Resting-State Functional MRI: Everything That Nonexperts Have Always Wanted to Know.

Resting-state fMRI was first described by Biswal et al in 1995 and has since then been widely used in both healthy subjects and patients with various neurologic, neurosurgical, and psychiatric disorders. As opposed to paradigm- or task-based functional MR imaging, resting-state fMRI does not require subjects to perform any specific task. The low-frequency oscillations of the resting-state fMRI signal have been shown to relate to the spontaneous neural activity. There are many ways to analyze resting-state fMRI data. In this review article, we will briefly describe a few of these and highlight the advantages and limitations of each. This description is to facilitate the adoption and use of resting-state fMRI in the clinical setting, helping neuroradiologists become familiar with these techniques and applying them for the care of patients with neurologic and psychiatric diseases.

Quantifying person-level brain network functioning to facilitate clinical translation.

Although advances in neuroimaging have yielded insights into the intrinsic organization of human brain networks and their relevance to psychiatric and neurological disorders, there has been no translation of these insights into clinical practice. One necessary step toward clinical translation is identifying a summary metric of network function that is reproducible, reliable, and has known normative data, analogous to normed neuropsychological tests. Our aim was therefore to establish the proof of principle for such a metric, focusing on the default mode network (DMN). We compared three candidate summary metrics: global clustering coefficient, characteristic path length, and average connectivity. Across three samples totaling 322 healthy, mostly Caucasian adults, average connectivity performed best, with good internal consistency (Cronbach's α=0.69-0.70) and adequate eight-week test-retest reliability (intra-class coefficient=0.62 in a subsample N=65). We therefore present normative data for average connectivity of the DMN and its sub-networks. These proof of principle results are an important first step for the translation of neuroimaging to clinical practice. Ultimately, a normed summary metric will allow a single patient's DMN function to be quantified and interpreted relative to normative peers.

Plasma and serum concentrations of cytarabine administered via continuous intravenous infusion to dogs with meningoencephalomyelitis of unknown etiology.

The objective of this study was to evaluate the plasma and serum concentrations of cytarabine (CA) administered via constant rate infusion (CRI) in dogs with meningoencephalomyelitis of unknown etiology (MUE). Nineteen client-owned dogs received a CRI of CA at a dose of 25 mg/m2 /h for 8 h as treatment for MUE. Dogs were divided into four groups, those receiving CA alone and those receiving CA in conjunction with other drugs. Blood samples were collected at 0, 1, 8, and 12 h after initiating the CRI. Plasma (n = 13) and serum (n = 11) cytarabine concentrations were measured by high-pressure liquid chromatography. The mean peak concentration (CMAX ) and area under the curve (AUC) after CRI administration were 1.70 ± 0.66 µg/mL and 11.39 ± 3.37 h·µg/mL, respectively, for dogs receiving cytarabine alone, 2.36 ± 0.35 µg/mL and 16.91 + 3.60 h·µg/mL for dogs administered cytarabine and concurrently on other drugs. Mean concentrations for all dogs were above 1.0 µg/mL at both the 1- and 8-h time points. The steady-state achieved with cytarabine CRI produces a consistent and prolonged exposure in plasma and serum, which is likely to produce equilibrium between blood and the central nervous system in dogs with a clinical diagnosis of MUE. Other medications commonly used to treat MUE do not appear to alter CA concentrations in serum and plasma.

Cyprinid herpesvirus 3 as a potential biological control agent for carp (Cyprinus carpio) in Australia: susceptibility of non-target species.

Carp (Cyprinus carpio L.) is a pest species in Australian waterways, and cyprinid herpesvirus 3 (CyHV-3) is being considered as a potential biological control (biocontrol) agent. An important consideration for any such agent is its target specificity. In this study, the susceptibility to CyHV-3 of a range of non-target species (NTS) was tested. The NTS were as follows: 13 native Australian, and one introduced, fish species; a lamprey species; a crustacean; two native amphibian species (tadpole and mature stages); two native reptilian species; chickens; and laboratory mice. Animals were exposed to 100-1000 times the approximate minimum amount of CyHV-3 required to cause disease in carp by intraperitoneal and/or bath challenge, and then examined clinically each day over the course of 28 days post-challenge. There were no clinical signs, mortalities or histological evidence consistent with a viral infection in a wide taxonomic range of NTS. Furthermore, there was no molecular evidence of infection with CyHV-3, and, in particular, all RT-PCRs for viral mRNA were negative. As a consequence, the results encourage further investigation of CyHV-3 as a potential biocontrol agent that is specific for carp.

Altered gray matter organization in children and adolescents with ADHD: a structural covariance connectome study.

Although multiple studies have reported structural deficits in multiple brain regions in attention-deficit hyperactivity disorder (ADHD), we do not yet know if these deficits reflect a more systematic disruption to the anatomical organization of large-scale brain networks. Here we used a graph theoretical approach to quantify anatomical organization in children and adolescents with ADHD. We generated anatomical networks based on covariance of gray matter volumes from 92 regions across the brain in children and adolescents with ADHD (n=34) and age- and sex-matched healthy controls (n=28). Using graph theory, we computed metrics that characterize both the global organization of anatomical networks (interconnectivity (clustering), integration (path length) and balance of global integration and localized segregation (small-worldness)) and their local nodal measures (participation (degree) and interaction (betweenness) within a network). Relative to Controls, ADHD participants exhibited altered global organization reflected in more clustering or network segregation. Locally, nodal degree and betweenness were increased in the subcortical amygdalae in ADHD, but reduced in cortical nodes in the anterior cingulate, posterior cingulate, mid temporal pole and rolandic operculum. In ADHD, anatomical networks were disrupted and reflected an emphasis on subcortical local connections centered around the amygdala, at the expense of cortical organization. Brains of children and adolescents with ADHD may be anatomically configured to respond impulsively to the automatic significance of stimulus input without having the neural organization to regulate and inhibit these responses. These findings provide a novel addition to our current understanding of the ADHD connectome.

A trans-diagnostic review of anxiety disorder comorbidity and the impact of multiple exclusion criteria on studying clinical outcomes in anxiety disorders.

Anxiety disorders are highly comorbid with each other and with other serious mental disorders. As our field progresses, we have the opportunity to pursue treatment study designs that consider these comorbidities. In this perspective review, we first characterized the prevalence of multiple anxiety disorder comorbidity by reanalyzing national survey data, then conducted an English-language PubMed search of studies analyzing the impact of exclusion criteria on treatment outcome data. In the prevalence data, 60% of people with an anxiety disorder had one or more additional anxiety or depression diagnosis. Because our commonly applied exclusion criteria focus on a single diagnosis and do not consider a multiple comorbidity profile, the impact of the criteria may be to exclude up to 92% of anxiety disorder treatment seekers. Moreover, the findings do not suggest a consistent relationship between the number of exclusion criteria and the effect size of treatment outcomes. Thus, future studies might consider a more trans-diagnostic rationale for determining exclusion criteria, one that is generalizable to real-world settings in which multiple diagnoses commonly co-occur. The findings also encourage a more systematic reporting of rationales for the choice of-and the implications of-each exclusion criterion.

Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression.

Few reliable predictors indicate which depressed individuals respond to antidepressants. Several studies suggest that a history of early-life trauma predicts poorer response to antidepressant therapy but results are variable and limited in adults. The major goal of the present study was to evaluate the role of early-life trauma in predicting acute response outcomes to antidepressants in a large sample of well-characterized patients with major depressive disorder (MDD). The international Study to Predict Optimized Treatment for Depression (iSPOT-D) is a randomized clinical trial with enrollment from December 2008 to January 2012 at eight academic and nine private clinical settings in five countries. Patients (n=1008) meeting DSM-IV criteria for MDD and 336 matched healthy controls comprised the study sample. Six participants withdrew due to serious adverse events. Randomization was to 8 weeks of treatment with escitalopram, sertraline or venlafaxine with dosage adjusted by the participant's treating clinician per routine clinical practice. Exposure to 18 types of traumatic events before the age of 18 was assessed using the Early-Life Stress Questionnaire. Impact of early-life stressors-overall trauma 'load' and specific type of abuse-on treatment outcomes measures: response: (⩾50% improvement on the 17-item Hamilton Rating Scale for Depression, HRSD17 or on the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated, QIDS_SR16) and remission (score ⩽7 on the HRSD17 and ⩽5 on the QIDS_SR16). Trauma prevalence in MDD was compared with controls. Depressed participants were significantly more likely to report early-life stress than controls; 62.5% of MDD participants reported more than two traumatic events compared with 28.4% of controls. The higher rate of early-life trauma was most apparent for experiences of interpersonal violation (emotional, sexual and physical abuses). Abuse and notably abuse occurring at ⩽7 years of age predicted poorer outcomes after 8 weeks of antidepressants, across the three treatment arms. In addition, the abuses occurring between ages 4 and 7 years differentially predicted the poorest outcome following the treatment with sertraline. Specific types of early-life trauma, particularly physical, emotional and sexual abuse, especially when occurring at ⩽7 years of age are important moderators of subsequent response to antidepressant therapy for MDD.

Development and application of molecular methods (PCR) for detection of Tasmanian Atlantic salmon reovirus.

Molecular (PCR) diagnostic tests for the detection and identification of aquareovirus in general, and Tasmanian Atlantic salmon reovirus (TSRV) specifically, were developed, and their diagnostic sensitivity and specificity were determined and compared with virus isolation in cell culture. Intralaboratory and interlaboratory comparison of PCR (conventional hemi-nested RT-PCR & RT-qPCR) and virus isolation in cell culture using finfish cell lines, CHSE-214 and EPC, was carried out for the detection and identification of TSRV using field samples of farmed Atlantic salmon Salmo salar, L. from various aquaculture sites around Tasmania. The interlaboratory comparison of diagnostic methods was carried out between two laboratories, AAHL-CSIRO and DPIPWE-Tasmania. A total of 144 fish from nine sites (12-33 fish per site) were sampled from two regions of Tasmania (Tamar River estuary in the north and Huon River estuary in the south-east) during late spring to early summer of 2009, and the data were analysed using different statistical approaches. The prevalence of TSRV ranged from 6% to 22% in both regions. All the diagnostic methods (data from both laboratories) had high specificity, while the estimated sensitivity varied between tests with RT-qPCR being the most sensitive (95.2%) method followed by virus isolation and then conventional hemi-nested RT-PCR.

High-fat diet induces leptin resistance in leptin-deficient mice.

The occurrence of type II diabetes is highly correlated with obesity, although the mechanisms linking the two conditions are incompletely understood. Leptin is a potent insulin sensitiser and, in leptin-deficient, insulin insensitive, Lep(ob/ob) mice, leptin improves glucose tolerance, indicating that leptin resistance may link obesity to insulin insensitivity. Leptin resistance occurs in response to a high-fat diet (HFD) and both hyperleptinaemia and inflammation have been proposed as causative mechanisms. Scrutinising the role of hyperleptinaemia in this process, central hyperleptinaemia in Lep(ob/ob) mice was induced by chronic i.c.v. infusion of leptin (4.2 µg/day) over 10 days. This treatment led to a dramatic decline in body weight and food intake, as well as an improvement in glucose tolerance. Transfer to HFD for 4 days markedly arrested the beneficial effects of leptin on these parameters. Because Lep(ob/ob) mice are exquisitely sensitive to leptin, the possibility that leptin could reverse HFD-induced glucose intolerance in these animals was investigated. HFD led to increased body weight and glucose intolerance compared to a low-fat diet (LFD). Older and heavier Lep(ob/ob) mice were used as body weight-matched controls. Mice in each group received either i.p. leptin (1.25 mg/kg) or vehicle, and glucose tolerance, food intake and the number of phosphorylated signal transducer and activator of transcription (pSTAT)3 immunoreactive cells in the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) were analysed. Leptin improved glucose tolerance (P = 0. 019) and reduced food intake in Lep(ob/ob) mice on LFD (P ≤ 0.001) but was ineffective in mice on HFD. Furthermore, when leptin was administered centrally, the glucose tolerance of Lep(ob/ob) mice on HFD was significantly impaired (P = 0.007). Although leptin induced the number of pSTAT3 immunoreactive cells in the ARC and VMH of Lep(ob/ob) mice on LFD, HFD was associated with elevated pSTAT3 immunoreactivity in vehicle-treated Lep(ob/ob) mice that was unaffected by leptin treatment, suggesting central leptin resistance. Negating central inflammation by co-administering a c-Jun n-terminal kinase (JNK) inhibitor reinstated the glucose-lowering effects of leptin. These findings demonstrate that Lep(ob/ob) mice develop leptin resistance on a HFD independent of hyperleptinaemia and also indicate that the JNK inflammatory pathway plays a key role in the induction of diet-induced glucose intolerance.

Engineered channels enhance cellular density in perfused scaffolds.

Scaffold-based tissue engineering provides cells with an engineered matrix to enhance and direct cell attachment, proliferation and differentiation. One critical limitation to current tissue engineering approaches is the inability to create densely populated constructs thicker than a few 100 µm. We hypothesized that development of porous, channeled scaffolds would increase cell density and uniformity of their spatial distribution through scaffold channel perfusion. Patterned polyurethane sheets were fabricated using a sprayed phase separation technique and laminated together to form 1.5 mm thick channeled scaffolds. Hydraulic permeability testing confirmed the presence of functional channels throughout the multilaminate construct. A continuous flow bioreactor was used to perfuse the construct with medium during the culture period. Cross-sectional cell densities and spatial uniformities were measured in channeled and nonchanneled scaffolds under different seeding and culture conditions. Channeled scaffolds were found to have higher densities of human mesenchymal stem cells than nonchanneled samples. Perfused scaffolds had more uniform spatial distribution of cells within the scaffold compared to statically cultured scaffolds. In conclusion, we have shown the channeled scaffolds to be a promising approach toward creating thick tissue-engineered constructs.

Traversing the ovine cervix - a challenge for cryopreserved semen and creative science.

This review brings together research findings on cervical relaxation in the ewe and its pharmacological stimulation for enhancement of the penetration needed for transcervical insemination and embryo transfer. On the basis that the success of artificial insemination is the percentage of ewes lambing, a review is made of recent research aimed at understanding and minimising the sub-lethal effects of freezing and thawing on the viability of spermatozoa, their membrane integrity and their ability to migrate through cervical mucus, as these characteristics have a major influence on fertility, particularly when semen is deposited, artificially, in the os cervix. Milestones of achievement are given for transcervical intrauterine insemination, embryo recovery and transfer and the birth of lambs of pre-determined sex, firstly following intracytoplasmic sperm injection, then laparoscopic intrauterine insemination using highly diluted flow-cytometrically sorted fresh semen and subsequently by os cervix insemination using sexed semen that had been frozen and thawed. Diversity of research endeavour (applied, cellular, molecular), research discipline (anatomy, histology, immunology, endocrinology) and research focus (cell, tissue, organ, whole animal) is embraced within the review as each has significant contributions to make in advancing recent scientific findings from the laboratory into robust on-farm transcervical insemination and embryo transfer techniques.

Anorexia nervosa: towards an integrative neuroscience model.

We reviewed the evidence for emotion-related disturbances in anorexia nervosa (AN) from behavioural, cognitive, biological and genetic domains of study. These domains were brought together within the framework of an integrative neuroscience model that emphasizes the role of emotion and feeling and their regulation, in brain organization. PsychInfo and Medline searches were performed to identify published peer-reviewed papers on AN within each domain. This review revealed evidence for 'Emotion', 'Thinking and Feeling' and 'Self-regulation' disturbances in AN that span non-conscious to conscious processes. An integrative neuroscience framework was then applied to develop a model of AN, from which hypotheses for empirical investigation are generated. We propose that AN reflects a core disturbance in emotion at the earliest time stage of information processing with subsequent effects on the later stages of thinking, feeling and self-regulation.

Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.

Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampal-prefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P=0.005) and symptoms (depression and anxiety, P<0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P=0.013), heart rate elevations (P=0.0002) and a decline in working memory (P=0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P<0.001), and associated lateral prefrontal cortex (P<0.001) and, in turn, higher depression (P=0.005). Higher depression was associated with poorer working memory (P=0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P<0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P=0.003) and associated medial prefrontal cortex (P<0.001), which in turn predicted startle-elicited heart rate variability (P=0.026) and higher anxiety (P=0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene-brain cognition pathways to these syndromes can be identified, even in a nonclinical sample. Such findings may aid establishing an evidence base for more tailored intervention strategies.

Effects of conjugated linoleic acid plus n-3 polyunsaturated fatty acids on insulin secretion and estimated insulin sensitivity in men.

BACKGROUND/OBJECTIVES: Dietary addition of either conjugated linoleic acid (CLA) or n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) has been shown to alter adiposity and circulating lipids, risk markers of cardiovascular diseases. However, CLA may decrease insulin sensitivity, an effect that may be reversed by n-3 LC-PUFA. Thus, the potential of CLA plus n-3 LC-PUFA to affect insulin secretion and sensitivity in non-diabetic young and old, lean and obese subjects was tested. SUBJECTS/METHODS: CLA (3 g daily) plus n-3 LC-PUFA (3 g daily) or control oil (6 g daily) was given to lean (n=12; BMI 20-26 kg/m(2)) or obese (n=10; BMI 29-35 kg/m(2)) young (20-37 years old) or lean (n=16) or obese (n=11) older men (50-65 years) for 12 weeks. The study had a double-blind, placebo-controlled randomized crossover design, and primary end points were insulin secretion and sensitivity during a standardized meal test, evaluated by modeling glucose, insulin and C-peptide data. RESULTS: The combination was well tolerated. There was no significant difference in fasting levels of glucose, insulin or C-peptide after CLA/n-3 LC-PUFA treatment compared with control oil. Neither insulin secretion nor estimated sensitivity was affected by CLA/n-3 LC-PUFA in lean or obese young subjects or in older lean subjects. However, in older obese subjects, estimated insulin sensitivity was reduced with CLA/n-3 LC-PUFA compared with control (P=0.024). CONCLUSIONS: The results do not support beneficial effects of CLA/n-3 LC-PUFA for beta-cell dysfunction or insulin resistance in humans but suggest that insulin sensitivity in older obese subjects is reduced.

Leptin sensitivity in the developing rat hypothalamus.

In adults, the adipocyte-derived hormone, leptin, regulates food intake and body weight principally via the hypothalamic arcuate nucleus (ARC). During early postnatal development, leptin functions to promote the outgrowth of neuronal projections from the ARC, whereas a selective insensitivity to the effects of leptin on food intake appears to exist. To investigate the mechanisms underlying the inability of leptin to regulate food intake during early development, leptin signaling was analyzed both in vitro using primary cultures of rat embryonic ARC neurones and in vivo by challenging early postnatal rats with leptin. In neuronal cultures, despite the presence of key components of the leptin signaling pathway, no detectable activation of either signal transducer and activator of transcription 3 or the MAPK pathways by leptin was detected. However, leptin down-regulated mRNA levels of proopiomelanocortin and neuropeptide Y and decreased somatostatin secretion. Leptin challenge in vivo at postnatal d (P) 7, P14, P21, and P28 revealed that, in contrast to adult and P28 rats, mRNA levels of neuropeptide Y, proopiomelanocortin, agouti-related peptide and cocaine- and amphetamine-regulated transcript were largely unaffected at P7, P14, and P21. Furthermore, leptin stimulation increased the suppressor of cytokine signaling-3 mRNA levels at P14, P21, and P28 in several hypothalamic nuclei but not at P7, indicating that selective leptin insensitivity in the hypothalamus is coupled to developmental shifts in leptin receptor signaling. Thus, the present study defines the onset of leptin sensitivity in the regulation of energy homeostasis in the developing hypothalamus.

Investigation of MCPH1 G37995C and ASPM A44871G polymorphisms and brain size in a healthy cohort.

Loss-of-function mutations in MCPH1 and ASPM are responsible for some cases of autosomal recessive primary microcephaly. Recent studies have indicated that certain common variants of these genes have been positively selected for during the evolution of modern humans. It is therefore possible that these variants may predispose to an increase in brain size in the normal human population. We genotyped the MCPH1 G37995C and ASPM A44871G polymorphisms in a cohort of 118 healthy people who had undergone structural magnetic resonance imaging analysis. We did not detect significant association of either MCPH1 G37995C or ASPM A44871G genotype with whole brain volume, cerebral cortical volume or proportion of grey matter in this cohort. Nor did we detect an association of combined MCPH1 37995C and ASPM 44871G allele dosage with these brain measurements. These results were also confirmed in an age-restricted subcohort of 94 individuals. This study suggests that phenotypes other than brain size may have been selected for in ASPM and MCPH1 variants during evolution of modern humans.

The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades.

Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy epsilon2 and epsilon4 carriers and matched epsilon3/epsilon3 controls, spanning ages 6-65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. epsilon4 subjects had better verbal fluency compared to epsilon3, an effect that was strongest in 51-65 year-olds. No epsilon4 deficits in cognition were found. In 6-15 year-olds, there were differences in total spatio-temporal wave activity between epsilon3 and epsilon4 subjects in the theta band, approximately 200ms post-stimulus. Differences in brain function in younger epsilon4 subjects and superior verbal fluency across the entire age range suggest that the APOE epsilon4 allele is an example of antagonistic pleiotropy.

Cognitive aging, executive function, and fractional anisotropy: a diffusion tensor MR imaging study.

BACKGROUND AND PURPOSE: Fractional anisotropy (FA) is a useful measure of connectivity in the brain that can be derived from the diffusion tensor imaging (DTI) dataset. This study investigated the relationship between FA and selected measures of cognition across a broad age group to explore a possible structural basis for cognitive changes with age. METHODS: FA images were generated from DTI data acquired at 1.5T in 87 healthy subjects (age range, 20-73 years). Relationships between a range of cognitive measures and FA were explored using regional and voxel-based analysis. RESULTS: Age and regional average FA were significantly associated in the frontal, parietal, and temporal lobes but not in the occipital lobe. This negative relationship was especially prominent in the prefrontal regions of the frontal lobe, where FA declined at a rate of approximately 3% per decade. Decreased FA in the frontal, temporal, and parietal lobes was associated with poorer cognitive performance in executive maze and in an attention-switching task. A voxel-level analysis of these data revealed that the executive function-FA association was particularly strong and regionally delineated over 2 continuous, bilateral areas extending from the prefrontal cortex to the parietal lobe, with projections to the anterior portions of the thalamus. CONCLUSIONS: We demonstrate a relationship between FA and a measure of executive function-a core cognitive component that is a key feature of cognitive aging. We propose that that FA may provide an early means for the detection of age-related cognitive change and suggest a need for prospective data to explore this association.