of the corpus callosum in healthy individuals and schizophrenia patients: a combined ERP and DTI study.

BACKGROUND: Several theories of schizophrenia have emphasized the role of aberrant neural timing in the etiology of the disease, possibly as a consequence of conduction delays caused by structural damage to the white-matter fasciculi. Consistent with this theory, increased inter-hemispheric transmission times (IHTTs) to unilaterally-presented visual stimuli have been reported in patients with schizophrenia. The present study investigated whether or not these IHTT abnormalities could be underpinned by structural damage to the visual fibers of the corpus callosum. METHODS: Thirty three schizophrenia patients and 22 matched controls underwent Event Related Potential (ERP) recording, and a subset of 19 patients and 16 controls also underwent 3T Diffusion-Tensor Imaging (DTI). Unilateral visual stimuli (squares, 2×2 degrees) were presented 6 degrees lateral to either side of a central fixation point. IHTTs (ipsilateral minus contralateral latencies) were calculated for the P1 and N1 components at parietal-occipital sites in current source density-transformed ERPs. The visual fibers of the corpus callosum were extracted with streamline tractography and the diffusion metrics of Fractional Anisotropy (FA) and Mode calculated. RESULTS: While both subject groups exhibited highly significant IHTTs across a range of posterior electrode pairs, and significantly shorter IHTTs from left-to-right hemisphere than vice versa, no significant groupwise differences in IHTT were observed. However, participants' IHTTs were linearly related to their FA and Mode, with longer IHTTs being associated with lower FA and more prolate diffusion ellipsoids. CONCLUSIONS: These results suggest that IHTTs are estimable from DTI measures of white matter integrity. In light of the range of diffusion abnormalities that have been reported in patients with schizophrenia, particularly in frontal fasciculi, these results support the conjecture that schizophrenia is associated with abnormalities in neural timing.

Corpus callosum abnormalities and their association with psychotic symptoms in patients with schizophrenia.

BACKGROUND: While the neuroanatomical underpinnings of the functional brain disconnectivity observed in patients with schizophrenia (SZ) remain elusive, white matter fiber bundles of the brain are a likely candidate, given that they represent the infrastructure for long-distance neural communication. METHODS: This study investigated for diffusion abnormalities in 19 patients with chronic SZ, relative to 19 matched control subjects, across tractography-defined segments of the corpus callosum. Diffusion-weighted images were acquired with 51 noncollinear gradients on a 3T scanner (1.7 mm isotropic voxels). The corpus callosum was extracted by means of whole-brain tractography and automated fiber clustering and was parcelled into six segments on the basis of fiber trajectories. The diffusion indexes of fractional anisotropy (FA) and mode were calculated for each segment. RESULTS: Relative to the healthy control subjects, the SZ patients exhibited mode increases in the parietal fibers, suggesting a relative absence of crossing fibers. Schizophrenia patients also exhibited FA reductions in the frontal fibers, which were underpinned by increases in radial diffusivity, consistent with myelin abnormalities. Significant correlations were observed between patients' degree of reality distortion and their FA and radial diffusivity, such that the most severely psychotic patients were the least abnormal in terms of their frontal fiber diffusivity. CONCLUSIONS: The SZ patients exhibited a variety of diffusion abnormalities in the corpus callosum, which were related to the severity of their psychotic symptoms. To the extent that diffusion abnormalities influence axonal transmission velocities, these results provide support for those theories that emphasize neural timing abnormalities in the etiology of schizophrenia.

Diffusion tensor anisotropy in the cingulate gyrus in schizophrenia.

It has been proposed that schizophrenia results partly from altered brain connectivity. The anterior cingulate cortex in particular has been demonstrated to be affected in schizophrenia, with studies reporting reduced volume, altered neuronal arrangement, decreased anisotropy in diffusion tensor images, and hypometabolism. We used a 3T Siemens scanner to acquire structural and diffusion tensor imaging in age-and sex-matched groups of 41 adults with chronic schizophrenia, 6 adults with recent-onset schizophrenia, and 38 healthy control subjects. We manually traced the anterior and posterior cingulate gyri on all subjects and then compared the volume and anisotropy across groups for the left and right anterior and posterior cingulate gyri. The anterior cingulate gyrus was divided axially into six equal segments, and the posterior cingulate gyrus into two segments. Volume was calculated for the anterior and posterior gyri, and average anisotropy was then calculated for each individual segment, looking separately at gray and white matter. We found decreased overall relative left and right gray matter volume in the anterior cingulate gyrus in persons with schizophrenia compared with healthy controls. Additionally, in both gray and white matter of the cingulate, we found that recent-onset patients had the highest anisotropy, chronic patients had the lowest, and controls were intermediate. These results provide additional evidence for the presence of both white and gray matter abnormalities in the cingulate gyrus, which has been implicated in schizophrenia.

Age and diffusion tensor anisotropy in adolescent and adult patients with schizophrenia.

Findings of white matter pathology as indicated by diffusion tensor anisotropy values in schizophrenia are well established, but the differences in this measure between the onset of the disease and the chronic state are not well known. To investigate the differences between these states in the progression of the disease of schizophrenia we acquired 1.5 T diffusion tensor anisotropy images on 35 adult patients with schizophrenia and schizoaffective disorder, 23 adolescents having their first psychotic episode, and age and sex matched controls (33 adults and 15 adolescents). Regions of interest in major cortical white matter tracts chosen as salient to the prefrontal executive deficit in schizophrenia were assessed using stereotaxic coordinates from the Talairach and Tournoux atlas. Regions of each tract along anterior-posterior and/or inferior-superior directions in both hemispheres were evaluated in multiway ANOVA. Tracts between the frontal lobe and other brain regions, but not temporal, occipital and interhemispheric tracts, showed a differential aging pattern in normals and patients indicating that the white matter pathology in these regions is not stable between the onset and the chronic state in schizophrenia. This suggests that tracts involved in the connectivity of the temporal lobe white matter deficits were already well in place in adolescent patients, while frontal lobe pathology continues to develop from adolescence to adulthood.

Diffusion tensor anisotropy in adolescents and adults.

We acquired diffusion tensor images on 33 normal adults aged 22-64 and 15 adolescents aged 14-21. We assessed relative anisotropy in stereotaxically located regions of interest in the internal capsule, corpus callosum, anterior thalamic radiations, frontal anterior fasciculus, fronto-occipital fasciculus, temporal lobe white matter, cingulum bundle, frontal inferior longitudinal fasciculus, frontal superior longitudinal fasciculus, and optic radiations. All of these structures except the optic radiations, corpus callosum, and frontal inferior longitudinal fasciculus exhibited differences in anisotropy between adolescents and adults. Areas with anisotropy increasing with age included the anterior limb of the internal capsule, superior levels of the frontal superior longitudinal fasciculus and the inferior portion of the temporal white matter. Areas with anisotropy decreasing with age included the posterior limb of the internal capsule, anterior thalamic radiations, fronto-occipital fasciculus, anterior portion of the frontal anterior fasciculus, inferior portion of the frontal superior longitudinal fasciculus, cingulum bundle and superior portion of the temporal axis. Sex differences were found in the majority of areas but were most marked in the cingulum bundle and internal capsule. These results suggest continuing white matter development between adolescence and adulthood.

Internal capsule, corpus callosum and long associative fibers in good and poor outcome schizophrenia: a diffusion tensor imaging survey.

BACKGROUND: Prior voxelwise studies of white matter anisotropy found widespread reductions involving all major fiber tracts of the schizophrenic brain. We set out to confirm these exploratory findings and evaluate their relation to illness severity using a hypothesis-driven region-of-interest approach. METHODS: 104 schizophrenia patients (51 with good outcomes, 53 with poor outcomes) and 41 matched comparison subjects participated in the study. Regions of interest were selected on the basis of published voxelwise findings and placed within major fiber tracts using Talairach's stereotaxic coordinates. RESULTS: Fractional anisotropy reductions in schizophrenia patients were confirmed in the left cingulum, anterior thalamic radiation, fronto-occipital and inferior longitudinal fasciculi, as well as bilaterally in the corpus callosum, anterior and posterior limbs of internal capsule, superior longitudinal fasciculus, optic radiation, and frontotemporal extrafascicular white matter. Anisotropy reductions were more extensive in patients with poor outcomes ("Kraepelinian"), particularly in the posterior corpus callosum, fronto-occipital fasciculus, left optic radiation and frontotemporal white matter. Lower anisotropy in the right hemisphere tracts was associated with more prominent positive symptomatology, whereas negative symptoms were inversely associated with anisotropy values in both hemispheres. CONCLUSIONS: These results support a global neural disconnectivity in schizophrenia patients, which is more severe in those with poor clinical outcomes.

Diffusion tensor imaging in schizophrenia.

BACKGROUND: Alignment of white matter axons as inferred from diffusion tensor imaging has indicated changes in schizophrenia in frontal and frontotemporal white matter. METHODS: Diffusion tensor anisotropy and anatomical magnetic resonance images were acquired in 64 patients with schizophrenia and 55 normal volunteers. Anatomical images were acquired with a magnetization prepared rapid gradient echo sequence, and diffusion tensor images used a pulsed gradient spin-echo acquisition. Images were aligned and warped to a standard brain, and anisotropy in normal volunteers and patients was compared using significance probability mapping. RESULTS: Patients showed widespread areas of reduced anisotropy, including the frontal white matter, the corpus callosum, and the frontal longitudinal fasciculus. CONCLUSIONS: These findings, which are consistent with earlier reports of frontal decreases in anisotropy, demonstrate that the effects are most prominent in frontal and callosal areas and are particularly widespread in frontal white matter regions.

Functional MRI of visuospatial working memory in schizotypal personality disorder: a region-of-interest analysis.

BACKGROUND: Functional MRI studies have begun to identify neural networks implicated in visuo-spatial working memory in healthy volunteers and patients with schizophrenia. The study of schizotypal personality disorder (SPD) provides regional analysis in unmedicated patients in the schizophrenia spectrum. METHOD: Unmedicated patients with SPD by DSM-IV criteria and normal controls were assessed with fMRI while performing a visuo-spatial working-memory task. It required the subjects to retain the location of three dots located on the circumference of an imaginary circle and then respond to a query display in which one dot was presented and the subject required to press a button to indicate whether the probe dot location was previously displayed. Subject groups did not differ significantly in spatial memory scores. The exact Talairach and Tournoux coordinates of brain areas previously reported to show activation with spatial memory tasks were assessed. RESULTS: The majority of these locations showed BOLD response activation significantly less in patients during the memory retention period, including the left ventral prefrontal cortex, superior frontal gyrus, intraparietal cortex and posterior inferior gyrus. Regions in the right middle prefrontal and prestriate cortex showed greater activation at a trend level for patients with SPD than for normal controls. In addition, we replicated the findings of increased activation with the task in healthy volunteers in the premotor areas, ventral prefrontal cortex and parietal cortex. CONCLUSIONS: SPD patients show decreased activation compared to healthy volunteers in key frontal regions and we also provided a partial replication of findings reported in healthy subjects.