SummaryColinear HOX expression during hindbrain and spinal cord development diversifies and assigns regional neural phenotypes to discrete rhombomeric and vertebral domains. Despite the precision of HOX patterning in vivo, in vitro approaches for differentiating human pluripotent stem cells (hPSCs) to posterior neural fates coarsely pattern HOX expression thereby generating cultures broadly specified to hindbrain or spinal cord regions. Here, we demonstrate that successive activation of fibroblast growth factor, Wnt/β-catenin, and growth differentiation factor signaling during hPSC differentiation generates stable, homogenous SOX2+/Brachyury+ neuromesoderm that exhibits progressive, full colinear HOX activation over 7 days. Switching to retinoic acid treatment at any point during this process halts colinear HOX activation and transitions the neuromesoderm into SOX2+/PAX6+ neuroectoderm with predictable, discrete HOX gene/protein profiles that can be further differentiated into region-specific cells, e.g., motor neurons. This fully defined approach significantly expands capabilities to derive regional neural phenotypes from diverse hindbrain and spinal cord domains.

Despite the prevalence and impact of mild traumatic brain injury (mTBI), common clinical assessment methods for mTBI have insufficient sensitivity and specificity. Moreover, few researchers have attempted to document underlying changes in physiology as a function of recovery from mTBI. Proton magnetic resonance spectroscopy (¹H-MRS) was used to assess neurometabolite concentrations in a supraventricular tissue slab in 30 individuals with semi-acute mTBI, and 30 sex-, age-, and education-matched controls. No significant group differences were evident on traditional measures of attention, memory, working memory, processing speed, and executive skills, though the mTBI group reported significantly more somatic, cognitive, and emotional symptoms. At a mean of 13 days post-injury, white matter concentrations of creatine (Cre) and phosphocreatine (PCre) and the combined glutamate-glutamine signal (Glx) were elevated in the mTBI group, while gray matter concentrations of Glx were reduced. Partial normalization of these three neurometabolites and N-acetyl aspartate occurred in the early days post-injury, during the semi-acute period of recovery. In addition, 17 mTBI patients (57%) returned for a follow-up evaluation (mean = 120 days post-injury). A significant group × time interaction indicated recovery in the mTBI group for gray matter Glx, and trends toward recovery in white matter Cre and Glx. An estimate of premorbid intelligence predicted the magnitude of neurometabolite normalization over the follow-up interval for the mTBI group, indicating that biological factors underlying intelligence may also be associated with more rapid recovery.

Background Adolescence is a period in which cognition and brain undergo dramatic parallel development. Whereas chronic use of alcohol and marijuana is known to cause cognitive impairments in adults, far less is known about the effect of these substances of abuse on adolescent cognition, including possible interactions with developmental processes. Methods Neuropsychological performance, alcohol use, and marijuana use were assessed in 48 adolescents (ages 12–18), recruited in three groups: a healthy control group (HC, n = 15), a group diagnosed with substance abuse or dependence (SUD, n = 19), and a group with a family history positive for alcohol use disorder (AUD) but no personal substance use disorder (FHP, n = 14). Age, drinks per drinking day, percentage days drinking, and percentage days using marijuana were considered as covariates in a MANCOVA in which 6 neuropsychological composites (Verbal Reasoning, Visuospatial Ability, Executive Function, Memory, Attention, and Processing Speed) served as dependent variables. Results More drinks per drinking day predicted poorer performance on Attention and Executive Function composites, and more frequent use of marijuana use was associated with poorer Memory performance. In separate analyses, adolescents in the SUD group had lower scores on Attention, Memory, and Processing Speed composites, and FHP adolescents had poorer Visuospatial Ability. Conclusions In combination, these analyses suggest that heavy alcohol use in adolescence leads to reduction in attention and executive functioning and that marijuana use exerts an independent deleterious effect on memory. At the same time, premorbid deficits associated with family history of AUD appeared to be specific to Visuospatial Ability.

The cortical (auditory and prefrontal) and/or subcortical (thalamic and hippocampal) generators of abnormal electrophysiological responses during sensory gating remain actively debated in the schizophrenia literature. Functional magnetic resonance imaging (fMRI) has the spatial resolution for disambiguating deep or simultaneous sources but has been relatively under-utilized to investigate generators of the gating response. Thirty patients with chronic schizophrenia (SP) and 30 matched controls participated in the current experiment. Hemodynamic response functions (HRF) for single (S1) and pairs (S1 + S2) of identical (IT; “gating-out” redundant information) or non-identical (NT; “gating-in” novel information) tones were generated through deconvolution. Increased or prolonged activation for patients in conjunction with deactivation for controls was observed within auditory cortex, prefrontal cortex and thalamus in response to single tones during the late hemodynamic response, and these group differences were not associated with clinical or cognitive symptomatology. Although patient hyper-activation to paired-tones conditions was present in several ROI, the effects were not statistically significant for either the gating-out or gating-in conditions. Finally, abnormalities in the post-undershoot of the auditory HRF were also observed for both single and paired tones conditions in patients. In conclusion, the amalgamation of the entire electrophysiological response to both S1 and S2 stimuli may limit hemodynamic sensitivity to paired tones during sensory gating, which may be more readily overcome by paradigms that utilize multiple stimuli rather than pairs. Patient hyperactivation following single tones is suggestive of deficits in basic inhibition, neurovascular abnormalities or a combination of both factors.