Forebrain Shh overexpression improves cognitive function and locomotor hyperactivity in an aneuploid mouse model of Down syndrome and its euploid littermates.

Down syndrome (DS) is the leading genetic cause of intellectual disability and causes early-onset dementia and cerebellar hypoplasia. The prevalence of attention deficit hyperactivity disorder is elevated in children with DS. The aneuploid DS mouse model "Ts65Dn" shows prominent brain phenotypes, including learning and memory deficits, cerebellar hypoplasia, and locomotor hyperactivity. Previous studies indicate that impaired Sonic hedgehog (Shh) signaling contributes to neurological phenotypes associated with DS and neurodegenerative diseases. However, because of a lack of working inducible Shh knock-in mice, brain region-specific Shh overexpression and its effects on cognitive function have not been studied in vivo. Here, with Gli1-LacZ reporter mice, we demonstrated that Ts65Dn had reduced levels of Gli1, a sensitive readout of Shh signaling, in both hippocampus and cerebellum at postnatal day 6. Through site-specific transgenesis, we generated an inducible human Shh knock-in mouse, TRE-bi-hShh-Zsgreen1 (TRE-hShh), simultaneously expressing dually-lipidated Shh-Np and Zsgreen1 marker in the presence of transactivator (tTA). Double transgenic mice "Camk2a-tTA;TRE-hShh" and "Pcp2-tTA;TRE-hShh" induced Shh overexpression and activated Shh signaling in a forebrain and cerebellum, respectively, specific manner from the perinatal period. Camk2a-tTA;TRE-hShh normalized locomotor hyperactivity and improved learning and memory in 3-month-old Ts65Dn, mitigated early-onset severe cognitive impairment in 7-month-old Ts65Dn, and enhanced spatial cognition in euploid mice. Camk2a-tTA;TRE-hShh cohort maintained until 600days old showed that chronic overexpression of Shh in forebrain from the perinatal period had no effect on longevity of euploid or Ts65Dn. Pcp2-tTA;TRE-hShh did not affect cognition but mitigated the phenotype of cerebellar hypoplasia in Ts65Dn. Our study provides the first in vivo evidence that Shh overexpression from the perinatal period protects DS brain integrity and enhances learning and memory in normal mice, indicating the broad therapeutic potential of Shh ligand for other neurological conditions. Moreover, the first inducible hShh site-specific knock-in mouse could be widely used for spatiotemporal Shh signaling regulation.

The effects of short-term low energy availability, achieved through diet or exercise, on cognitive function in oral contraceptive users and eumenorrheic women.

To date, no research has explored the effects of low energy availability on cognitive performance using dietary and exercise regimens relevant to athletes. Twenty female participants (10 eumenorrheic, 10 oral contraceptive [OC] users) completed three 3-day conditions: 1) controlled-balanced energy availability without exercise (BAL; 45 kcal·kg lean body mass [LBM]-1·day-1); 2) diet-induced low energy availability without exercise (DIET; 15 kcal·kg LBM-1·day-1); and 3) exercise-induced low energy availability (EX; 15 kcal·kg LBM-1·day-1, including 30 kcal·kg LBM-1·day-1 treadmill running at 70% maximal oxygen uptake). A cognitive test battery was completed before and after each 3-day condition. Mental rotation test accuracy improved in the BAL condition, but there was a decline in accuracy in the EX condition (BAL, +2.5%; EX, -1.4%; P = 0.042, d = 0.85). DIET (+1.3%) was not different to BAL or EX (P > 0.05). All other measures of cognitive performance were not affected by condition (P > 0.05) and OC use did not affect cognitive responses (P > 0.05). Accuracy in the mental rotation test was impaired when low energy availability was induced through increased exercise energy expenditure. All other aspects of cognition were unaffected by 3 days of low energy availability through diet or exercise. OC use did not mediate the effect of low energy availability on cognition. Novelty: Cognitive function was not affected by 3 days of diet-induced low energy availability. Only spatial awareness was impaired during 3 days of exercise-induced low energy availability. Reproductive hormones affected spatial awareness independent of energy availability.

Longitudinal Changes in Optical Quality, Spatial Vision, and Depth Vision after Laser Refractive Surgery for Myopia.

SIGNIFICANCE: Laser refractive surgery procedures are efficacious at correcting myopia, but they result in long-term deterioration of optical quality that affects monocular and binocular visual performance. The study shows that the optical quality of the two eyes needs to be similar to optimize binocular visual performance after surgery. PURPOSE: This study aimed to systematically analyze longitudinal changes in optical quality, high- and low-contrast logMAR acuity and random-dot stereoacuity before and after three refractive surgery procedures for correcting myopia. METHODS: A total of 106 subjects (laser-assisted in situ keratomileusis, 40; photorefractive keratectomy, 26; small-incision lenticule extraction, 40) with myopia and astigmatism ≤1.5 D participated in this prospective cohort-based study. All aforementioned outcome variables were measured in both eyes pre-operatively and 1 week and 1, 3, and 6 months post-operatively. RESULTS: Pre-operative myopic spherical equivalent of refraction (median [25th to 75th interquartile range], -6.4 D [-8.0 to -4.2 D] for laser-assisted in situ keratomileusis, -4.3 D [-5.0 to -3.5 D] for photorefractive keratectomy, -5.5 D [-6.5 to -4.3 D] for small-incision lenticule extraction) was corrected to within ±0.75 D of emmetropia in all cohorts up to 6 months post-operatively (P < .001). Higher-order wavefront aberrations, uncorrected high- and low-contrast logMAR acuity, and stereoacuity all worsened and remained so up to 6 months post-operatively, relative to pre-operative values (P < .001). Stereoacuity worsened with both interocular average and difference in the magnitude of higher-order aberrations, whereas logMAR acuities worsened only with interocular average of these aberrations (r ≥ 0.40; P < .01 for all). CONCLUSIONS: Although the refractive surgery procedures tested here correct myopia, they result in a sustained (up to 6 months) loss of optical quality and spatial and depth-related visual functions post-operatively. Both interocular average and difference in the eye's optical quality seem to impair binocular visual functions after refractive surgery for myopia.

Fetal Alcohol Spectrum Disorders in a Rocky Mountain Region City: Child Characteristics, Maternal Risk Traits, and Prevalence.

OBJECTIVE: To document prevalence and traits of children with fetal alcohol spectrum disorders (FASD) and maternal risk factors in a Rocky Mountain city. METHODS: Variations on active case ascertainment methods were used in 2 first-grade cohorts in all city schools. The consent rate was 59.2%. Children were assessed for physical growth, dysmorphology, and neurobehavior and their mothers interviewed. RESULTS: Thirty-eight children were diagnosed with FASD and compared with 278 typically developing controls. Total dysmorphology scores summarized well the key physical indicators of FASD and defined specific diagnostic groups. On average, children with FASD performed significantly poorer than controls on intellectual, adaptive, learning, attention, and behavioral tasks. More mothers of children with FASD reported drinking prior to pregnancy and in the first and second trimesters, and had partners with drinking problems than mothers of controls; however, reports of comorbid alcohol use and 6 other drugs were similar for mothers of children with FASD and mothers of controls. Mothers of children with FASD were significantly younger at pregnancy, had lower average weight before pregnancy and less education, initiated prenatal clinic visits later, and reported more health problems (e.g., stomach ulcers and accidents). Children with FASD had significantly lower birth weight and more problems at birth, and were less likely to be living with biological mother and father. Controlling for other drug and tobacco use, a FASD diagnosis is 6.7 times (OR = 6.720, 95% CI = 1.6 to 28.0) more likely among children of women reporting prepregnancy drinking of 3 drinks per drinking day (DDD) and 7.6 times (OR = 7.590, 95% CI = 2.0 to 31.5) more likely at 5 DDD. Prevalence of FAS was 2.9-5.8 per 1,000 children, and total FASD was 34.9 to 82.5 per 1,000 children or 3.5 to 8.3% at this site. CONCLUSION: This site had the second highest prevalence of FASD of the 4 Collaboration on FASD Prevalence sites and clearly identifiable child and maternal risk traits.

Fetal Alcohol Spectrum Disorders in a Midwestern City: Child Characteristics, Maternal Risk Traits, and Prevalence.

OBJECTIVE: To determine the characteristics of children with fetal alcohol spectrum disorders (FASD) and their mothers in a Midwestern city. METHODS: Case-control samples were drawn from 2 separate first-grade cohorts (combined N = 4,047) in every city school using different methods. In Cohort Sample 1, all consented small children (≤25th centile on height, weight, and/or head circumference) entered the study along with a random sample from all enrolled students. Cohort Sample 2 was drawn totally at random. Child growth, dysmorphology, and neurobehavior were assessed using the Collaboration on FASD Prevalence (CoFASP) criteria, and mothers were interviewed. RESULTS: For the samples combined, 891 children received dysmorphology examinations, and 692 were case-conferenced for final diagnosis. Forty-four children met criteria for FASD. Total dysmorphology scores differentiated diagnostic groups: fetal alcohol syndrome (FAS), 16.7; partial FAS, 11.8; alcohol-related neurodevelopmental disorder (ARND), 6.1; and typically developing controls, 4.2. Neurobehavioral tests distinguished children with FASD from controls, more for behavioral problems than cognitive delay. Children with ARND demonstrated the poorest neurobehavioral indicators. An adjusted regression model of usual prepregnancy drinking indicated that maternal reports of 3 drinks per drinking day (DDD) were significantly associated with a FASD diagnosis (p = 0.020, OR = 10.1, 95% CI = 1.44 to 70.54), as were 5 or more DDD (p < 0.001, OR = 26.47, 95% CI = 4.65 to 150.62). Other significant maternal risk factors included the following: self-reported drinking in any trimester; smoking and cocaine use during pregnancy; later pregnancy recognition and later and less prenatal care; lower maternal weight, body mass index (BMI), and head circumference; and unmarried status. There was no significant difference in FASD prevalence by race, Hispanic ethnicity, or socioeconomic status at this site, where the prevalence of FASD was 14.4 to 41.2 per 1,000 (1.4 to 4.1%). CONCLUSION: This city displayed the lowest prevalence of FASD of the 4 CoFASP sites. Nevertheless, FASD were common, and affected children demonstrated a common, recognizable, and measurable array of traits.

Innovation in Neurosurgery: The Concept of Cognitive Mapping.

In recent years, advances in cortical-subcortical mapping, intraoperative neurophysiology, and neuropsychology have increased the ability to remove intrinsic brain tumors, expanding indications and maximizing the extent of resection. This has provided a significant improvement in progression-free survival, time of malignant transformation (in low-grade gliomas), and overall survival. Although current techniques enable preservation of language and motor functions during surgery, the maintenance of a complex set of functions defined with the term cognition is not always achievable. Cognition is defined as every neural process underlying a high human function and includes motor haptic and visuospatial functions, memory, social interactions, empathy, and emotions. In this regard, an extensive preoperative and postoperative neuropsychological evaluation is strongly suggested to assess cognitive impairment due to tumor growth, to assess surgical result, and to plan cognitive rehabilitation. This article discusses the main recent innovations introduced for cognitive mapping with the aim to preserve cognitive functions, which are essential to maintain a high quality of life.

Alzheimer's Disease-Like Pathologies and Cognitive Impairments Induced by Formaldehyde in Non-Human Primates.

BACKGROUND: Formaldehyde (FA) has been implicated in Alzheimer's disease (AD) pathology as an age-related factor and as a protein cross-linker known to aggregate Amyloid-Beta (Aß) and tau protein in vitro. Higher levels of FA have also been found in patients with greater cognitive impairment and in AD patient brains. OBJECTIVE: To directly evaluate the effect of chronically elevated FA levels on the primate brain with respect to AD pathological markers. METHOD: Young rhesus macaques (5-8 yrs, without AD related mutations) were given chronic intracerebroventricular (i.c.v.) injections of FA or vehicle over a 12-month period. Monkeys were monitored for changes in cognitive ability and evaluated post-mortem for common AD pathological markers. RESULTS: Monkeys injected with FA were found to have significant spatial working memory impairments. Histopathological analysis revealed the presence of amyloid-ß+ neuritic-like plaques, neurofibrillary tangle-like formations, increased tau protein phosphorylation, neuronal loss and reactive gliosis in three memory (and AD) related brain areas (the hippocampus, entorhinal cortex and prefrontal cortex (PFC)) of monkeys receiving i.c.v. injections of FA. ELISA assays revealed that the amounts of pT181 and Aß42 were markedly higher in the PFC and hippocampus of FA treated monkeys. CONCLUSION: FA was found to induce major AD-like pathological markers and cognitive impairments in young rhesus monkeys independent of genetic predispositions. This suggests FA may play a significant role in the initiation and progression of the disease.

Patching for Diplopia Contraindicated in Patients with Brain Injury?

PURPOSE: Patching for double vision is a common palliative treatment for head-trauma patients with acquired strabismus when prisms are not feasible. METHODS: We review literature on spatial neglect and discuss possible effects of monocular occlusion on spatial attention. RESULTS: Patching the left eye has been shown to worsen spatial judgments in some brain-injured patients with left neglect by inhibiting the right superior colliculus further impairing contralateral leftward orienting (the Sprague Effect). CONCLUSIONS: Because more peripheral parts of the visual field increasingly project to the contralateral superior colliculus with the temporal crescent being entirely contralateral, avoiding patching of the temporal crescent was advised, and in most cases can be achieved by taping off the spectacle lens and avoiding an elastic eye patch.

Prenatal and postnatal polybrominated diphenyl ether exposure and visual spatial abilities in children.

Polybrominated diphenyl ethers (PBDEs) are associated with impaired visual spatial abilities in toxicological studies, but no epidemiologic study has investigated PBDEs and visual spatial abilities in children. The Health Outcomes and Measures of the Environment Study, a prospective birth cohort (2003-2006, Cincinnati, OH), was used to examine prenatal and childhood PBDEs and visual spatial abilities in 199 children. PBDEs were measured at 16±3 weeks gestation and at 1, 2, 3, 5, and 8 years using gas chromatography/isotope dilution high-resolution mass spectrometry. We used the Virtual Morris Water Maze to measure visual spatial abilities at 8 years. In covariate-adjusted models, 10-fold increases in BDE-47, -99, and -100 at 5 years were associated with shorter completion times by 5.2s (95% Confidence Interval [CI] -9.3, -1.1), 4.5s (95% CI -8.1, -0.9), and 4.7s (95% CI -9.0, -0.3), respectively. However, children with higher BDE-153 at 3 years had longer completion times (ß=5.4s, 95% CI -0.3, 11.1). Prenatal PBDEs were associated with improved visual spatial memory retention, with children spending a higher percentage of their search path in the correct quadrant. Child sex modified some associations between PBDEs and visual spatial learning. Longer path lengths were observed among males with increased BDE-47 at 2 and 3 years, while females had shorter paths. In conclusion, prenatal and postnatal BDE-28, -47, -99, and -100 at 5 and 8 years were associated with improved visual spatial abilities, whereas a pattern of impairments in visual spatial learning was noted with early childhood BDE-153 concentrations.

Executive functions in men and postmenopausal women.

INTRODUCTION: This study was designed to assess sex differences in older adults (55-65 years old) in executive functions and to examine the influence of hormone therapy (HT) in postmenopausal women. METHOD: We have assessed task performance in memory, visuospatial, and executive functions in 29 women using HT, 29 women who never used HT, and 30 men. RESULTS: Men outperformed never users in task switching and updating. HT users outperformed never users in updating. HT users outperformed never users and men in visual divided attention. DISCUSSION: The present study support previous findings that sex and HT impact cognition and bring new insights on sex and HT-related differences in executive functions.

El papel del cuerpo calloso en el procesamiento visoespacial / The role of the corpus callosum in the visuospatial processing

El procesamiento visoespacial es una función adaptativa del organismo que permite su interacción con los elementos que se encuentran en su medio ambiente. Se considera una función superior, ya que involucra sistemas de reconocimiento y de memoria, entre otros. Hasta el momento se ha descrito la participación de diversas estructuras cerebrales en el procesamiento de información visoespacial, por ejemplo, tradicionalmente se considera una especialización funcional por parte del hemisferio derecho; sin embargo aún existen muchas controversias con respecto a la participación de diversas áreas cerebrales tanto ipsilaterales como contralaterales en estás funciones visoespaciales. En el presente trabajo se discute el papel de la comunicación interhemisferica, y específicamente del papel que juega el cuerpo calloso en el procesamiento visoespacial. Se inicia con una descripción de las vías de procesamiento visoespacial desde el ojo hasta la corteza V1 y las conexiones anatómicas funcionales que se establecen a partir de ésta. Posteriormente se resume la estructura-función del cuerpo calloso y se revisan los trabajos que han reportado relaciones entre éste y la función visoespacial. Por último, se revisan algunas de las patologías neurológicas que cursan con afectación del cuerpo calloso y que se ha reportado en la literatura que afectan a la función visoespacial...

The visuospatial processing is an adaptive function of the organism that allows it to interact with the elements that are in their environment. It is considered a high-order function as it involves recognition systems, memory, among others. So far described the participation of various brain structures in processing visuospatial information, for example, is traditionally considered a functional specialization by the right hemisphere, but there are still many controversies regarding the participation of various brain areas, both ipsilateral and contralateral in the visuospatial functions. In this paper we discuss the role of interhemispheric communication, and specifically the role of the corpus callosum in visuospatial processing. It begins with a description of visuospatial processing pathways from the eye to the cortex V1 and the anatomical-functional connections are established from this. Later summarizes the structure-function of the corpus callosum and reviews the studies that have reported relationships between this and visuospatial function. Finally we review some of the neurological disorders that present with involvement of the corpus callosum and it has been reported in the literature that affect visuospatial function...

Accuracy of virtually planned and conventionally placed implants in edentulous cadaver maxillae and mandibles: a preliminary report.

STATEMENT OF PROBLEM: The accuracy of mental navigation is thought to depend on the clinician's spatial ability. Mental navigation, therefore, is associated with deviations between the mental plan and the definitive implant position. To learn more about the deviation that might occur, it is important to evaluate the accuracy of mental navigation during placement of implants. PURPOSE: The purpose of the study was to compare accuracy outcomes between virtually planned and conventionally placed implants, and among surgeons with varying experience. MATERIAL AND METHODS: Five completely edentulous sets of maxillae and mandibles from human cadaver heads were scanned by computed tomography. Five surgeons planned and placed 60 implants into these jaws, and accuracy was analyzed for 4 parameters: coronal and apical positions, angulation, and depth. The preoperative and postoperative computed tomographies were aligned in voxel-based registration software, which allowed comparison between virtually planned implant positions and actual implant positions. Data were analyzed with the t test (α=.05), ANOVA, and the Scheffé test. RESULTS: Mean (standard deviation) values were as follows: apex, 2.33 ±1.20 mm (range, 0.51-6.31 mm); coronal, 1.88 ±1.02 mm (range, 0.2-5.0 mm); angle, 7.34 ±3.62 degrees (range, 0.19-16.57 degrees); and depth, 0.03 ±1.15 mm (range, -3.47 to 2.10 mm). The apex and coronal position and the angle differed significantly between the virtually planned and actually placed implants. Significant between-surgeon differences were found in implant depth and coronal position. The apex and coronal positions differed significantly between the upper and lower jaw, with better performance achieved in the upper jaw. CONCLUSIONS: The results found statistically significant differences between the virtually planned and conventionally placed implants and among the 5 surgeons.