A novel sorting method for the enrichment of early human spermatocytes from clinical biopsies.

OBJECTIVE: To determine if early spermatocytes can be enriched from a human testis biopsy using fluorescence-activated cell sorting (FACS). DESIGN: Potential surface markers for early spermatocytes were identified using bioinformatics analysis of single-cell RNA-sequenced human testis tissue. Testicular sperm extraction samples from three participants with normal spermatogenesis were digested into single-cell suspensions and cryopreserved. Two to four million cells were obtained from each and sorted by FACS as separate biologic replicates using antibodies for the identified surface markers. A portion from each biopsy remained unsorted to serve as controls. The sorted cells were then characterized for enrichment of early spermatocytes. SETTING: A laboratory study. PATIENTS: Three men with a diagnosis of obstructive azoospermia (age range, 30-40 years). INTERVENTION: None. MAIN OUTCOME MEASURES: Sorted cells were characterized for RNA expression of markers encompassing the stages of spermatogenesis. Sorting markers were validated by their reactivity on human testis formalin-fixed paraffin-embedded tissue. RESULTS: Serine protease 50 (TSP50) and SWI5-dependent homologous recombination repair protein 1 were identified as potential surface proteins specific for early spermatocytes. After FACS sorting, the TSP50-sorted populations accounted for 1.6%-8.9% of total populations and exhibited the greatest average-fold increases in RNA expression for the premeiotic marker stimulated by retinoic acid (STRA8), by 23-fold. Immunohistochemistry showed the staining pattern for TSP50 to be strong in premeiotic undifferentiated embryonic cell transcription factor 1-/doublesex and Mab-3 related transcription factor 1-/STRA8+ spermatogonia as well as SYCP3+/protamine 2- spermatocytes. CONCLUSION: This work shows that TSP50 can be used to enrich early STRA8-expressing spermatocytes from human testicular biopsies, providing a means for targeted single-cell RNA sequencing analysis and in vitro functional interrogation of germ cells during the onset of meiosis. This could enable investigation into details of the regulatory pathways underlying this critical stage of spermatogenesis, previously difficult to enrich from whole tissue samples.

Differentiation of Peritubular Myoid-Like Cells from Human Induced Pluripotent Stem Cells.

Infertility affects 10-15% of couples, with half attributed to male factors. An improved understanding of the cell-type-specific dysfunction contributing to male infertility is needed to improve available therapies; however, human testicular tissues are difficult to obtain for research purposes. To overcome this, researchers have begun to use human induced pluripotent stem cells (hiPSCs) to generate various testis-specific cell types in vitro. Peritubular myoid cells (PTMs) are one such testicular cell type that serves a critical role in the human testis niche but, to date, have not been derived from hiPSCs. This study set forth to generate a molecular-based differentiation method for deriving PTMs from hiPSCs, mirroring in vivo patterning factors. Whole transcriptome profiling and quantitative polymerase chain reaction (qPCR) show that this differentiation method is sufficient to derive cells with PTM-like transcriptomes, including upregulation of hallmark PTM functional genes, secreted growth and matrix factors, smooth muscle, integrins, receptors, and antioxidants. Hierarchical clustering shows that they acquire transcriptomes similar to primary isolated PTMs, and immunostaining shows the acquisition of a smooth muscle phenotype. Overall, these hiPSC-PTMs will allow in vitro study of patient-specific PTM development and function in spermatogenesis and infertility.

Tractography-Based Modeling Explains Treatment Outcomes in Patients Undergoing Deep Brain Stimulation for Obsessive-Compulsive Disorder.

BACKGROUND: Deep brain stimulation (DBS) is an established and expanding therapy for treatment-refractory obsessive-compulsive disorder. Previous work has suggested that a white matter circuit providing hyperdirect input from the dorsal cingulate and ventrolateral prefrontal regions to the subthalamic nucleus could be an effective neuromodulatory target. METHODS: We tested this concept by attempting to retrospectively explain through predictive modeling the ranks of clinical improvement as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) in 10 patients with obsessive-compulsive disorder who underwent DBS to the ventral anterior limb of internal capsule with subsequent programming uninformed by the putative target tract. RESULTS: Rank predictions were carried out using the tract model by a team that was completely uninvolved in DBS planning and programming. Predicted Y-BOCS improvement ranks significantly correlated with actual Y-BOCS improvement ranks at the 6-month follow-up (r = 0.75, p = .013). Predicted score improvements correlated with actual Y-BOCS score improvements (r = 0.72, p = .018). CONCLUSIONS: Here, we provide data in a first-of-its-kind report suggesting that normative tractography-based modeling can blindly predict treatment response in DBS for obsessive-compulsive disorder.

Decoding Depression Severity From Intracranial Neural Activity.

BACKGROUND: Disorders of mood and cognition are prevalent, disabling, and notoriously difficult to treat. Fueling this challenge in treatment is a significant gap in our understanding of their neurophysiological basis. METHODS: We recorded high-density neural activity from intracranial electrodes implanted in depression-relevant prefrontal cortical regions in 3 human subjects with severe depression. Neural recordings were labeled with depression severity scores across a wide dynamic range using an adaptive assessment that allowed sampling with a temporal frequency greater than that possible with typical rating scales. We modeled these data using regularized regression techniques with region selection to decode depression severity from the prefrontal recordings. RESULTS: Across prefrontal regions, we found that reduced depression severity is associated with decreased low-frequency neural activity and increased high-frequency activity. When constraining our model to decode using a single region, spectral changes in the anterior cingulate cortex best predicted depression severity in all 3 subjects. Relaxing this constraint revealed unique, individual-specific sets of spatiospectral features predictive of symptom severity, reflecting the heterogeneous nature of depression. CONCLUSIONS: The ability to decode depression severity from neural activity increases our fundamental understanding of how depression manifests in the human brain and provides a target neural signature for personalized neuromodulation therapies.

Human in vitro spermatogenesis as a regenerative therapy - where do we stand?

Spermatogenesis involves precise temporal and spatial gene expression and cell signalling to reach a coordinated balance between self-renewal and differentiation of spermatogonial stem cells through various germ cell states including mitosis, and meiosis I and II, which result in the generation of haploid cells with a unique genetic identity. Subsequently, these round spermatids undergo a series of morphological changes to shed excess cytoplast, develop a midpiece and tail, and undergo DNA repackaging to eventually form millions of spermatozoa. The goal of recreating this process in vitro has been pursued since the 1920s as a tool to treat male factor infertility in patients with azoospermia. Continued advances in reproductive bioengineering led to successful generation of mature, functional sperm in mice and, in the past 3 years, in humans. Multiple approaches to study human in vitro spermatogenesis have been proposed, but technical and ethical obstacles have limited the ability to complete spermiogenesis, and further work is needed to establish a robust culture system for clinical application.

Prefrontal network engagement by deep brain stimulation in limbic hubs.

Prefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown. Here, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS). We demonstrate a shared frontotemporal circuit consisting of the ventromedial prefrontal cortex, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found participant-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation. Our findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.

Automated optimization of deep brain stimulation parameters for modulating neuroimaging-based targets.

Objective.Therapeutic efficacy of deep brain stimulation (DBS) in both established and emerging indications, is highly dependent on accurate lead placement and optimized clinical programming. The latter relies on clinicians' experience to search among available sets of stimulation parameters and can be limited by the time constraints of clinical practice. Recent innovations in device technology have expanded the number of possible electrode configurations and parameter sets available to clinicians, amplifying the challenge of time constraints. We hypothesize that patient specific neuroimaging data can effectively assist the clinical programming using automated algorithms.Approach.This paper introduces the DBS Illumina 3D algorithm as a tool which uses patient-specific imaging to find stimulation settings that optimizes activating a target area while minimizing the stimulation of areas outside the target that could result in unknown or undesired side effects. This approach utilizes preoperative neuroimaging data paired with the postoperative reconstruction of the lead trajectory to search the available stimulation space and identify optimized stimulation parameters. We describe the application of this algorithm in three patients with treatment-resistant depression who underwent bilateral implantation of DBS in subcallosal cingulate cortex and ventral capsule/ventral striatum using tractography optimized targeting with an imaging defined target previously described.Main results.Compared to the stimulation settings selected by the clinicians (informed by anatomy), stimulation settings produced by the algorithm that achieved similar or greater target coverage, produced a significantly smaller stimulation area that spilled outside the target (P= 0.002).Significance. The DBS Illumina 3D algorithm is seamlessly integrated with the clinician programmer software and effectively and rapidly assists clinicians with the analysis of image based anatomy, and provides a starting point to search the highly complex stimulation parameter space and arrive at the stimulation settings that optimize activating a target area.

Fast and accurate matching of cellular barcodes across short-reads and long-reads of single-cell RNA-seq experiments.

Single-cell RNA sequencing allows for characterizing the gene expression landscape at the cell type level. However, because of its use of short-reads, it is severely limited at detecting full-length features of transcripts such as alternative splicing. New library preparation techniques attempt to extend single-cell sequencing by utilizing both long-reads and short-reads. These techniques split the library material, after it is tagged with cellular barcodes, into two pools: one for short-read sequencing and one for long-read sequencing. However, the challenge of utilizing these techniques is that they require matching the cellular barcodes sequenced by the erroneous long-reads to the cellular barcodes detected by the short-reads. To overcome this challenge, we introduce scTagger, a computational method to match cellular barcodes data from long-reads and short-reads. We tested scTagger against another state-of-the-art tool on both real and simulated datasets, and we demonstrate that scTagger has both significantly better accuracy and time efficiency.

Automated rare sperm identification from low-magnification microscopy images of dissociated microsurgical testicular sperm extraction samples using deep learning.

OBJECTIVE: To develop a machine learning algorithm to detect rare human sperm in semen and microsurgical testicular sperm extraction (microTESE) samples using bright-field (BF) microscopy for nonobstructive azoospermia patients. DESIGN: Spermatozoa were collected from fertile men. Testis biopsies were collected from microTESE samples determined to be clinically negative for sperm. A convolutional neural network based on the U-Net architecture was trained using 35,761 BF image patches with fluorescent ground truth image pairs to segment sperm. The algorithm was validated using 7,663 image patches. The algorithm was tested using 7,663 image patches containing abundant sperm, as well as 7,985 image patches containing rare sperm. SETTING: In vitro fertilization center and university laboratories. PATIENT(S): Normospermic and nonobstructive azoospermia patients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Precision (positive predictive value [PPV]), recall (sensitivity), and F1-score of detected sperm locations. RESULT(S): For sperm-only samples, our algorithm achieved 91% PPV, 95.8% sensitivity, and 93.3% F1-score at ×10 magnification. For dissociated microTESE samples doped with an abundant quantity of sperm, our algorithm achieved 84.0% PPV, 72.7% sensitivity, and 77.9% F1-score. For dissociated microTESE samples doped with rare sperm, our algorithm achieved 84.4% PPV, 86.1% sensitivity, and 85.2% F1-score. CONCLUSION(S): Rare sperm can be detected in patients' testis biopsy samples for potential subsequent use in in vitro fertilization-intracytoplasmic sperm injection. A machine learning algorithm can use BF images at ×10 magnification to accurately detect sperm locations using automated imaging.

Using clinically derived human tissue to 3-dimensionally bioprint personalized testicular tubules for in vitro culturing: first report.

OBJECTIVE: To study the feasibility and spermatogenic potential of 3-dimensional (3D) bioprinting personalized human testicular cells derived from a patient with nonobstructive azoospermia (NOA). DESIGN: A human testicular biopsy from a single donor with NOA was dissociated into single cells, expanded in vitro, and 3D bioprinted into tubular structures akin to the seminiferous tubule using AGC-10 bioink and an RX1 bioprinter with a CENTRA coaxial microfluidic printhead from Aspect Biosystems. Three-dimensional organoid cultures were used as a nonbioprinted in vitro control. SETTING: Academic medical center. PATIENT(S): A 31-year-old man with NOA with testis biopsy demonstrating Sertoli cell-only syndrome. INTERVENTION(S): Three-dimensional bioprinting and in vitro culturing of patient-derived testis cells. MAIN OUTCOME MEASURE(S): Cellular viability after printing was determined, along with the expression of phenotypic and spermatogenic functional genetic markers after 12 days of in vitro culture. RESULT(S): Testicular cultures were expandable in vitro and generated sufficiently large numbers for 3D bioprinting at 35 million cells per mL of bioink. Viability 24 hours after printing was determined to be 93.4% ± 2.4%. Immunofluorescence staining for the phenotype markers SRY-Box transcription factor 9, insulin-like 3, actin alpha 2 smooth muscle, and synaptonemal complex protein 3 after 12 days was positive, confirming the presence of Sertoli, Leydig, peritubular myoid, and meiotic germ cells. Reverse transcription qualitative polymerase chain reaction analysis showed that after 12 days in spermatogenic media, the bioprints substantially up-regulated spermatogenic gene expression on par with nonbioprinted controls and showed a particularly significant improvement in genes involved in spermatogonial stem cell maintenance: inhibitor of deoxyribonucleic acid binding 4 by 365-fold; fibroblast growth factor 3 by 94,152-fold; stem cell growth factor receptor KIT by twofold; stimulated by retinoic acid 8 by 125-fold; deleted in azoospermia-like by 114-fold; synaptonemal complex protein 3 by sevenfold; zona pellucida binding protein by twofold; transition protein 1 by 2,908-fold; and protamine 2 by 11-fold. CONCLUSION(S): This study demonstrates for the first time the feasibility of 3D bioprinting adult human testicular cells. We show that the bioprinting process is compatible with high testicular cell viability and without loss of the main somatic phenotypes within the testis tissue. We demonstrate an increase in germ cell markers in the 3D bioprinted tubules after 12 days of in vitro culture. This platform may carry future potential for disease modeling and regenerative opportunities in a personalized medicine framework.

Imaging versus electrographic connectivity in human mood-related fronto-temporal networks.

BACKGROUND: The efficacy of psychiatric DBS is thought to be driven by the connectivity of stimulation targets with mood-relevant fronto-temporal networks, which is typically evaluated using diffusion-weighted tractography. OBJECTIVE: Leverage intracranial electrophysiology recordings to better predict the circuit-wide effects of neuromodulation to white matter targets. We hypothesize strong convergence between tractography-predicted structural connectivity and stimulation-induced electrophysiological responses. METHODS: Evoked potentials were elicited by single-pulse stimulation to two common DBS targets for treatment-resistant depression - the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VCVS) - in two patients undergoing DBS with stereo-electroencephalographic (sEEG) monitoring. Evoked potentials were compared with predicted structural connectivity between DBS leads and sEEG contacts using probabilistic, patient-specific diffusion-weighted tractography. RESULTS: Evoked potentials and tractography showed strong convergence in both patients in orbitofrontal, ventromedial prefrontal, and lateral prefrontal cortices for both SCC and VCVS stimulation targets. Low convergence was found in anterior cingulate (ACC), where tractography predicted structural connectivity from SCC targets but produced no evoked potentials during SCC stimulation. Further, tractography predicted no connectivity to ACC from VCVS targets, but VCVS stimulation produced robust evoked potentials. CONCLUSION: The two connectivity methods showed significant convergence, but important differences emerged with respect to the ability of tractography to predict electrophysiological connectivity between SCC and VCVS to regions of the mood-related network. This multimodal approach raises intriguing implications for the use of tractography in surgical targeting and provides new data to enhance our understanding of the network-wide effects of neuromodulation.

Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression.

BACKGROUND: Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states. METHODS: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined. RESULTS: A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results. CONCLUSIONS: These preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.

Effect of bioactive Biosilicate® /F18 glass scaffolds on osteogenic differentiation of human adipose stem cells.

This study evaluated the gene expression profile of the human adipose-derived stem cells (hASCs) grown on the Biosilicate® /F18 glass (BioS-2P/F18) scaffolds. hASCs were cultured using the osteogenic medium (control), the scaffolds, and their ionic extract. We observed that ALP activity was higher in hASCs grown on the BioS-2P/F18 scaffolds than in hASCs cultured with the ionic extract or the osteogenic medium on day 14. Moreover, the dissolution product group and the control exhibited deposited calcium, which peaked on day 21. Gene expression profiles of cell cultured using the BioS-2P/F18 scaffolds and their extract were evaluated in vitro using the RT2 Profiler polymerase chain reaction (PCR) microarray on day 21. Mineralizing tissue-associated proteins, differentiation factors, and extracellular matrix enzyme expressions were measured using quantitative PCR. The gene expression of different proteins involved in osteoblast differentiation was significantly up-regulated in hASCs grown on the scaffolds, especially BMP1, BMP2, SPP1, BMPR1B, ITGA1, ITGA2, ITGB1, SMAD1, and SMAD2, showing that both the composition and topographic features of the biomaterial could stimulate osteogenesis. This study demonstrated that gene expression of hASCs grown on the scaffold surface showed significantly increased gene expression related to hASCs cultured with the ionic extract or the osteogenic medium, evidencing that the BioS-2P/F18 scaffolds have a substantial effect on cellular behavior of hASCs.

Cerebral perfusion is associated with blast exposure in military personnel without moderate or severe TBI.

Due to the use of improvised explosive devices, blast exposure and mild traumatic brain injury (mTBI) have become hallmark injuries of the Iraq and Afghanistan wars. Although the mechanisms of the effects of blast on human neurobiology remain active areas of investigation, research suggests that the cerebrovasculature may be particularly vulnerable to blast via molecular processes that impact cerebral blood flow. Given that recent work suggests that blast exposure, even without a subsequent TBI, may have negative consequences on brain structure and function, the current study sought to further understand the effects of blast exposure on perfusion. One hundred and eighty military personnel underwent pseudo-continuous arterial spin labeling (pCASL) imaging and completed diagnostic and clinical interviews. Whole-brain analyses revealed that with an increasing number of total blast exposures, there was significantly increased perfusion in the right middle/superior frontal gyri, supramarginal gyrus, lateral occipital cortex, and posterior cingulate cortex as well as bilateral anterior cingulate cortex, insulae, middle/superior temporal gyri and occipital poles. Examination of other neurotrauma and clinical variables such as close-range blast exposures, mTBI, and PTSD yielded no significant effects. These results raise the possibility that perfusion may be an important neural marker of brain health in blast exposure.

Subcortical brain morphometry of avoidant personality disorder.

BACKGROUND: Avoidant personality disorder (AvPD) is a condition typified by social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation. AvPD has a high comorbidity rate with other personality disorders and other psychological diagnostic categories. There is very little research investigating subcortical volumetry in AvPD. We studied subcortical brain morphometry in AvPD as compared to both healthy controls and comorbidity-matched psychiatric controls (patients in the same clinic matched for age, sex and all psychiatric diagnoses except for AvPD). METHODS: We compared volumetric measures of 9 bilateral subcortical brain regions between AvPD patients, healthy controls, and psychiatric controls (n = 100 each group). The Bonferroni correction was used to control for multiple comparisons across regions (p < 0.0028). RESULTS: Compared to healthy controls, AvPD patients had lower volume of the left accumbens and left thalamus. However, no significant results were found when comparing AvPD patients and psychiatric controls. An exploratory study of cortical regions showed similar results: statistically significant differences between HC and AvPD (left lateral occipital, left and right pericalcarine smaller in AvPD) but no differences between AvPD and PC. LIMITATIONS: MRI and neuroimaging provides correlational information, and no causal claims can be made. CONCLUSIONS: These results suggest there may be no overt subcortical volumetric differences specific to AvPD, and provide strong cautionary advice when comparing patients to healthy controls, a common practice in psychiatry biomarker research.

3D Printing Breast Tissue Models: A Review of Past Work and Directions for Future Work.

Breast cancer often results in the removal of the breast, creating a need for replacement tissue. Tissue engineering offers the promise of generating such replacements by combining cells with biomaterial scaffolds and serves as an attractive potential alternative to current surgical repair methods. Such engineered tissues can also serve as important tools for drug screening and provide in vitro models for analysis. 3D bioprinting serves as an exciting technology with significant implications and applications in the field of tissue engineering. Here we review the work that has been undertaken in hopes of generating the recognized in-demand replacement breast tissue using different types of bioprinting. We then offer suggestions for future work needed to advance this field for both in vitro and in vivo applications.

Individual differences in sustained attention are associated with cortical thickness.

Several studies have examined how individual differences in sustained attention relate to functional brain measures (e.g., functional connectivity), but far fewer studies relate sustained attention ability, or cognition in general, to individual differences in cortical structure. Functional magnetic resonance imaging meta-analyses and patient work have highlighted that frontoparietal regions, lateralized to the right hemisphere, are critical for sustained attention, though recent work implicates a broader expanse of brain regions. The current study sought to determine if and where variation in cortical thickness is significantly associated with sustained attention performance. Sustained attention was measured using the gradual onset continuous performance task and the Test of Variables of Attention in 125 adult Veteran participants after acquiring two high-resolution structural MRI scans. Whole-brain vertex-wise analyses of the cortex demonstrated that better sustained attention was associated with increased thickness in visual, somatomotor, frontal, and parietal cortices, especially in the right hemisphere. Network-based analyses revealed relationships between sustained attention and cortical thickness in the dorsal attention, ventral attention, somatomotor, and visual networks. These results indicate cortical thickness in multiple regions and networks is associated with sustained attention, and add to the growing knowledge of how structural MRI can help explain individual differences in cognition.

A Novel Toolkit for Characterizing the Mechanical and Electrical Properties of Engineered Neural Tissues.

We have designed and validated a set of robust and non-toxic protocols for directly evaluating the properties of engineered neural tissue. These protocols characterize the mechanical properties of engineered neural tissues and measure their electrophysical activity. The protocols obtain elastic moduli of very soft fibrin hydrogel scaffolds and voltage readings from motor neuron cultures. Neurons require soft substrates to differentiate and mature, however measuring the elastic moduli of soft substrates remains difficult to accurately measure using standard protocols such as atomic force microscopy or shear rheology. Here we validate a direct method for acquiring elastic modulus of fibrin using a modified Hertz model for thin films. In this method, spherical indenters are positioned on top of the fibrin samples, generating an indentation depth that is then correlated with elastic modulus. Neurons function by transmitting electrical signals to one another and being able to assess the development of electrical signaling serves is an important verification step when engineering neural tissues. We then validated a protocol wherein the electrical activity of motor neural cultures is measured directly by a voltage sensitive dye and a microplate reader without causing damage to the cells. These protocols provide a non-destructive method for characterizing the mechanical and electrical properties of living spinal cord tissues using novel biosensing methods.

Clinically significant cognitive dysfunction in OEF/OIF/OND veterans: Prevalence and clinical associations.

OBJECTIVE: Cognitive performance in trauma-exposed populations, such as combat Veterans, has been shown to be worse than in nonexposed peers. However, cognitive performance has typically been within the normal range (within 1 SD of normative mean), and the prevalence of clinically significant cognitive dysfunction (i.e., performance more than 1 SD below the mean on multiple measures in a domain) in younger adults with trauma exposure remains unknown. The objective of our study was to measure this. METHOD: We applied Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) cutoffs for clinically significant cognitive dysfunction (>1 SD below the mean in multiple measures within a domain) in the domains of memory, executive function, and attention to a sample of combat-exposed Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND; N = 368, mean age = 31.7 years, 90% men) Veterans. We then compared psychiatric, physiological, and neural measures, as well as functional outcomes, between those with and without cognitive dysfunction. RESULTS: Veterans with cognitive dysfunction (n = 129, 35.1%) had lower premorbid reading ability and more severe psychological distress, including increased anxiety, depression, posttraumatic stress disorder (PTSD), sleep difficulties, pain, and alcohol consumption. Those with cognitive dysfunction also had worse functional outcomes, with mild but significant disability. In contrast, we found associations between outcome and age, traumatic brain injury, physiological and neural measures to be weak or not significant. CONCLUSIONS: Together, this suggests that premorbid abilities and trauma-related psychological symptoms contribute significantly to cognitive dysfunction in OEF/OIF/OND Veterans, and that neurological insult and aging may play less of a role. Cognitive dysfunction may be at least partially ameliorated by treating trauma-related symptoms. (PsycINFO Database Record (c) 2019 APA, all rights reserved).