Using synchronized brain rhythms to bias memory-guided decisions.

Functional interactions between the prefrontal cortex and hippocampus, as revealed by strong oscillatory synchronization in the theta (6-11 Hz) frequency range, correlate with memory-guided decision-making. However, the degree to which this form of long-range synchronization influences memory-guided choice remains unclear. We developed a brain machine interface that initiated task trials based on the magnitude of prefrontal hippocampal theta synchronization, then measured choice outcomes. Trials initiated based on strong prefrontal-hippocampal theta synchrony were more likely to be correct compared to control trials on both working memory-dependent and -independent tasks. Prefrontal-thalamic neural interactions increased with prefrontal-hippocampal synchrony and optogenetic activation of the ventral midline thalamus primarily entrained prefrontal theta rhythms, but dynamically modulated synchrony. Together, our results show that prefrontal-hippocampal theta synchronization leads to a higher probability of a correct choice and strengthens prefrontal-thalamic dialogue. Our findings reveal new insights into the neural circuit dynamics underlying memory-guided choices and highlight a promising technique to potentiate cognitive processes or behavior via brain machine interfacing.

The Kinesin Gene KIF26B Modulates the Severity of Post-Traumatic Heterotopic Ossification.

The formation of pathological bone deposits within soft tissues, termed heterotopic ossification (HO), is common after trauma. However, the severity of HO formation varies substantially between individuals, from relatively isolated small bone islands through to extensive soft tissue replacement by bone giving rise to debilitating symptoms. The aim of this study was to identify novel candidate therapeutic molecular targets for severe HO. We conducted a genome-wide scan in men and women with HO of varying severity following hip replacement for osteoarthritis. HO severity was dichotomized as mild or severe, and association analysis was performed with adjustment for age and sex. We next confirmed expression of the gene encoded by the lead signal in human bone and in primary human mesenchymal stem cells. We then examined the effect of gene knockout in a murine model of osseous trans-differentiation, and finally we explored transcription factor phosphorylation in key pathways perturbed by the gene. Ten independent signals were suggestively associated with HO severity, with KIF26B as the lead. We subsequently confirmed KIF26B expression in human bone and upregulation upon BMP2-induced osteogenic differentiation in primary human mesenchymal stem cells, and also in a rat tendo-Achilles model of post-traumatic HO. CRISPR-Cas9 mediated knockout of Kif26b inhibited BMP2-induced Runx2, Sp7/Osterix, Col1A1, Alp, and Bglap/Osteocalcin expression and mineralized nodule formation in a murine myocyte model of osteogenic trans-differentiation. Finally, KIF26B deficiency inhibited ERK MAP kinase activation during osteogenesis, whilst augmenting p38 and SMAD 1/5/8 phosphorylation. Taken together, these data suggest a role for KIF26B in modulating the severity of post-traumatic HO and provide a potential novel avenue for therapeutic translation.

Pathophysiology and Emerging Molecular Therapeutic Targets in Heterotopic Ossification.

The term heterotopic ossification (HO) describes bone formation in tissues where bone is normally not present. Musculoskeletal trauma induces signalling events that in turn trigger cells, probably of mesenchymal origin, to differentiate into bone. The aetiology of HO includes extremely rare but severe, generalised and fatal monogenic forms of the disease; and as a common complex disorder in response to musculoskeletal, neurological or burn trauma. The resulting bone forms through a combination of endochondral and intramembranous ossification, depending on the aetiology, initiating stimulus and affected tissue. Given the heterogeneity of the disease, many cell types and biological pathways have been studied in efforts to find effective therapeutic strategies for the disorder. Cells of mesenchymal, haematopoietic and neuroectodermal lineages have all been implicated in the pathogenesis of HO, and the emerging dominant signalling pathways are thought to occur through the bone morphogenetic proteins (BMP), mammalian target of rapamycin (mTOR), and retinoic acid receptor pathways. Increased understanding of these disease mechanisms has resulted in the emergence of several novel investigational therapeutic avenues, including palovarotene and other retinoic acid receptor agonists and activin A inhibitors that target both canonical and non-canonical signalling downstream of the BMP type 1 receptor. In this article we aim to illustrate the key cellular and molecular mechanisms involved in the pathogenesis of HO and outline recent advances in emerging molecular therapies to treat and prevent HO that have had early success in the monogenic disease and are currently being explored in the common complex forms of HO.

Gathering Global Perspectives to Establish the Research Priorities and Minimum Data Sets for Degenerative Cervical Myelopathy: Sampling Strategy of the First Round Consensus Surveys of AO Spine RECODE-DCM.

STUDY DESIGN: Survey. INTRODUCTION: AO Spine Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy (AO Spine RECODE-DCM) is an international initiative that aims to accelerate knowledge discovery and improve outcomes by developing a consensus framework for research. This includes defining the top research priorities, an index term and a minimum data set (core outcome set and core data elements set - core outcome set (COS)/core data elements (CDE)). OBJECTIVE: To describe how perspectives were gathered and report the detailed sampling characteristics. METHODS: A two-stage, electronic survey was used to gather and seek initial consensus. Perspectives were sought from spinal surgeons, other healthcare professionals and people with degenerative cervical myelopathy (DCM). Participants were allocated to one of two parallel streams: (1) priority setting or (2) minimum dataset. An email campaign was developed to advertise the survey to relevant global stakeholder individuals and organisations. People with DCM were recruited using the international DCM charity Myelopathy.org and its social media channels. A network of global partners was recruited to act as project ambassadors. Data from Google Analytics, MailChimp and Calibrum helped optimise survey dissemination. RESULTS: Survey engagement was high amongst the three stakeholder groups: 208 people with DCM, 389 spinal surgeons and 157 other healthcare professionals. Individuals from 76 different countries participated; the United States, United Kingdom and Canada were the most common countries of participants. CONCLUSION: AO Spine RECODE-DCM recruited a diverse and sufficient number of participants for an international PSP and COS/CDE process. Whilst PSP and COS/CDE have been undertaken in other fields, to our knowledge, this is the first time they have been combined in one process.

Evaluation of airflow characteristics before and after septoplasty in unilateral cleft patients with a deviated nasal septum: a computational fluid dynamics study.

The aim of this study was to evaluate changes in airflow characteristics before and after septoplasty in unilateral cleft lip and palate (UCLP) patients using computational fluid dynamics (CFD) models. The study was designed as a prospective cohort study involving pre- and postoperative computed tomography data from 12 UCLP patients with a deviated nasal septum who underwent septoplasty. CFD analysis of nasal airflow was conducted to study changes in velocity, pressure, volume, nasal resistance, and wall shear stress of the nasal domain before and after surgery. The study results demonstrated a statistically significant difference in pressure drop after septoplasty: median 116.10Pa (interquartile range (IQR) 749.02Pa) preoperative compared with 43.39Pa (IQR 349.01Pa) postoperative (P= 0.004). Maximum wall shear stress was found to be approximately three times lower after septoplasty: median 6.15 Pa (IQR 1908.62 Pa) preoperative versus median 2.51 Pa (IQR 540.06 Pa) postoperative (P=0.002). Changes in nasal resistance were also found to be statistically significant: median 460.59 Pa·s/l (IQR 1946.99 Pa·s/l) preoperative versus median 166.61 Pa·s/l (IQR 694.08 Pa·s/l) postoperative (P=0.04). These values demonstrate significant changes in flow dynamics after surgery indicative of a more uniform airflow pattern and stabilization of the nasal mucosa.

Lumbar Puncture Test in Normal Pressure Hydrocephalus: Does the Volume of CSF Removed Affect the Response to Tap?

BACKGROUND AND PURPOSE: There is limited evidence to support the use of high-volume lumbar taps over lower-volume taps in the diagnosis of normal pressure hydrocephalus. The purpose of this study is to detect whether the volume of CSF removed from patients undergoing high-volume diagnostic lumbar tap test for normal pressure hydrocephalus is significantly associated with post-lumbar tap gait performance. MATERIALS AND METHODS: This retrospective study included 249 consecutive patients who underwent evaluation for normal pressure hydrocephalus. The patients were analyzed both in their entirety and as subgroups that showed robust response to the lumbar tap test. The volume of CSF removed was treated as both a continuous variable and a discrete variable. Statistical tests were repeated with log-normalized volumes. RESULTS: This study found no evidence of a relationship between the volume of CSF removed during the lumbar tap test and subsequent gait test performance in the patient population (Pearson coefficient r = 0.049-0.129). Log normalization of the volume of CSF removed and controlling for age and sex failed to yield a significant relationship. Subgroup analyses focusing on patients who showed greater than 20% improvement in any of the gait end points or who were deemed sufficiently responsive clinically to warrant surgery also yielded no significant relationships between the volume of CSF removed and gait outcomes, but there were preliminary findings that patients who underwent tap with larger-gauge needles had better postprocedure ambulation among patients who showed greater than 20% improvement in immediate time score (P = .04, n = 62). CONCLUSIONS: We found no evidence to support that a higher volume of CSF removal impacts gait testing, suggesting that a high volume of CSF removal may not be necessary in a diagnostic lumbar tap test.

Early glial activation precedes neurodegeneration in the cerebral cortex after SIV infection: a 3D, multivoxel proton magnetic resonance spectroscopy study.

OBJECTIVES: As ∼40% of HIV-infected individuals experience neurocognitive decline, we investigated whether proton magnetic resonance spectroscopic imaging ((1) H-MRSI) detects early metabolic abnormalities in the cerebral cortex of a simian immunodeficiency virus (SIV)-infected rhesus monkey model of neuroAIDS. METHODS: The brains of five rhesus monkeys before and 4 or 6 weeks after SIV infection (with CD8(+) T-cell depletion) were assessed with T2 -weighted quantitative magnetic resonance imaging (MRI) and 16×16×4 multivoxel (1) H-MRSI (echo time/repetition time = 33/1440 ms). Grey matter and white matter masks were segmented from the animal MRIs and used to produce cortical masks co-registered to (1) H-MRSI data to yield cortical metabolite concentrations of the glial markers myo-inositol (mI), creatine (Cr) and choline (Cho), and of the neuronal marker N-acetylaspartate (NAA). The cortex volume within the large, 28 cm(3) (∼35% of total monkey brain) volume of interest was also calculated for each animal pre- and post-infection. Mean metabolite concentrations and cortex volumes were compared pre- and post-infection using paired sample t-tests. RESULTS: The mean (± standard deviation) pre-infection concentrations of the glial markers mI, Cr and Cho were 5.8 ± 0.9, 7.2 ± 0.4 and 0.9 ± 0.1 mM, respectively; these concentrations increased 28% (p ≈ 0.06), 15% and 10% (both p < 0.05), respectively, post-infection. The mean concentration of neuronal marker NAA remained unchanged (7.0 ± 0.6 mM pre-infection vs. 7.3 ± 0.8 mM post-infection; p ≈ 0.37). The mean cortex volume was also unchanged (8.1 ± 1.1 cm(3) pre-infection vs. 8.3 ± 0.5 cm(3) post-infection; p ≈ 0.76). CONCLUSIONS: These results support the hypothesis that early cortical glial activation occurs after SIV infection prior to the onset of neurodegeneration. This suggests HIV therapeutic interventions should potentially target early glial activation in the cerebral cortex.

Eosinophilic granuloma presenting as post-traumatic scalp hematoma with epidural hemorrhage. A case report.

Langerhans cell histiocytosis (LCH) encompasses a range of clinical presentations. Pure osseous involvement is referred to as eosinophilic granuloma (EG), whereas systemic involvement can either be classified as Hand-Schuller-Christian disease or Letterer-Siwe syndrome. It is estimated that of the total incidence of LCH (0.5 per 100,000 children per year in the United States), nearly 70% are categorized as EG (1). We describe a case of clinically occult calvarial eosinophilic granuloma brought to medical attention only after a traumatic event led to scalp and epidural hemorrhage at the site of the lesion. Osseous EG initially presents as a painful or tender mass, at times even mimicking osteomyelitis. Computed tomography (CT) reveals a lytic lesion with beveled edges. Magnetic resonance (MR) imaging is often non-specific, but usually demonstrates a marrow-replacing process that is T1 hypointense, T2 hyperintense, with homogenous enhancement. The complex MR imaging findings in our case provided a unique perspective regarding the presentation of EG. Once pathology established eosinophilic granuloma, skeletal survey confirmed the lesion was solitary, despite a compelling history of present illness.

Letterer siwe disease.

A 1-year-old boy presented with recurrent pyoderma-like lesions and purulent ear discharge of 6 months duration. The biopsy helped to confirm Letterer Siwe disease. Purpuric lesion on palms and soles which is a reputedly lethal sign of the disease was also present in the child who died within a few days.

Effects of medium composition on the morphology and function of rat hepatocytes cultured as spheroids and monolayers.

Primary hepatocytes cultured as monolayers or as spheroids were studied to compare the effects of four different culture media (Williams' E, Chee's, Sigma Hepatocyte, and HepatoZYME medium). Rat hepatocytes were cultured as conventional monolayers for 3 d or as spheroids for 2 wk. For spheroid formation a method was emplOyed that combined the use of a nonadherent substratum with rotation of cultures. Hepatocyte integrity and morphology were assessed by light and electron microscopy and by reduced glutathione content. Hepatocyte function was measured by albumin secretion and 7-ethoxycoumarin metabolism. Chee's medium was found to be optimal for maintenance of hepatocyte viability and function in monolayers, but it failed to support spheroid formation. For spheroid formation and for the maintenance of spheroid morphology and function, Sigma HM was found to be optimal. These results demonstrate that the medium requirements of hepatocytes differ markedly depending on the culture model employed. Spheroid culture allowed better preservation of morphology and function of hepatocytes compared with conventional monolayer culture. Hepatocytes in spheroids formed bile canaliculi. and expressed an actin distribution resembling that found in hepatocytes in vivo. Albumin secretion was maintained at the same level as that found during the first d in primary culture, and 7-ethoxycoumarin metabolism was maintained over 2 wk in culture at approximately 30% of the levels found in freshly isolated hepatocytes. The improved morphology and function of hepatocyte cultures as spheroids may provide a more appropriate in vitro model for certain applications where the maintenance of liver-specific functions in long-term culture is crucial.

Ocular and systemic lesions in children with HIV.

The spectrum of ocular lesions in children with HIV infection is different from that seen in adults. Ocular lesions in pediatric AIDS patients have not been studied in India. We analyzed the clinical profile, demographic characteristics, ocular and systemic lesions in children with AIDS seen in a referral eye institute in India. The clinical profile and demographic features were studied and complete ocular examination was done. Systemic findings were evaluated at an AIDS care center and recorded in a precoded proforma. Out of the 218 cases of HIV infection seen at our hospital between December 1993 and October 1999, 12 (5.50%) were below 15 years of age. Seven (58.33%) were males and 5 (41.66%) were females with the mean age of 6.5 years and median age of 6.2 years. Vertical transmission was the most common mode of infection (58.33%). Seven (58.33%) of these patients had systemic infection, the most common being pulmonary tuberculosis (42.85%). Ocular lesions were found in 6 (50%) patients. The most common ocular lesions were anterior uveitis and cytomegalovirus retinitis (CMV) (33%) followed by retinal detachment (16.66%) and vitreous hemorrhage (16.66%). High prevalence of ocular lesions in pediatric AIDS patients in India in a referral eye centre was observed. The most common lesions were anterior uveitis followed by CMV retinitis. The management in such cases was often challenging in a developing country like India.

Ocular lesions associated with HIV infection in India: a series of 100 consecutive patients evaluated at a referral center.

PURPOSE: To document the ocular disorders seen in patients known to be infected with human immunodeficiency (HIV) virus at a referral eye clinic in India. METHODS: The first 100 individuals known to be HIV-positive at a referral eye clinic between 1993 and 1998 were enrolled in a prospective study. They underwent complete ocular and systemic evaluation. RESULTS: Most of the patients (76%) were in the 20-to 40-year age group. Heterosexual exposure to commercial sex workers was the most common risk factor (70%) for HIV infection. Cytomegalovirus (CMV) retinitis (17%) and HIV retinopathy (15%) were the most common HIV-associated ophthalmic lesions. Pulmonary tuberculosis (67%) and oropharyngeal candidiasis (66%) were the most commonly associated systemic infections. Ocular involvement was most common in children who contracted the disease through perinatal transmission (66.7%) and in homosexual patients (60%). Ocular involvement was comparatively less common in patients who contracted the disease through blood transfusions (33%) or exposure to commercial sex workers (24.3%). CONCLUSIONS: This study shows that the spectrum of ocular lesions associated with HIV infection in India is different from that seen elsewhere in the world. The prevalence of CMV retinitis and HIV retinopathy is lower in India, and there have been no cases of ocular Kaposi sarcoma. Adnexal infections, albeit rare, were seen in our series. The nonavailability and cost of therapy influenced the visual prognosis in these patients.

[The computed and magnetic resonance tomographic anatomy of the normal hippocampal area and in neurosurgical pathology]. / Komp'iuterno- i magnitno-rezonansno-tomograficheskaia anatomiia oblasti gippokampa v norme i pri neirokhirurgicheskoi patologii.

To make a correct diagnosis, a volumetric presentation of the anatomy of perihippocampal fluid spaces (PHFS) may be useful if there are abnormalities in the medial portion of the temporal region. Pathological processes in the region result in changes in the normal anatomy of PHFS. Hippocampal atrophy accompanied by enlarged PHFS is a sign of Alzheimer's disease (1081 patients). These changes are best detected on frontal MR images, but they can be seen at routine CT study. Hydrocephalus (88 patients) is characterized by dilatation of the lower horn of the lateral ventricles without increased dimensions of the transverse fissure. Normotensive hydrocephalus and Alzheimer's disease may be differentiated in evaluating the PHFS. The understanding of the anatomy of PHFS is useful in making a better assessment of the degree of both intra- and extracerebral tumors (in 296 patients) and arterioventricular malformations (in 12 patients) in the medial portions of the temporal regions.

Focal dilation and paradoxical collapse of cortical fissures and sulci in patients with normal-pressure hydrocephalus.

OBJECT: The authors describe a subgroup of patients with shunt-proven normal-pressure hydrocephalus (NPH) who presented with focal fissural and sulcal dilation on imaging studies. The specific radiological features and methods of differentiating this condition from cortical atrophy are delineated. METHODS: Normal-pressure hydrocephalus has been described as dilation of the ventricles that is out of proportion to the sulci. Sulcal dilation has been taken as evidence of cortical atrophy and has even been used as a criterion to exclude patients from undergoing a shunting procedure. The authors describe five cases of patients with shunt-proven NPH who presented with focal dilation of cortical fissures and sulci. In three of the cases, there was a paradoxical decrease in the size of the dilated fissures and sulci that paralleled the decrease in the size of the lateral ventricles following successful shunting. CONCLUSIONS: This study demonstrates that focal fissural and sulcal dilation may represent reservoirs of cerebrospinal fluid analogous to the ventricular system. Patients should not be denied a shunting procedure solely on the basis of focally dilated fissures of sulci.

MR differential diagnosis of normal-pressure hydrocephalus and Alzheimer disease: significance of perihippocampal fissures.

PURPOSE: In the older patient with dilated ventricles, it is often difficult to differentiate normal pressure hydrocephalus (NPH) from cerebral atrophy caused by Alzheimer disease (AD). This study was undertaken to see if dilatation of the perihippocampal fissures (PHFs) could be used as a distinguishing characteristic of these two disorders. METHODS: MR images of 17 patients with AD were compared with those from an equal number of patients with NPH who improved after ventriculoperitoneal shunting. The PHFs, lateral ventricles, third ventricle, and temporal horns were graded subjectively. Objective, computer-aided volumetric measurements of the PHFs and lateral ventricles were obtained. The preshunt images of the NPH patients were evaluated. RESULTS: Significant differences between the two groups were found for the PHFs and lateral ventricles by both the subjective and objective methods, with a high degree of correlation between the two methods. CONCLUSION: The degree of dilatation of PHFs appears to be a sensitive and specific marker for differentiating AD from NPH by both subjective and objective means, with a very small overlap between the two groups. This observation may have relevance in day-to-day practice.

The perihippocampal fissures: normal anatomy and disease states.

Understanding the three-dimensional anatomy of the perihippocampal fissures (PHFs) can be helpful in making the correct diagnosis of diseases of the mesial temporal lobe. Disorders of the parenchyma and cerebrospinal fluid spaces are reflected by specific changes in the PHFs. A marker for Alzheimer disease and mesial temporal sclerosis is atrophy of the hippocampus and associated dilatation of the PHFs. This finding is best visualized on coronal magnetic resonance images but can and should be appreciated on routine computed tomographic scans. Hydrocephalus is characterized by dilatation of the temporal horn of the lateral ventricle without dilatation of the transverse fissure and its extensions. Normal-pressure hydrocephalus can usually be distinguished from Alzheimer disease on the basis of the pattern of dilatation of the PHFs. Understanding the anatomy of the PHFs often makes it possible to better characterize the extents of intra- and extraaxial tumors of the mesial temporal lobe.