Mapping Age Differences in Brain Energy Metabolites and Metabolic Markers of Cellular Membrane Production and Degradation With 31P Magnetic Resonance Spectroscopy.

Using Phosphorus Magnetic Resonance Spectroscopy (31P MRS), we examined five metabolites associated with brain energy cycle, and cellular membrane production and degradation in 11 brain regions of 48 children (age 6-15), and 80 middle-aged and older adults (age 52-87). Levels of phosphomonoesters (PMEs) and phosphodiesters (PDEs), gamma plus alpha adenosine triphosphate (γαATP), phosphocreatine (PCr) and inorganic phosphate (Pi), were residualized on the total amplitude value. PMEs were greater in children compared to adults, whereas PDEs showed the opposite age difference. Higher γαATP and lower Pi were found in children compared to adults. The age group differences were particularly salient in the association cortices and anterior white matter. Among children, age correlated negatively with PMEs and positively with PDEs in association cortices. Compared to children, adults had lower intracellular pH. The results suggest reduction in membrane synthesis and increase in membrane degradation in adolescents and to a greater degree in adults compared to younger children. Concomitant reduction in γαATP and increase in Pi are consistent with reduced energy consumption in adolescents and further drop in middle-aged and older adults, although it is impossible to distinguish declines in energy supply from reduced demand due to shrinking neuropil, without longitudinal studies.

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.

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.

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.

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.

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.

Pharmacological stress impairs working memory performance and attenuates dorsolateral prefrontal cortex glutamate modulation.

Working memory processes are associated with the dorsolateral prefrontal cortex (dlPFC). Prior research using proton functional magnetic resonance spectroscopy (1H fMRS) observed significant dlPFC glutamate modulation during letter 2-back performance, indicative of working memory-driven increase in excitatory neural activity. Acute stress has been shown to impair working memory performance. Herein, we quantified dlPFC glutamate modulation during working memory under placebo (oral lactose) and acute stress conditions (oral yohimbine 54 mg + hydrocortisone 10 mg). Using a double-blind, randomized crossover design, participants (N = 19) completed a letter 2-back task during left dlPFC 1H fMRS acquisition (Brodmann areas 45/46; 4.5 cm3). An automated fitting procedure integrated with LCModel was used to quantify glutamate levels. Working memory-induced glutamate modulation was calculated as percentage change in glutamate levels from passive visual fixation to 2-back levels. Results indicated acute stress significantly attenuated working memory-induced glutamate modulation and impaired 2-back response accuracy, relative to placebo levels. Follow-up analyses indicated 2-back performance significantly modulated glutamate levels relative to passive visual fixation during placebo but not acute stress. Biomarkers, including blood pressure and saliva cortisol, confirmed that yohimbine + hydrocortisone dosing elicited a significant physiological stress response. These findings support a priori hypotheses and demonstrate that acute stress impairs dlPFC function and excitatory activity. This study highlights a neurobiological mechanism through which acute stress may contribute to psychiatric dysfunction and derail treatment progress. Future research is needed to isolate noradrenaline vs. cortisol effects and evaluate anti-stress medications and/or behavioral interventions.

Cortical-hippocampal functional connectivity during covert consolidation sub-serves associative learning: Evidence for an active "rest" state.

We studied modulation of undirected functional connectivity (uFC) in cortical-hippocampal sub-networks during associative learning. Nineteen healthy individuals were studied (fMRI acquired on a Siemens Verio 3T), and uFC was studied between nodes in a network of regions identified by standard activation models based on bivariate correlational analyses of time series data. The paradigm alternated between Memory Encoding, Rest and Retrieval. "Rest" intervals promoted covert consolidation. Over the task, performance was broadly separable into linear (Early) and asymptomatic (Late) regimes, with late performance reflecting successful memory consolidation. Significant modulation of uFC was observed during periods of covert consolidation. The sub-networks which were modulated constituted connections between frontal regions such as the dorsal prefrontal cortex (dPFC) and dorsal anterior cingulate cortex (dACC), the medial temporal lobe (hippocampus, HPC), the superior parietal cortex (SPC) and the fusiform gyrus (FG). uFC patterns were dynamic in that sub-networks modulated during Early learning (dACC ↔ SPC, dACC ↔ FG, dPFC ↔ HPC) were not identical to those modulated during Late learning (dACC ↔ HPC, dPFC ↔ FG, FG ↔ SPC). Covert consolidation exerts systematic effects, and these results add to emerging evidence for the constructive role of the brain's "resting state" in potentiating action.

Differences in steady-state glutamate levels and variability between 'non-task-active' conditions: Evidence from 1H fMRS of the prefrontal cortex.

Proton functional magnetic resonance spectroscopy (1H fMRS) is a noninvasive neuroimaging technique capable of detecting dynamic changes in glutamate related to task-related demands at a temporal resolution under 1 min. Several recent 1H fMRS studies demonstrated elevated steady-state levels of glutamate of 2% or greater during different 'task-active' conditions, relative to a 'non-task-active' control condition. However, the 'control' condition from these studies does vary with respect to the degree of constraining behavior, which may lead to different glutamate levels or variability between 'control' conditions. The purpose of this 1H fMRS study was to compare the steady-state levels and variability of glutamate in the left dorsolateral prefrontal cortex (dlPFC) of 16 healthy adults across four different putative 'non-task-active' conditions: relaxed with eyes closed, passive visual fixation crosshair, visual flashing checkerboard, and finger tapping. Results showed significantly lower glutamate levels during the passive visual fixation crosshair than the visual flashing checkerboard and the finger tapping conditions. Moreover, glutamate was significantly less variable during the passive visual fixation crosshair and the visual flashing checkerboard than the relaxed eyes closed condition. Of the four conditions, the passive visual fixation crosshair condition demonstrated the lowest and least variable glutamate levels potentially reflecting the least dlPFC engagement, but greatest behavioral constraint. These results emphasize the importance of selecting a proper 'control' condition to reflect accurately a 'non-task-active' steady-state level of glutamate with minimal variability during 1H MRS investigations.

Functional dynamics of hippocampal glutamate during associative learning assessed with in vivo 1H functional magnetic resonance spectroscopy.

fMRI has provided vibrant characterization of regional and network responses associated with associative learning and memory; however, their relationship to functional neurochemistry is unclear. Here, we introduce a novel application of in vivo proton functional magnetic resonance spectroscopy (1H fMRS) to investigate the dynamics of hippocampal glutamate during paired-associated learning and memory in healthy young adults. We show that the temporal dynamics of glutamate differed significantly during processes of memory consolidation and retrieval. Moreover, learning proficiency was predictive of the temporal dynamics of glutamate such that fast learners were characterized by a significant increase in glutamate levels early in learning, whereas this increase was only observed later in slow learners. The observed functional dynamics of glutamate provides a novel in vivo marker of brain function. Previously demonstrated N-methyl-D-aspartate (NMDA) receptor mediated synaptic plasticity during associative memory formation may be expressed in glutamate dynamics, which the novel application of 1H MRS is sensitive to. The novel application of 1H fMRS can provide highly innovative vistas for characterizing brain function in vivo, with significant implications for studying glutamatergic neurotransmission in health and disorders such as schizophrenia.

Test-retest reliability and concurrent validity of in vivo myelin content indices: Myelin water fraction and calibrated T1 w/T2 w image ratio.

In an age-heterogeneous sample of healthy adults, we examined test-retest reliability (with and without participant repositioning) of two popular MRI methods of estimating myelin content: modeling the short spin-spin (T2 ) relaxation component of multi-echo imaging data and computing the ratio of T1 -weighted and T2 -weighted images (T1 w/T2 w). Taking the myelin water fraction (MWF) index of myelin content derived from the multi-component T2 relaxation data as a standard, we evaluate the concurrent and differential validity of T1 w/T2 w ratio images. The results revealed high reliability of MWF and T1 w/T2 w ratio. However, we found significant correlations of low to moderate magnitude between MWF and the T1 w/T2 w ratio in only two of six examined regions of the cerebral white matter. Notably, significant correlations of the same or greater magnitude were observed for T1 w/T2 w ratio and the intermediate T2 relaxation time constant, which is believed to reflect differences in the mobility of water between the intracellular and extracellular compartments. We conclude that although both methods are highly reliable and thus well-suited for longitudinal studies, T1 w/T2 w ratio has low criterion validity and may be not an optimal index of subcortical myelin content. Hum Brain Mapp 38:1780-1790, 2017. © 2017 Wiley Periodicals, Inc.

Altered metabolomic-genomic signature: A potential noninvasive biomarker of epilepsy.

OBJECTIVE: This study aimed to identify noninvasive biomarkers of human epilepsy that can reliably detect and localize epileptic brain regions. Having noninvasive biomarkers would greatly enhance patient diagnosis, patient monitoring, and novel therapy development. At the present time, only surgically invasive, direct brain recordings are capable of detecting these regions with precision, which severely limits the pace and scope of both clinical management and research progress in epilepsy. METHODS: We compared high versus low or nonspiking regions in nine medically intractable epilepsy surgery patients by performing integrated metabolomic-genomic-histological analyses of electrically mapped human cortical regions using high-resolution magic angle spinning proton magnetic resonance spectroscopy, cDNA microarrays, and histological analysis. RESULTS: We found a highly consistent and predictive metabolite logistic regression model with reduced lactate and increased creatine plus phosphocreatine and choline, suggestive of a chronically altered metabolic state in epileptic brain regions. Linking gene expression, cellular, and histological differences to these key metabolites using a hierarchical clustering approach predicted altered metabolic vascular coupling in the affected regions. Consistently, these predictions were validated histologically, showing both neovascularization and newly discovered, millimeter-sized microlesions. SIGNIFICANCE: Using a systems biology approach on electrically mapped human cortex provides new evidence for spatially segregated, metabolic derangements in both neurovascular and synaptic architecture in human epileptic brain regions that could be a noninvasively detectable biomarker of epilepsy. These findings both highlight the immense power of a systems biology approach and identify a potentially important role that magnetic resonance spectroscopy can play in the research and clinical management of epilepsy.

Adult age differences in subcortical myelin content are consistent with protracted myelination and unrelated to diffusion tensor imaging indices.

Post mortem studies suggest protracted myelination of subcortical white matter into the middle age followed by gradual decline in the late adulthood. To date, however, establishing the proposed inverted-U pattern of age-myelin association proved difficult, as the most common method of investigating white matter, diffusion tensor imaging (DTI), usually reveals only linear associations between DTI indices and age among healthy adults. Here we use a novel method of estimating Myelin Water Fraction (MWF) based on modeling the short spin-spin (T2) relaxation component from multi-echo T2 relaxation imaging data and assess subcortical myelin content within six white matter tracts in a sample of healthy adults (N=61, age 18-84 years). Myelin content evidenced a quadratic relationship with age, in accord with the pattern observed postmortem studies. In contrast, DTI-derived indices that are frequently cited as proxies for myelination, fractional anisotropy (FA) and radial diffusivity (RD), exhibited linear or null relationships with age. Furthermore, the magnitude of age differences in MWF varied across the white matter tracts. Myelin content estimated by MWF was unrelated to FA and correlated with RD only in the splenium. These findings are consistent with the notion that myelination continues throughout the young adulthood into the middle age. The results demonstrate that single-tensor DTI cannot serve as a source of specific proxies for myelination of white matter tracts.

An in vivo 1H magnetic resonance spectroscopy study of the deep cerebellar nuclei in children with fetal alcohol spectrum disorders.

BACKGROUND: Prenatal alcohol exposure has been linked to impairment in cerebellar structure and function, including eyeblink conditioning. The deep cerebellar nuclei, which play a critical role in cerebellar-mediated learning, receive extensive inputs from brain stem and cerebellar cortex and provide the point of origin for most of the output fibers to other regions of the brain. We used in vivo (1) H magnetic resonance spectroscopy (MRS) to examine effects of prenatal alcohol exposure on neurochemistry in this important cerebellar region. METHODS: MRS data from the deep cerebellar nuclei were acquired from 37 children with heavy prenatal alcohol exposure and 17 non- or minimally exposed controls from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa. RESULTS: Increased maternal alcohol consumption around time of conception was associated with lower N-Acetylaspartate (NAA) levels in the deep nuclei (r = -0.33, p < 0.05). Higher levels of alcohol consumption during pregnancy were related to lower levels of the choline-containing metabolites (r = -0.37, p < 0.01), glycerophosphocholine plus phosphocholine (Cho). Alcohol consumption levels both at conception (r = 0.35, p < 0.01) and during pregnancy (r = 0.38, p < 0.01) were related to higher levels of glutamate plus glutamine (Glx). All these effects continued to be significant after controlling for potential confounders. CONCLUSIONS: The lower NAA levels seen in relation to prenatal alcohol exposure may reflect impaired neuronal integrity in the deep cerebellar nuclei. Our finding of lower Cho points to disrupted Cho metabolism of membrane phospholipids, reflecting altered neuropil development with potentially reduced content of dendrites and synapses. The alcohol-related alterations in Glx may suggest a disruption of the glutamate-glutamine cycling involved in glutamatergic excitatory neurotransmission.

The mesolimbic system and the loss of higher order network features in schizophrenia when learning without reward.

Introduction: Schizophrenia is characterized by a loss of network features between cognition and reward sub-circuits (notably involving the mesolimbic system), and this loss may explain deficits in learning and cognition. Learning in schizophrenia has typically been studied with tasks that include reward related contingencies, but recent theoretical models have argued that a loss of network features should be seen even when learning without reward. We tested this model using a learning paradigm that required participants to learn without reward or feedback. We used a novel method for capturing higher order network features, to demonstrate that the mesolimbic system is heavily implicated in the loss of network features in schizophrenia, even when learning without reward. Methods: fMRI data (Siemens Verio 3T) were acquired in a group of schizophrenia patients and controls (n=78; 46 SCZ, 18 ≤ Age ≤ 50) while participants engaged in associative learning without reward-related contingencies. The task was divided into task-active conditions for encoding (of associations) and cued-retrieval (where the cue was to be used to retrieve the associated memoranda). No feedback was provided during retrieval. From the fMRI time series data, network features were defined as follows: First, for each condition of the task, we estimated 2nd order undirected functional connectivity for each participant (uFC, based on zero lag correlations between all pairs of regions). These conventional 2nd order features represent the task/condition evoked synchronization of activity between pairs of brain regions. Next, in each of the patient and control groups, the statistical relationship between all possible pairs of 2nd order features were computed. These higher order features represent the consistency between all possible pairs of 2nd order features in that group and embed within them the contributions of individual regions to such group structure. Results: From the identified inter-group differences (SCZ ≠ HC) in higher order features, we quantified the respective contributions of individual brain regions. Two principal effects emerged: 1) SCZ were characterized by a massive loss of higher order features during multiple task conditions (encoding and retrieval of associations). 2) Nodes in the mesolimbic system were over-represented in the loss of higher order features in SCZ, and notably so during retrieval. Discussion: Our analytical goals were linked to a recent circuit-based integrative model which argued that synergy between learning and reward circuits is lost in schizophrenia. The model's notable prediction was that such a loss would be observed even when patients learned without reward. Our results provide substantial support for these predictions where we observed a loss of network features between the brain's sub-circuits for a) learning (including the hippocampus and prefrontal cortex) and b) reward processing (specifically constituents of the mesolimbic system that included the ventral tegmental area and the nucleus accumbens. Our findings motivate a renewed appraisal of the relationship between reward and cognition in schizophrenia and we discuss their relevance for putative behavioral interventions.

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.

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.

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.

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.

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.