The importance of covert memory consolidation in schizophrenia: Dysfunctional network profiles of the hippocampus and the dorsolateral prefrontal cortex.

Altered brain network profiles in schizophrenia (SCZ) during memory consolidation are typically observed during task-active periods such as encoding or retrieval. However active processes are also sub served by covert periods of memory consolidation. These periods are active in that they allow memories to be recapitulated even in the absence of overt sensorimotor processing. It is plausible that regions central to memory formation like the dlPFC and the hippocampus, exert network signatures during covert periods. Are these signatures altered in patients? The question is clinically relevant because real world learning and memory is facilitated by covert processing, and may be impaired in schizophrenia. Here, we compared network signatures of the dlPFC and the hippocampus during covert periods of a learning and memory task. Because behavioral proficiency increased non-linearly, functional connectivity of the dlPFC and hippocampus [psychophysiological interaction (PPI)] was estimated for each of the Early (linear increases in performance) and Late (asymptotic performance) covert periods. During Early periods, we observed hypo-modulation by the hippocampus but hyper-modulation by dlPFC. Conversely, during Late periods, we observed hypo-modulation by both the dlPFC and the hippocampus. We stitch these results into a conceptual model of network deficits during covert periods of memory consolidation.

Learning without contingencies: A loss of synergy between memory and reward circuits in schizophrenia.

Motivational deficits in schizophrenia may interact with foundational cognitive processes including learning and memory to induce impaired cognitive proficiency. If such a loss of synergy exists, it is likely to be underpinned by a loss of synchrony between the brains learning and reward sub-networks. Moreover, this loss should be observed even during tasks devoid of explicit reward contingencies given that such tasks are better models of real world performance than those with artificial contingencies. Here we applied undirected functional connectivity (uFC) analyses to fMRI data acquired while participants engaged in an associative learning task without contingencies or feedback. uFC was estimated and inter-group differences (between schizophrenia patients and controls, n = 54 total, n = 28 patients) were assessed within and between reward (VTA and NAcc) and learning/memory (Basal Ganglia, DPFC, Hippocampus, Parahippocampus, Occipital Lobe) sub-networks. The task paradigm itself alternated between Encoding, Consolidation, and Retrieval conditions, and uFC differences were quantified for each of the conditions. Significantly reduced uFC dominated the connectivity profiles of patients across all conditions. More pertinent to our motivations, these reductions were observed within and across classes of sub-networks (reward-related and learning/memory related). We suggest that disrupted functional connectivity between reward and learning sub-networks may drive many of the performance deficits that characterize schizophrenia. Thus, cognitive deficits in schizophrenia may in fact be underpinned by a loss of synergy between reward-sensitivity and cognitive processes.

Multimodal neuroimaging data from a 5-week heart rate variability biofeedback randomized clinical trial.

We present data from the Heart Rate Variability and Emotion Regulation (HRV-ER) randomized clinical trial testing effects of HRV biofeedback. Younger (N = 121) and older (N = 72) participants completed baseline magnetic resonance imaging (MRI) including T1-weighted, resting and emotion regulation task functional MRI (fMRI), pulsed continuous arterial spin labeling (PCASL), and proton magnetic resonance spectroscopy (1H MRS). During fMRI scans, physiological measures (blood pressure, pulse, respiration, and end-tidal CO2) were continuously acquired. Participants were randomized to either increase heart rate oscillations or decrease heart rate oscillations during daily sessions. After 5 weeks of HRV biofeedback, they repeated the baseline measurements in addition to new measures (ultimatum game fMRI, training mimicking during blood oxygen level dependent (BOLD) and PCASL fMRI). Participants also wore a wristband sensor to estimate sleep time. Psychological assessment comprised three cognitive tests and ten questionnaires related to emotional well-being. A subset (N = 104) provided plasma samples pre- and post-intervention that were assayed for amyloid and tau. Data is publicly available via the OpenNeuro data sharing platform.

The topology, stability, and instability of learning-induced brain network repertoires in schizophrenia.

There is a paucity of graph theoretic methods applied to task-based data in schizophrenia (SCZ). Tasks are useful for modulating brain network dynamics, and topology. Understanding how changes in task conditions impact inter-group differences in topology can elucidate unstable network characteristics in SCZ. Here, in a group of patients and healthy controls (n = 59 total, 32 SCZ), we used an associative learning task with four distinct conditions (Memory Formation, Post-Encoding Consolidation, Memory Retrieval, and Post-Retrieval Consolidation) to induce network dynamics. From the acquired fMRI time series data, betweenness centrality (BC), a metric of a node's integrative value was used to summarize network topology in each condition. Patients showed (a) differences in BC across multiple nodes and conditions; (b) decreased BC in more integrative nodes, but increased BC in less integrative nodes; (c) discordant node ranks in each of the conditions; and (d) complex patterns of stability and instability of node ranks across conditions. These analyses reveal that task conditions induce highly variegated patterns of network dys-organization in SCZ. We suggest that the dys-connection syndrome that is schizophrenia, is a contextually evoked process, and that the tools of network neuroscience should be oriented toward elucidating the limits of this dys-connection.

Basal glutamate in the hippocampus and the dorsolateral prefrontal cortex in schizophrenia: Relationships to cognitive proficiency investigated with structural equation modelling.

OBJECTIVES: Schizophrenia is characterised by deficits across multiple cognitive domains and altered glutamate related neuroplasticity. The purpose was to investigate whether glutamate deficits are related to cognition in schizophrenia, and whether glutamate-cognition relationships are different between schizophrenia and controls. METHODS: Magnetic resonance spectroscopy (MRS) at 3 Tesla was acquired from the dorsolateral prefrontal cortex (dlPFC) and hippocampus in 44 schizophrenia participants and 39 controls during passive viewing visual task. Cognitive performance (working memory, episodic memory, and processing speed) was assessed on a separate session. Group differences in neurochemistry and mediation/moderation effects using structural equation modelling (SEM) were investigated. RESULTS: Schizophrenia participants showed lower hippocampal glutamate (p = .0044) and myo-Inositol (p = .023) levels, and non-significant dlPFC levels. Schizophrenia participants also demonstrated poorer cognitive performance (p < .0032). SEM-analyses demonstrated no mediation or moderation effects, however, an opposing dlPFC glutamate-processing speed association between groups was observed. CONCLUSIONS: Hippocampal glutamate deficits in schizophrenia participants are consistent with evidence of reduced neuropil density. Moreover, SEM analyses indicated that hippocampal glutamate deficits in schizophrenia participants as measured during a passive state were not driven by poorer cognitive ability. We suggest that functional MRS may provide a better framework for investigating glutamate-cognition relationships in schizophrenia.

Associations between myelin water imaging and measures of fall risk and functional mobility in multiple sclerosis.

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.

Real-Time fMRI Neurofeedback Training as a Neurorehabilitation Approach on Depressive Disorders: A Systematic Review of Randomized Control Trials.

Real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-nf) training is an emerging intervention for neurorehabilitation. However, its translation into clinical use on participants with clinical depression is unclear, the effect estimates from randomized control trials and the certainty of the supporting evidence on the effect estimates are unknown. As the number of studies on neurofeedback increases every year, and better quality evidence becomes available, we evaluate the evidence of all randomized control trials available on the clinical application of rt-fMRI-nf training on participants with clinical depression. We performed electronic searches in Pubmed, Embase, CENTRAL, rtFIN database, Epistemonikos, trial registers, reference lists, other systematic reviews, conference abstracts, and cross-citation in Google Scholar. Reviewers independently selected studies, extracted data and evaluated the risk of bias. The certainty of the evidence was judged using the GRADE framework. This review complies with PRISMA guidelines and was submitted to PROSPERO registration. We found 435 results. After the selection process, we included 11 reports corresponding to four RCTs. The effect of rt-fMRI-nf on improving the severity of clinical depression scores demonstrated a tendency to favor the intervention; however, the general effect was not significant. At end of treatment, SMD (standardized mean difference): -0.32 (95% CI -0.73 to 0.10). At follow-up, SMD: -0.33 (95% CI -0.91, 1.25). All the studies showed changes in BOLD fMRI activation after training; however, only one study confirmed regulation success during a transfer run. Whole-brain analyses suggests that rt-fMRI nf may alter activity patterns in brain networks. More studies are needed to evaluate quality of life, acceptability, adverse effects, cognitive tasks, and physiology measures. We conclude that the current evidence on the effect of rt-fMRI-nf training for decision-making outcomes in patients with clinical depression is still based on low certainty of the evidence.

Altered high-energy phosphate and membrane metabolism in Pelizaeus-Merzbacher disease using phosphorus magnetic resonance spectroscopy.

Pelizaeus-Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus-Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus-Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P < 0.0001 and P = 0.0002) and phosphocreatine levels were significantly higher (P < 0.0001) in Pelizaeus-Merzbacher disease patients compared with controls. Additionally, there was a significant group-by-brain area interaction for phosphocreatine with post-hoc analyses demonstrating significantly higher phosphocreatine levels in patients with Pelizaeus-Merzbacher disease compared with controls across multiple brain areas (anterior and posterior white matter, superior parietal lobe, posterior cingulate cortex, hippocampus, occipital cortex, striatum and thalamus; all P ≤ 0.0042). Phosphoethanolamine, glycerophosphoethanolamine and adenosine triphosphate levels were not significantly different between groups. For the first-time, widespread alterations in phosphorus magnetic resonance spectroscopy metabolite levels of Pelizaeus-Merzbacher disease patients are being reported. Specifically, increased high-energy phosphate storage levels of phosphocreatine concomitant with decreased inorganic orthophosphate across multiple areas suggest a widespread reduction in the high-energy phosphate utilization in Pelizaeus-Merzbacher disease, and the membrane phospholipid metabolite deficits suggest a widespread degradation in the neuropil content/maintenance of patients with Pelizaeus-Merzbacher disease which includes axons, dendrites and astrocytes within cortex and the myelin microstructure and oligodendrocytes within white matter. These results provide greater insight into the neuropathology of Pelizaeus-Merzbacher disease both in terms of energy expenditure and membrane phospholipid metabolites. Future longitudinal studies are warranted to investigate the utility of phosphorus magnetic resonance spectroscopy as surrogate biomarkers in monitoring treatment intervention for Pelizaeus-Merzbacher disease.

Test-retest and repositioning effects of white matter microstructure measurements in selected white matter tracts.

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.

Evidence of altered metabolism of cellular membranes in bipolar disorder comorbid with post-traumatic stress disorder.

In proton magnetic resonance spectroscopy (¹H MRS) studies, aberrant levels of choline-containing compounds that include glycerophosphocholine plus phosphocholine (GPC+PC), can signify alterations in the metabolism of cellular membrane phospholipids (MPLs) from a healthy baseline. In a recent ¹H MRS study, we reported increased GPC+PC in cortical and subcortical areas of adult patients with bipolar disorder I (BP-I). Post-traumatic stress disorder (PTSD) can worsen the severity of BP-I, but it is unclear whether the effect of a PTSD comorbidity in BP-I is associated with altered MPL metabolism. The purpose of this study was to re-investigate the ¹H MRS data to determine whether the regional extent of elevated GPC+PC was greater in BP-I patients with PTSD (BP-I/wPTSD) compared to BP-I without comorbid PTSD (BP-I/woPTSD) patients and healthy controls. GPC+PC levels from four brain areas [the anterior cingulate cortex (ACC), anterior-dorsal ACC, caudate, and putamen] were measured in 14 BP-I/wPTSD, 36 BP-I/woPTSD, and 44 healthy controls using a multi-voxel 1H MRS approach on a 3 Tesla system with high spatial resolution and absolute quantification. Results show a significant increase in GPC+PC levels from the caudate and putamen of BP-I/wPTSD patients compared to healthy controls (P<0.05) and in the putamen compared to BP-I/woPTSD patients (P<0.05). These findings are consistent with evidence of elevated degradation of MPLs in the neuropil that is more pronounced in BP-I patients with comorbid PTSD.

The benefit of negative pressure dressings in vascular surgery patients with infrainguinal incisions.

OBJECTIVE: Within the vascular patient population, there is an increased risk of developing wound complications especially in infrainguinal incisions. There has been increasing interest in using closed incisional negative pressure dressings to decrease the risk of wound complications. To assess the efficacy of these incisional wound dressings, we studied surgical site infections (SSI) and seroma rates of infrainguinal incisions in our vascular patient population. METHODS: This was a multi-institutional, retrospective study from July 2015 to June 2019. In 2017, our institution began using the Prevena incisional wound system. Wound complication rates were compared with the non-Prevena group before 2017. There were a total of 100 infrainguinal incisions (left and right combined) that received the Prevena wound system and 138 infrainguinal incisions that had not. The primary end point was to assess for wound complication rates, including SSIs and seroma formation. SSIs were graded based on the American College of Surgeons National Surgical Quality Improvement Plan SSI criteria. Seroma formation was diagnosed based on clinical diagnosis, imaging studies (ultrasound examination, computed tomography scan) or needle aspiration of fluid collection. RESULTS: This analysis showed a statistically significant decrease in the rate of SSIs in the Prevena group when compared with the non-Prevena group (P = .012). There was no statistical difference between the two groups in the rate of seroma formation (P = .155). Of the 100 incisions that received the Prevena wound system, 1.2% (1/82) had a femoral SSI and 22.0% (4/18) had a popliteal SSI. For seroma formation, 24.4% (20/82) had a femoral seroma and 11.1% (2/18) had a popliteal seroma. Of the 138 incisions that did not have the Prevena wound system, 9.6% (10/104) had a femoral SSI and 8.8% (3/34) had a popliteal SSI. For seroma formation, 24.0% (25/104) had a femoral seroma and 8.8% (3/34) had a popliteal seroma. Comorbid conditions were assessed in the two study groups and there was no statistical significance regarding rates of SSIs between the groups. CONCLUSIONS: The use of an incisional negative pressure dressing decreases the rate of SSIs in infrainguinal incisions. Regarding the use of these wound systems for seromas, our study did not show a statistically significant decrease in seroma rates.

Altered neurochemistry in the anterior white matter of bipolar children and adolescents: a multivoxel 1H MRS study.

Abnormalities within frontal lobe gray and white matter of bipolar disorder (BD) patients have been consistently reported in adult and pediatric studies, yet little is known about the neurochemistry of the anterior white matter (AWM) in pediatric BD and how medication status may affect it. The present cross-sectional 3T 1H MRS study is the first to use a multivoxel approach to study the AWM of BD youth. Absolute metabolite levels from four bilateral AWM voxels were collected from 49 subjects between the ages of 8 and 18 (25 healthy controls (HC); 24 BD) and quantified. Our study found BD subjects to have lower levels of N-acetylaspartate (NAA) and glycerophosphocholine plus phosphocholine (GPC + PC), metabolites that are markers of neuronal viability and phospholipid metabolism and have also been implicated in adult BD. Further analysis indicated that the observed patterns were mostly driven by BD subjects who were medicated at the time of scanning and had an ADHD diagnosis. Although limited by possible confounding effects of mood state, medication, and other mood comorbidities, these findings serve as evidence of altered neurochemistry in BD youth that is sensitive to medication status and ADHD comorbidity.

N-acetylcysteine reduces cocaine-seeking behavior and anterior cingulate glutamate/glutamine levels among cocaine-dependent individuals.

N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm3 ). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.

Sexual Dimorphism in the Brain Correlates of Adult-Onset Depression: A Pilot Structural and Functional 3T MRI Study.

Major Depressive Disorder (MDD) is a disabling illness affecting more than 5% of the elderly population. Higher female prevalence and sex-specific symptomatology have been observed, suggesting that biologically-determined dimensions might affect the disease onset and outcome. Rumination and executive dysfunction characterize adult-onset MDD, but sex differences in these domains and in the related brain mechanisms are still largely unexplored. The present pilot study aimed to explore any interactions between adult-onset MDD and sex on brain morphology and brain function during a Go/No-Go paradigm. We hypothesized to detect diagnosis by sex effects on brain regions involved in self-referential processes and cognitive control. Twenty-four subjects, 12 healthy (HC) (mean age 68.7 y, 7 females and 5 males) and 12 affected by adult-onset MDD (mean age 66.5 y, 5 females and 7 males), underwent clinical evaluations and a 3T magnetic resonance imaging (MRI) session. Diagnosis and diagnosis by sex effects were assessed on regional gray matter (GM) volumes and task-related functional MRI (fMRI) activations. The GM volume analyses showed diagnosis effects in left mid frontal cortex (p < 0.01), and diagnosis by sex effects in orbitofrontal, olfactory, and calcarine regions (p < 0.05). The Go/No-Go fMRI analyses showed MDD effects on fMRI activations in left precuneus and right lingual gyrus, and diagnosis by sex effects on fMRI activations in right parahippocampal gyrus and right calcarine cortex (p < 0.001, ≥ 40 voxels). Our exploratory results suggest the presence of sex-specific brain correlates of adult-onset MDD-especially in regions involved in attention processing and in the brain default mode-potentially supporting cognitive and symptom differences between sexes.

Microstructure of Human Corpus Callosum across the Lifespan: Regional Variations in Axon Caliber, Density, and Myelin Content.

The myeloarchitecture of the corpus callosum (CC) is characterized as a mosaic of distinct differences in fiber density of small- and large-diameter axons along the anterior-posterior axis; however, regional and age differences across the lifespan are not fully understood. Using multiecho T2 magnetic resonance imaging combined with multi-T2 fitting, the myelin water fraction (MWF) and geometric-mean of the intra-/extracellular water T2 (geomT2IEW) in 395 individuals (7-85 years; 41% males) were examined. The approach was validated where regional patterns along the CC closely resembled the histology; MWF matched mean axon diameter and geomT2IEW mirrored the density of large-caliber axons. Across the lifespan, MWF exhibited a quadratic association with age in all 10 CC regions with evidence of a positive linear MWF-age relationship among younger participants and minimal age differences in the remainder of the lifespan. Regarding geomT2IEW, a significant linear age × region interaction reflected positive linear age dependence mostly prominent in the regions with the highest density of small-caliber fibers-genu and splenium. In all, these two indicators characterize distinct attributes that are consistent with histology, which is a first. In addition, these results conform to rapid developmental progression of CC myelination leveling in middle age as well as age-related degradation of axon sheaths in older adults.

Sex differences in brain metabolites in anxiety and mood disorders.

Gender differences in mood and anxiety disorders are well-established. However, the neural basis of these differences is not clear yet, especially in terms of brain metabolism. Indeed, although several proton Magnetic Resonance Spectroscopy (¹H MRS) investigations reported different metabolic levels in both depression and anxiety disorders, which have been also linked to symptoms severity and response to treatment, the role of gender on these differences have not been explored yet. Therefore, this study aims at investigating the role of sex in neurometabolic alterations associated with both mood and anxiety disorders. A 3T single-voxel ¹H MRS acquisition of the dorsolateral prefrontal cortex was acquired from 14 Major Depressive Disorder, 10 Generalized Anxiety Disorder (GAD), 11 Panic Disorder (PD), patients and 16 healthy controls (HC). Among males, PD patients showed significantly lower GPC+PC (also observed in GAD+PD) and Glu levels compared to HC. Finally, a significant group x sex interaction effect was observed in the GPC+PC and Glu levels. We proved the presence of an association between sex and brain metabolites in anxiety spectrum.

A neurobiological correlate of stress-induced nicotine-seeking behavior among cigarette smokers.

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.

Regionally Distinct Alterations in Membrane Phospholipid Metabolism in Schizophrenia: A Meta-analysis of Phosphorus Magnetic Resonance Spectroscopy Studies.

BACKGROUND: Existing data on altered membrane phospholipid metabolism in schizophrenia are diverse. We conducted a meta-analysis of studies of phosphorus magnetic resonance spectroscopy, a noninvasive imaging approach that can assess molecular biochemistry of cortex by measuring phosphomonoester (PME) and phosphodiester (PDE) levels, which can provide evidence of altered biochemical processes involved in neuropil membrane expansion and contraction in schizophrenia. METHODS: We analyzed PME and PDE data in the frontal and temporal lobes in subjects with schizophrenia from 24 peer-reviewed publications using the MAVIS package in R by building random- and fixed-effects models. Heterogeneity of effect sizes, effects of publication bias, and file drawer analysis were also assessed. RESULTS: Subjects with schizophrenia showed lower PME levels in the frontal regions (p = .008) and elevated PDE levels in the temporal regions (p < .001) with significant heterogeneity. We noted significant publication bias and file drawer effect for frontal PME and PDE and temporal PDE levels, but not for temporal PME levels. Fail-safe analysis estimated that a high number of negative studies were required to provide nonsignificant results. CONCLUSIONS: Despite methodological differences, these phosphorus magnetic resonance spectroscopy studies demonstrate regionally specific imbalance in membrane phospholipid metabolism related to neuropil in subjects with schizophrenia compared with control subjects reflecting neuropil contraction. Specifically, decreased PME levels in the frontal regions and elevated PDE levels in the temporal regions provide evidence of decreased synthesis and increased degradation of neuropil membrane, respectively. Notwithstanding significant heterogeneity and publication bias, a large number of negative studies are required to render the results of this meta-analysis nonsignificant. These findings warrant further postmortem and animal studies.

Neurobiological Divergence of the Positive and Negative Schizophrenia Subtypes Identified on a New Factor Structure of Psychopathology Using Non-negative Factorization: An International Machine Learning Study.

BACKGROUND: Disentangling psychopathological heterogeneity in schizophrenia is challenging, and previous results remain inconclusive. We employed advanced machine learning to identify a stable and generalizable factorization of the Positive and Negative Syndrome Scale and used it to identify psychopathological subtypes as well as their neurobiological differentiations. METHODS: Positive and Negative Syndrome Scale data from the Pharmacotherapy Monitoring and Outcome Survey cohort (1545 patients; 586 followed up after 1.35 ± 0.70 years) were used for learning the factor structure by an orthonormal projective non-negative factorization. An international sample, pooled from 9 medical centers across Europe, the United States, and Asia (490 patients), was used for validation. Patients were clustered into psychopathological subtypes based on the identified factor structure, and the neurobiological divergence between the subtypes was assessed by classification analysis on functional magnetic resonance imaging connectivity patterns. RESULTS: A 4-factor structure representing negative, positive, affective, and cognitive symptoms was identified as the most stable and generalizable representation of psychopathology. It showed higher internal consistency than the original Positive and Negative Syndrome Scale subscales and previously proposed factor models. Based on this representation, the positive-negative dichotomy was confirmed as the (only) robust psychopathological subtypes, and these subtypes were longitudinally stable in about 80% of the repeatedly assessed patients. Finally, the individual subtype could be predicted with good accuracy from functional connectivity profiles of the ventromedial frontal cortex, temporoparietal junction, and precuneus. CONCLUSIONS: Machine learning applied to multisite data with cross-validation yielded a factorization generalizable across populations and medical systems. Together with subtyping and the demonstrated ability to predict subtype membership from neuroimaging data, this work further disentangles the heterogeneity in schizophrenia.

The Assertive Brain: Anterior Cingulate Phosphocreatine plus Creatine Levels Correlate With Self-Directedness in Healthy Adolescents.

Despite various advances in the study of the neurobiological underpinnings of personality traits, the specific neural correlates associated with character and temperament traits are not yet fully understood. Therefore, this study aims to fill this gap by exploring the biochemical basis of personality, which is explored with the temperament and character inventory (TCI), during brain development in a sample of adolescents. Twenty-six healthy adolescents (aged between 13 and 21 years; 17 males and 9 females) with behavioral and emotional problems underwent a TCI evaluation and a 3T single-voxel proton magnetic resonance spectroscopy (1H MRS) acquisition of the anterior cingulate cortex (ACC). Absolute metabolite levels were estimated using LCModel: significant correlations between metabolite levels and selective TCI scales were identified. Specifically, phosphocreatine plus creatine (PCr+Cre) significantly correlated with self-directedness, positively, and with a self-transcendence (ST), negatively, while glycerophosphocholine plus phosphocholine (GPC+PC) and myo-inositol negatively correlated with ST. To the best of our knowledge, this is the first study reporting associations of brain metabolites with personality traits in adolescents. Therefore, our results represent a step forward for personality neuroscience within the study of biochemical systems and brain structures.