Biochemical, physiological and clinical effects of l-methylfolate in schizophrenia: a randomized controlled trial.

Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials. ClinicalTrials.gov, NCT01091506.

Progression from selective to general involvement of hippocampal subfields in schizophrenia.

Volume deficits of the hippocampus in schizophrenia have been consistently reported. However, the hippocampus is anatomically heterogeneous; it remains unclear whether certain portions of the hippocampus are affected more than others in schizophrenia. In this study, we aimed to determine whether volume deficits in schizophrenia are confined to specific subfields of the hippocampus and to measure the subfield volume trajectories over the course of the illness. Magnetic resonance imaging scans were obtained from Data set 1: 155 patients with schizophrenia (mean duration of illness of 7 years) and 79 healthy controls, and Data set 2: an independent cohort of 46 schizophrenia patients (mean duration of illness of 18 years) and 46 healthy controls. In addition, follow-up scans were collected for a subset of Data set 1. A novel, automated method based on an atlas constructed from ultra-high resolution, post-mortem hippocampal tissue was used to label seven hippocampal subfields. Significant cross-sectional volume deficits in the CA1, but not of the other subfields, were found in the schizophrenia patients of Data set 1. However, diffuse cross-sectional volume deficits across all subfields were found in the more chronic and ill schizophrenia patients of Data set 2. Consistent with this pattern, the longitudinal analysis of Data set 1 revealed progressive illness-related volume loss (~2-6% per year) that extended beyond CA1 to all of the other subfields. This decline in volume correlated with symptomatic worsening. Overall, these findings provide converging evidence for early atrophy of CA1 in schizophrenia, with extension to other hippocampal subfields and accompanying clinical sequelae over time.

Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.

This corrects the article DOI: 10.1038/mp.2017.42.

Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.

In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise.

New neurons are produced within the hippocampus of the mammalian brain throughout life. Evidence from animal studies has suggested that the function of these adult-born neurons is linked to cognition and emotion. Until we are able to detect and measure levels of adult neurogenesis in living human brains-a formidable challenge for now-we cannot establish its functional importance in human health, disease and new treatment development. Current non-invasive neuroimaging modalities can provide live snapshots of the brain's structure, chemistry, activity and connectivity. This review explores whether existing macroscopic imaging methods can be used to understand the microscopic dynamics of adult hippocampal neurogenesis in living individuals. We discuss recent studies that have found correlations between neuroimaging measures of human hippocampal biology and levels of pro- or anti-neurogenic stimuli, weigh whether these correlations reflect changes in adult neurogenesis, detail the conceptual and technical limitations of these studies and elaborate on what will be needed to validate in vivo neuroimaging measures of adult neurogenesis for future investigations.

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Local and downstream effects of excitotoxic lesions in the rat medial prefrontal cortex on In vivo 1H-MRS signals.

The rat medial prefrontal cortex (mPFC) regulates subcortical dopamine transmission via projections to the striatum and ventral tegmental area. We used in vivo proton magnetic resonance spectroscopy (1H-MRS) at 4.7 T to determine whether excitotoxic lesions of the mPFC result in alterations of N-acetylaspartate (NAA), a marker of neuronal integrity, both locally and downstream in the striatum. Lesioned rats exhibited persistent reductions of NAA and other metabolites within the prefrontal cortex; selective reductions of NAA were seen in the striatum, but not in the parietal cortex. Consistent with earlier reports, lesioned rats exhibited a transient enhancement in amphetamine-induced hyperlocomotion. Prefrontal NAA losses correlated with lesion extent. In the striatum, while there was no change in tissue volume, expression of striatal glutamic acid decarboxylase-67 mRNA was significantly reduced. In vivo NAA levels thus appear sensitive to both local and downstream alterations in neuronal integrity, and may signal meaningful effects at cellular and behavioral levels.

Digoxin and propranolol in the prophylaxis of supraventricular tachydysrhythmias after coronary artery bypass surgery.

Supraventricular tachydysrhythmia is a bothersome and potentially harmful occurrence after coronary artery bypass graft operation (CABG). Use of digoxin prophylaxis preoperatively has yielded conflicting results in lowering the incidence of supraventricular tachydysrhythmia. In this study, three groups of patients were formed. Group 1 served as the control; no prophylactic medication was given. Group 2 was given digoxin prophylaxis beginning immediately after operation. Group 3 received digoxin postoperatively as did Group 2, plus orally administered propranolol beginning on postoperative day 2. No difference in the incidence of supraventricular tachydysrhythmia was found between Groups 1 and 2 (28.2% versus 28.9%). However, the incidence in Group 3 was 2.2%, and this represented a statistically significant difference (p less than 0.005) compared with either Group or 2. The combined use of digoxin and propranolol postoperatively significantly reduced the incidence of supraventricular tachydysrhythmia after CABG.

Indirect laryngoscopy.

Indirect laryngoscopy is one of the procedural methods used for achieving a histopathologic diagnosis of cancer of the larynx. A chronologic historical summary of the development of mirror laryngoscopy is presented. The details of the procedure employed for obtaining a biopsy with the aid of topical anesthesia is discussed.

Nuclear scanning in necrotizing progressive "malignant" external otitis.

The usefulness of radionuclear scanning in the treatment of 18 patients with necrotizing progressive "malignant" external otitis is discussed. A Tc 99-m bone scan, a valuable test since results are positive in early cases of osteomyelitis of the temporal bone and base of skull, showed increased uptake in all 18 patients. In 6 patients, Ga-67 citrate scans were obtained at the start of therapy and at 5-6 week intervals thereafter. The serial gallium scans were useful in evaluating the effectiveness of therapy since the uptake decrease with control of infection.

Stereotyped behavior: effects of d-amphetamine and methylphenidate in the young rat.

The proclivity of d-amphetamine and methylphenidate to induce perseverative motoric and vocal side effects detracts from the clinical efficacy of these stimulants in the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). In an attempt to develop a model for these deleterious treatment effects, this study explored the behavioral influences exerted by d-amphetamine and methylphenidate in the young laboratory rat. This experiment revealed that doses of these stimulants that typically induce stereotypy provoke diverging behavioral profiles: while animals given 5 mg/kg d-amphetamine exhibited repetitive sniffing activity, rats treated with 30 mg/kg methyl-phenidate displayed perseverative gnawing behaviors. Although pretreatment with the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) significantly attenuated both stimulant-induced stereotypies, the effect of PCPA on d-amphetamine-induced sniffing was more profound than on methylphenidate-induced gnawing. High-performance liquid chromatography (HPLC) analysis of monoamine levels in the striatum, frontal cortex, and thalamus indicated that PCPA induced an overall 89% depletion of serotonin across all conditions. These findings shed some light on the neurochemical mechanisms that underlie the differential effects of d-amphetamine and methylphenidate on stereotyped motor activity in the rat, and suggest future experiments for understanding the role of serotonin in such effects. Further, these results have implications for the differential side effects observed from each of these stimulants when used clinically in children with ADHD.

Combined pre-operative irradiation and surgery for advanced cancer of the larynx and laryngopharynx. (A 14 year correlative statistical and histopathological study).

A carefully planned clinical program of combined pre-operative radiation and surgery has been conducted by the Department of Otolaryngology at The Mount Sinai Hospital for 14 years in an effort to improve the survival rate for advanced cancer of the larynx and laryngopharynx. An extensive histopathological study of resected larynges and radical neck specimens was undertaken in 1961 in order to determine the effects of pre-operative radiation. A very careful statistical analysis has been made of the survival experience of this series of cases. The three and five year survival rates have been computed by the actuarial method. The histopathological study entailed a serial section study of 26 larynges and 21 radical neck dissection specimens. These studies have been most informative as to the nature of the radiobiologic process involved in the destruction of laryngeal cancer. In addition, the study has been revealing as to the ability of radiation to sterilize cancer in the neck specimens. The clinical correlate of this histologic finding has been the observation of reduced cervical recurrences in patients treated with combined therapy. In conclusion, our statistics seem to indicate that our combined therapy method has improved the survival rates of patients with advanced cancer of the larynx and laryngopharynx.