Stress is known to influence smoking relapse. Experimental studies indicate that acute stress increases nicotine‐seeking behavior, yet neurobiological mechanisms remain poorly understood. Herein, we ...investigated disrupted excitatory neural activity in the dorsolateral prefrontal cortex (dlPFC) as a mechanism of stress‐induced nicotine‐seeking behavior. Non–treatment‐seeking cigarette smokers were screened for psychiatric, medical, and neuroimaging contraindications. Using a double‐blind, placebo‐controlled, randomized crossover design, participants (N = 21) completed two oral‐dosing sessions: stress (yohimbine 54 mg + hydrocortisone 10 mg) vs placebo (lactose 54 mg + lactose 10 mg). During each experimental session, working memory proficiency, dlPFC excitatory neural activity, nicotine‐seeking behavior, and subjective effects were measured. dlPFC excitatory neural activity was quantified via glutamate modulation during working memory performance using functional proton magnetic resonance spectroscopy. Nicotine‐seeking behavior was assayed using a cigarette puffs vs money choice progressive ratio task. Results indicated that yohimbine + hydrocortisone evoked a sustained physiological stress response (elevated heart rate, blood pressure, saliva cortisol, and saliva α‐amylase levels; ps < .05). Relative to placebo levels, acute stress increased nicotine‐seeking behavior (ps < .05), disrupted dlPFC glutamate modulation (p = .025), and impaired dlPFC function (working memory proficiency; ps < .05). The stress‐induced increase in nicotine‐seeking behavior was linearly related to the stress‐induced disruption of dlPFC glutamate modulation (R2 = 0.24‐0.37; ps < .05). These findings suggest that disrupted dlPFC excitatory neural activity is a neurobiological correlate of acute stress‐induced nicotine‐seeking behavior. These findings further emphasize the central role of the dlPFC in regulating drug‐seeking behavior. Future studies are needed to evaluate interventions to improve dlPFC resilience to acute stress effects, including neurostimulation, working memory training, and “anti‐stress” medications.
Stress is known to increase nicotine‐seeking behavior; yet neurobiological mechanisms remain poorly understood. Our findings indicate pharmacological stress increased nicotine‐seeking behavior, impaired dorsolateral prefrontal cortex function, and disrupted dorsolateral prefrontal cortex glutamate modulation. The effects of stress on dorsolateral prefrontal cortex glutamate modulation were correlated with stress‐induced nicotine‐seeking behavior, suggesting a mechanistic relationship.
A recent report suggested Complement 4 (C4A) gene copy numbers (GCN) as risk factors for schizophrenia. Rodent model showed association of C4 with synaptic pruning suggesting its pathophysiological ...significance (Sekar, A. et al. (2016)). We, therefore, predicted that C4A GCN would be positively correlated with neuropil contraction in the human brain among schizophrenia patients showing more prominent correlations in ventral regions among young adults and dorsal regions among adolescents since neuromaturation progresses dorsoventrally. Whole-brain, multi-voxel, in vivo phosphorus magnetic resonance spectroscopy (
P MRS) assessed neuropil changes by estimating levels of membrane phospholipid (MPL) precursors and catabolites. Increased MPL catabolites and/or decreased MPL precursors indexed neuropil contraction. Digital droplet PCR-based assay was used to estimate C4A and C4B GCN. We evaluated two independent cohorts (young adult-onset early-course schizophrenia (YASZ = 15) and adolescent-onset schizophrenia (AOSZ = 12) patients), and controls matched for each group, n = 22 and 15, respectively. Separate forward stepwise linear regression models with Akaike information Criterion were built for MPL catabolites and precursors. YASZ cohort: Consistent with the rodent model (Sekar, A. et al. 2016)), C4A GCN positively correlated with neuropil contraction (increased pruning/decreased formation) in the inferior frontal cortex and inferior parietal lobule. AOSZ cohort: C4A GCN positively correlated with neuropil contraction in the dorsolateral prefrontal cortex and thalamus. Exploratory analysis of C4B GCN showed positive correlation with neuropil contraction in the cerebellum and superior temporal gyrus among YASZ while AOSZ showed neuropil contraction in the prefrontal and subcortical structures. Thus, C4A and C4B GCN are associated with neuropil contraction in regions often associated with schizophrenia, and may be neuromaturationally dependent.
Background and Purpose
Myelin water fraction (MWF) deficits as measured by myelin water imaging (MWI) have been related to worse motor function in persons with multiple sclerosis (PwMS). However, it ...is unknown if measures from MWI metrics in motor areas relate to fall risk measures in PwMS. The objective of this study was to examine the relationship between MWI measures in motor areas to performance on clinical measures of fall risk and disability in PwMS.
Methods
Sixteen individuals with relapsing‐remitting MS participated (1 male, 15 female; age 47.1 years 12.3; Expanded Disability Status Scale 4.0 range 0‐6.5) and completed measures of walking and fall risk (Timed 25 Foot Walk T25FW and Timed Up and Go). MWF and the geometric mean of the intra‐/extracellular water T2 (geomT2IEW) values reflecting myelin content and contribution of large‐diameter axons/density, respectively, were assessed in three motor‐related regions.
Results
The geomT2IEW of the corticospinal tract (r = –.599; p = .018) and superior cerebellar peduncles (r = –.613; p = .015) demonstrated significant inverse relationships with T25FW, suggesting that decreased geomT2IEW was related to slower walking. Though not significant, MWF in the corticospinal tract and superior cerebellar peduncles also demonstrated fair relationships with the T25FW, suggesting that worse performance on the T25FW was associated with lower MWF values.
Conclusions
MWI of key motor regions was associated with walking performance in PwMS. Further MWI studies are needed to identify relationships between pathology and clinical function in PwMS to guide targeted rehabilitation therapies aimed at preventing falls.
Abstract Background Proton magnetic resonance spectroscopy (1 H MRS) enables in-vivo measurement of several relevant brain metabolites and has provided evidence of a range of neurochemical ...abnormalities in schizophrenia, especially in glutamate and N-acetyl-aspartate (NAA). While individuals at high familial risk for schizophrenia (HR) exhibit some neurobiological findings observed in the disorder,1 H MRS findings and their clinical correlates are not well characterized in this population. Methods We compared 23 adolescent and young adult offspring of schizophrenia patients with 24 age- and sex-matched healthy controls using1 H MRS. We acquired multi-voxel, short TE1 H MRS measurements at 1.5 T and obtained metabolite concentrations of N-acetyl-aspartate (NAA), combined glutamate and glutamine (Glu + Gln) and choline-containing compounds (GPC + PC) for the left and right thalamus, anterior cingulate gyrus, and caudate. We also assessed the relationship between regional metabolite levels, clinical measures and brain volume in a subset of 16 high-risk and 15 control subjects. Results Compared to healthy controls, high-risk subjects showed reductions in NAA levels in all three regions (thalamus, caudate, and anterior cingulate cortex), increases in Glu + Gln in the thalamus and caudate, and increases in GPC + PC in the anterior cingulate. In HR, thalamic Glu + Gln concentration was positively correlated and thalamic NAA inversely correlated with measures of schizotypy. Anterior cingulate GPC + PC and caudate Glu + Gln were significantly correlated with attenuated psychotic symptom severity. Anterior cingulate NAA was correlated with executive function. Conclusions Our data suggest the occurrence of metabolic alterations in young relatives of schizophrenia patients similar to those seen in patients with established illness. The observed correlations with cognitive deficits and psychosis-related psychopathology suggest that these metabolic measures may have value as biomarkers of risk for schizophrenia.
Background
The Institute of Medicine recommends developing a broader workforce of mental health providers, including nontraditional providers, to expand services for older adults. Cognitive behavior ...therapy (CBT) is effective for late‐life generalized anxiety disorder (GAD), but no study has examined outcomes with delivery by lay providers working under the supervision of licensed providers. The current study examined the effects of CBT delivered by lay, bachelor‐level providers (BLP) relative to Ph.D.‐level expert providers (PLP), and usual care (UC) in older adults with GAD.
Methods
Participants were 223 older adults (mean age, 66.9 years) with GAD recruited from primary care clinics at two sites and assigned randomly to BLP (n = 76), PLP (n = 74), or UC (n = 73). Assessments occurred at baseline and 6 months. CBT in BLP and PLP included core and elective modules (3 months: skills training; 3 months: skills review) delivered in person and by telephone, according to patient choice.
Results
CBT in both BLP and PLP groups significantly improved GAD severity (GAD Severity Scale), anxiety (Spielberger State‐Trait Anxiety Inventory; Structured Interview Guide for the Hamilton Anxiety Scale), depression (Patient Health Questionnaire), insomnia (Insomnia Severity Index), and mental health quality of life (Short‐Form‐12), relative to UC. Response rates defined by 20% reduction from pre‐ to posttreatment in at least three of four primary outcomes were higher for study completers in BLP and PLP relative to UC (BLP: 38.5%; PLP: 40.0%; UC: 19.1%).
Conclusion
Lay providers, working under the supervision of licensed providers, can deliver effective CBT.
Background Understanding individual differences in the development of extrapyramidal side effects (EPS) as a response to antipsychotic therapy is essential to individualize treatment. Methods We ...performed genomewide association studies to search for genetic susceptibility to EPS. Our sample consisted of 738 schizophrenia patients, genotyped for 492K single nucleotide polymorphisms (SNPs). We studied three quantitative measures of antipsychotic adverse drug reactions—the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale (AIMS)—as well as a clinical diagnosis of probable tardive dyskinesia. Results Two SNPs for SAS, rs17022444 and rs2126709 with p = 1.2 × 10−10 and p = 3.8 × 10−7 , respectively, and one for AIMS, rs7669317 with p = 7.7 × 10−8 , reached genomewide significance ( Q value < .1). rs17022444 and rs7669317 were located in intergenic regions and rs2126709 was located in ZNF202 on 11q24. Fourteen additional signals were potentially interesting ( Q value < .5). The ZNF202 is a transcriptional repressor controlling, among other genes, PLP1 , which is the major protein in myelin. Mutations in PLP1 cause Pelizaeus-Merzbacher disease, which has Parkinsonism as an occurring symptom. Altered mRNA expression of PLP1 is associated with schizophrenia. Conclusions Although our findings require replication and validation, this study demonstrates the potential of genomewide association studies to discover genes and pathways that mediate adverse effects of antipsychotics.
Abstract Objective This study examined rates of specific anxiety diagnoses (posttraumatic stress disorder, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety ...disorder, and specific phobia) and anxiety disorder not otherwise specified (anxiety NOS) in a national sample of Veterans and assessed their mental health service utilization. Method This study used administrative data extracted from Veteran Health Administration outpatient records to identify patients with a new anxiety diagnosis in fiscal year 2010 (N = 292,244). Logistic regression analyses examined associations among diagnostic specificity, diagnostic location, and mental health service utilization. Results Anxiety NOS was diagnosed in 38% of the sample. Patients in specialty mental health were less likely to receive an anxiety NOS diagnosis than patients in primary care (odds ratio OR = 0.36). Patients with a specific anxiety diagnosis were more likely to receive mental health services than those with anxiety NOS (OR = 1.65), as were patients diagnosed in specialty mental health compared with those diagnosed in primary care (OR = 16.29). Conclusion Veterans diagnosed with anxiety NOS are less likely to access mental health services than those with a specific anxiety diagnosis, suggesting the need for enhanced diagnostic and referral practices, particularly in primary care settings.
The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency ...of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1′ site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
We used intra-class effect decomposition (ICED) to evaluate the reliability of myelin water fraction (MWF) and geometric mean T2 relaxation time (geomT2IEW) estimated from a multi-echo MRI sequence. ...Our evaluation addressed test-retest reliability, with and without participant re-positioning, for seven commonly assessed white matter tracts: anterior and posterior limbs of the internal capsule, dorsal and ventral branches of the cingulum, the inferior fronto-occipital fasciculus, the superior longitudinal fasciculus, and the fornix in 20 healthy adults. We acquired two back-to-back scans in a single session, and a third after a break and repositioning the participant in the scanner. For both indices and for all white matter tracts assessed, reliability for an immediate retest, and after the participant's repositioning in the scanner was high. Variance partitioning revealed that in addition to measurement noise, which was significant in all regions, repositioning contributed to unreliability mainly in longer association fibers. Hemispheric location did not significantly contribute to unreliability in any region of interest (ROI). Thus, despite non-negligible error of measurement, for all ROIs, MWF and geomT2IEW have good test–retest reliability, regardless of the hemispheric location and are, therefore, suitable for longitudinal investigations in healthy adults.
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