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Introduction: Auditory hallucinations or voices are experienced by 75% of people diagnosed with schizophrenia. We presumed that auditory cortex of schizophrenia patients who experience hallucinations is tonically “tuned” to internal auditory channels, at the cost of processing external sounds, both speech and nonspeech. Accordingly, we predicted that patients who hallucinate would show less auditory cortical activation to external acoustic stimuli than patients who did not. Methods: At 9 Functional Imaging Biomedical Informatics Research Network (FBIRN) sites, whole-brain images from 106 patients and 111 healthy comparison subjects were collected while subjects performed an auditory target detection task. Data were processed with the FBIRN processing stream. A region of interest analysis extracted activation values from primary (BA41) and secondary auditory cortex (BA42), auditory association cortex (BA22), and middle temporal gyrus (BA21). Patients were sorted into hallucinators (n = 66) and nonhallucinators (n = 40) based on symptom ratings done during the previous week. Results: Hallucinators had less activation to probe tones in left primary auditory cortex (BA41) than nonhallucinators. This effect was not seen on the right. Discussion: Although “voices” are the anticipated sensory experience, it appears that even primary auditory cortex is “turned on” and “tuned in” to process internal acoustic information at the cost of processing external sounds. Although this study was not designed to probe cortical competition for auditory resources, we were able to take advantage of the data and find significant effects, perhaps because of the power afforded by such a large sample. [ABSTRACT FROM PUBLISHER]

Context: Loss of the capacity to experience pleasure (anhedonia) is a core clinical feature of schizophrenia. Although functional imaging techniques have been successful in identifying the neural basis of cognitive impairments in schizophrenia, no attempts to date have been made to investigate neural systems underlying emotional disturbances.Objective: To study the neural basis of emotional processing in schizophrenia by exploring the pattern of brain responses to olfactory stimuli in patients and healthy volunteers.Design: Positron emission tomographic study of patients with schizophrenia and healthy volunteers. Positron emission tomographic data were collected between July 21, 1995, and September 11, 1997, and data analyses were conducted in 1999-2001.Setting: The Mental Health Clinical Research Center at the University of Iowa, Iowa City.Participants: Sixteen healthy volunteers with a mean age of 29.5 years and 18 patients with schizophrenia and a mean age of 30.0 years.Main Outcome Measure: Areas of relative increase or decrease in regional cerebral blood flow, measured using positron emission tomography and the [(15)O]water method while participants performed an emotion-induction olfactory task to determine response to pleasant (vanillin) and unpleasant (4-methylvaleric acid) odors, compared between patients and healthy volunteers.Results: Patients with schizophrenia subjectively experienced unpleasant odors in a manner similar to healthy volunteers but showed impairment in the experience of pleasant odors. The analysis of the regional cerebral blood flow revealed that patients failed to activate limbic/paralimbic regions (eg, insular cortex, nucleus accumbens, and parahippocampal gyrus) during the experience of unpleasant odors, recruiting a compensatory set of frontal cortical regions instead.Conclusion: Abnormalities in the complex functional interactions between mesolimbic and frontal regions may underlie emotional disturbances in schizophrenia. [ABSTRACT FROM AUTHOR]

The ability to increase cardiac output during dynamic exercise is paramount for the ability to maintain workload performance. Reflex control of the cardiovascular system during exercise is complex and multifaceted involving multiple feedforward and feedback systems. One major reflex thought to mediate the autonomic adjustments to exercise is termed the muscle metaboreflex and is activated via afferent neurons within active skeletal muscle which respond to the accumulation of interstitial metabolites during exercise when blood flow and O 2 delivery are insufficient to meet metabolic demands. This is one of the most powerful cardiovascular reflexes capable of eliciting profound increases in sympathetic nerve activity, arterial blood pressure, central blood volume mobilization, heart rate and cardiac output. This review summarizes the mechanisms meditating muscle metaboreflex-induced increases in cardiac output. Although much has been learned from studies using anaesthetized and/or decerebrate animals, we focus on studies in conscious animals and humans performing volitional exercise. We discuss the separate and interrelated roles of heart rate, ventricular contractility, ventricular preload and ventricular-vascular coupling as well as the interaction with other cardiovascular reflexes which modify muscle metaboreflex control of cardiac output. We discuss how these mechanisms may be altered in subjects with heart failure with reduced ejection fraction and offer suggestions for future studies., (© 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Metabolic syndrome (MetS) describes a set of disorders that collectively influence cardiovascular health, and includes hypertension, obesity, insulin resistance, diabetes, and dyslipidemia. All these components (hypertension, obesity, dyslipidemia, and prediabetes/diabetes) have been shown to modify autonomic function. The major autonomic dysfunction that has been documented with each of these components is in the control of sympathetic outflow to the heart and periphery at rest and during exercise through modulation of the arterial baroreflex and the muscle metaboreflex. Many studies have described MetS components in singularity or in combination with the other major components of metabolic syndrome. However, many studies lack the capability to study all the factors of metabolic syndrome in one model or have not focused on studying the effects of how each component as it arises influences overall autonomic function. The goal of this review is to describe the current understanding of major aspects of metabolic syndrome that most likely contribute to the consequent/associated autonomic alterations during exercise and discuss their effects, as well as bring light to alternative mechanisms of study.

Exercise intolerance is a hallmark symptom of heart failure and to a large extent stems from reductions in cardiac output that occur due to the inherent ventricular dysfunction coupled with enhanced muscle metaboreflex-induced functional coronary vasoconstriction, which limits increases in coronary blood flow. This creates a further mismatch between O 2 delivery and O 2 demand, which may activate the cardiac sympathetic afferent reflex (CSAR), causing amplification of the already increased sympathetic activity in a positive-feedback fashion. We used our chronically instrumented conscious canine model to evaluate if chronic ablation of afferents responsible for the CSAR would attenuate the gain of muscle metaboreflex before and after induction of heart failure. After afferent ablation, the gain of the muscle metaboreflex control of mean arterial pressure was significantly reduced before (-239.5 ± 16 to -95.2 ± 8 mmHg/L/min) and after the induction of heart failure (-185.6 ± 14 to -95.7 ± 12 mmHg/L/min). Similar results were observed for the strength (gain) of muscle metaboreflex control of heart rate, cardiac output, and ventricular contractility. Thus, we conclude that the CSAR contributes significantly to the strength of the muscle metaboreflex in normal animals with heart failure serving as an effective positive-feedback amplifier thereby further increasing sympathetic activity. NEW & NOTEWORTHY The powerful pressor responses from the CSAR arise via O 2 delivery versus O 2 demand imbalance. Muscle metaboreflex activation (MMA) simultaneously elicits coronary vasoconstriction (which is augmented in heart failure) and profound increases in cardiac work thereby upsetting oxygen balance. Whether MMA activates the CSAR thereby amplifying MMA responses is unknown. We observed that removal of the CSAR afferents attenuated the strength of the muscle metaboreflex in normal and subjects with heart failure.

Slow heart rate recovery following exercise may be influenced by persistent sympathoexcitation. This study examined 1 ) the effect of muscle metaboreflex activation (MMA) on heart rate recovery following dynamic exercise; and 2 ) whether the effect of MMA on heart rate recovery is reversible by reducing sympathoexcitation [baroreflex activation via phenylephrine (PE)] in canines. Twenty-two young adults completed control and MMA protocols during cycle ergometry at 110% ventilatory threshold with 5 min recovery. Heart rate recovery kinetics [tau (τ), amplitude, end-exercise, and end-recovery heart rate] and root mean square of successive differences (RMSSD) were measured. Five chronically instrumented canines completed control, MMA (50%-60% imposed reduction in hindlimb blood flow), and MMA with end-exercise PE infusion (MMA + PE) protocols during moderate exercise (6.4 km·h -1 ) and 3 min recovery. Heart rate recovery kinetics and MAP were measured. MAP increased during MMA versus control in canines ( P < 0.001). Heart rate recovery τ was slower during MMA versus control in humans (17% slower; P = 0.011) and canines (150% slower; P = 0.002). Heart rate recovery τ was faster during MMA + PE versus MMA (40% faster; P = 0.034) and was similar to control in canines ( P = 0.426). Amplitude, end-exercise, and end-recovery heart rate were similar between conditions in humans (all P ≥ 0.122) and in canines (all P ≥ 0.084). MMA decreased RMSSD in early recovery ( P = 0.004). MMA-induced sympathoexcitation slows heart rate recovery and this effect is markedly attenuated with PE. Therefore, elevated sympathoexcitation via MMA impairs heart rate recovery and inhibition of this stimulus normalizes, in part, heart rate recovery. NEW & NOTEWORTHY Augmented sympathoexcitation, via muscle metaboreflex activation, functionally slows heart rate recovery in both young healthy adults and chronically instrumented canines. Furthermore, elevated sympathoexcitation corresponded with lower parasympathetic activity, as assessed by heart rate variability, during the first 3 min of recovery. Finally, sympathoinhibition, via phenylephrine infusion, normalizes heart rate recovery during muscle metaboreflex activation.

Individuals with schizophrenia (SZ) show aberrant activations, assessed via functional magnetic resonance imaging (fMRI), during auditory oddball tasks. However, associations with cognitive performance and genetic contributions remain unknown. This study compares individuals with SZ to healthy volunteers (HVs) using two cross-sectional data sets from multi-center brain imaging studies. It examines brain activation to auditory oddball targets, and their associations with cognitive domain performance, schizophrenia polygenic risk scores (PRS), and genetic variation (loci). Both sample 1 (137 SZ vs. 147 HV) and sample 2 (91 SZ vs. 98 HV), showed hypoactivation in SZ in the left-frontal pole, and right frontal orbital, frontal pole, paracingulate, intracalcarine, precuneus, supramarginal and hippocampal cortices, and right thalamus. In SZ, precuneus activity was positively related to cognitive performance. Schizophrenia PRS showed a negative correlation with brain activity in the right-supramarginal cortex. GWA analyses revealed significant single-nucleotide polymorphisms associated with right-supramarginal gyrus activity. RPL36 also predicted right-supramarginal gyrus activity. In addition to replicating hypoactivation for oddball targets in SZ, this study identifies novel relationships between regional activity, cognitive performance, and genetic loci that warrant replication, emphasizing the need for continued data sharing and collaborative efforts., Competing Interests: Declaration of Competing Interest Dr. Nakahara is employed by Astellas Pharma Inc. Dr. Bustillo consulted with Novartis and Otsuka Pharmaceuticals. Dr. Mathalon is a consultant for Bristol-Myers Squibb and consulted for Roche Pharmaceuticals. Dr. Preda consulted for Boehringer-Ingelheim. Dr. Potkin has financial interests in Bristol-Myers Squibb, Eisai, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Lundbeck, Merck, Novartis, Organon, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, Novartis, Lundbeck, Merck, Sunovion and has received grant funding from Amgen, Baxter, Bristol-Myers Squibb, Cephalon, Inc., Eli Lilly, Forest Laboratories, Genentech, Janssen Pharmaceutical, Merck, Otsuka, Pfizer, Roche, Sunovion, Takeda Pharmaceutical, Vanda Pharmaceutical, NIAAA, NIBIB, NIH/NCRR, University of Southern California, UCSF, UCSD, Baylor College of Medicine. The remaining authors declare no potential conflict of interest. None of the authors of this manuscript are affiliated with or receive compensation from NeuroComp Systems, Inc., MATRICS Assessment, Inc., or Neurcog Trials, Inc., (Copyright © 2023. Published by Elsevier B.V.)

Blood flow restriction training (BFRT) employs partial vascular occlusion of exercising muscle and has been shown to increase muscle performance while using reduced workload and training time. Numerous studies have demonstrated that BFRT increases muscle hypertrophy, mitochondrial function, and beneficial vascular adaptations. However, changes in cardiovascular hemodynamics during the exercise protocol remain unknown, as most studies measured blood pressure before the onset and after the cessation of exercise. With reduced perfusion to the exercising muscle during BFRT, the resultant accumulation of metabolites within the ischemic muscle could potentially trigger a large reflex increase in blood pressure, termed the muscle metaboreflex. At low workloads, this pressor response occurs primarily via increases in cardiac output. However, when increases in cardiac output are limited (e.g., heart failure or during severe exercise), the reflex shifts to peripheral vasoconstriction as the primary mechanism to increase blood pressure, potentially increasing the risk of a cardiovascular event. Using our chronically instrumented conscious canine model, we utilized a 60% reduction in femoral blood pressure applied to the hindlimbs during steady-state treadmill exercise (3.2 km/h) to reproduce the ischemic environment observed during BFRT. We observed significant increases in heart rate (+19 ± 3 beats/min), stroke volume (+2.52 ± 1.2 mL), cardiac output (+1.21 ± 0.2 L/min), mean arterial pressure (+18.2 ± 2.4 mmHg), stroke work (+1.93 ± 0.2 L/mmHg), and nonischemic vascular conductance (+3.62 ± 1.7 mL/mmHg), indicating activation of the muscle metaboreflex. NEW & NOTEWORTHY Blood flow restriction training (BFRT) increases muscle mass, strength, and endurance. There has been minimal consideration of the reflex cardiovascular responses that could be elicited during BFRT sessions. We showed that during low-intensity exercise BFRT may trigger large reflex increases in blood pressure and sympathetic activity due to muscle metaboreflex activation. Thus, we urge caution when employing BFRT, especially in patients in whom exaggerated cardiovascular responses may occur that could cause sudden, adverse cardiovascular events.

The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross-species study using small and large animals, we comprehensively tested the agreement and validity of multiple single-beat surrogate metrics of LV contractility against the field-standard metrics derived from inferior vena cava occlusion (IVCO). Fifty-six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single-beat metrics of LV contractility. All single-beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load-independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single-beat metrics, only LV maximal pressure normalized to end-diastolic volume (EDV), end-systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate-to-excellent agreement with their IVCO-derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large-animal models. Our findings demonstrate that single-beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small- and large-animal models KEY POINTS: Validating and comparing indices of cardiac contractility that avoid caval occlusion would offer considerable advantages for the field of cardiovascular physiology. We comprehensively test the underlying assumptions of multiple single-beat indices of cardiac contractility in rodents and translate these findings to pigs and conscious dogs. We show that when performing caval occlusion is unfeasible, single-beat metrics can be utilized to accurately quantify cardiac inotropic function in basic and preclinical research employing various small and large animal species. We report that maximal left-ventricular (LV)-pressure normalized to end-diastolic volume (EDV), LV end-systolic pressure normalized to EDV and the maximal rate of rise of the LV pressure waveform normalized to EDV are the best three single-beat metrics to measure cardiac inotropic function in both small- and large-animal models., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach-unilateral reduction in renal blood flow to ∼30% of control values until systolic pressure ≥ 140 mmHg and a diastolic pressure ≥ 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients.

Climate change is widely known to affect plant phenology, but little is known about how these impacts manifest in the widespread sagebrush ecosystem of the Western United States, which supports a number of wildlife species of concern. Shifts in plant phenology can trigger consequences for the plants themselves as well as the communities of consumers that depend upon them. We assembled historical observations of first-flowering dates for 51 species collected in the 1970s and 1980s in a montane sagebrush community in the Greater Yellowstone Ecosystem and compared these to contemporary phenological observations targeting the same species and locations (2016-2019). We also assembled regional climate data (average spring temperature, day of spring snowmelt, and growing degree days) and tested the relationship between first-flowering time and these variables for each species. We observed the largest change in phenology in early-spring flowers, which, as a group, bloomed on average 17 days earlier, and as much as 36 days earlier, in the contemporary data set. Mid-summer flowers bloomed on average 10 days earlier, nonnative species 15 days earlier, and berry-producing shrubs 5 days earlier, while late summer flowering plants did not shift. The greatest correlates of early-spring and mid-summer flowering were average spring temperature and day of snowmelt, which was 21 days earlier, on average, in 2016-2019 relative to the 1973-1978 observations. The shifts in flowering phenology that we observed could indicate developing asynchronies or novel synchronies of these plant resources and wildlife species of conservation concern, including Greater Sage-grouse, whose nesting success is tied to availability of spring forbs; grizzly bears, which rely heavily on berries for their fall diet; and pollinators. This underscores the importance of maintaining a diverse portfolio of native plants in terms of species composition, genetics, phenological responsiveness to climatic cues, and ecological importance to key wildlife and pollinator species. Redundancy within ecological niches may also be important considering that species roles in the community may shift as climate change affects them differently. These considerations are particularly relevant to restoration and habitat-enhancement projects in sagebrush communities across western North America., (© 2022 The Ecological Society of America.)

Autonomic alterations in blood pressure are primarily a result of arterial baroreflex modulation of systemic vascular resistance and cardiac output on a beat-by-beat basis. The combined central and peripheral control by the baroreflex likely acts to maintain efficient energy transfer from the heart to the systemic vasculature; termed ventricular-vascular coupling. This level of control is maintained whether at rest or during exercise in healthy subjects. During heart failure, the ventricular-vascular relationship is uncoupled and baroreflex dysfunction is apparent. We investigated if baroreflex dysfunction in heart failure exacerbated ventricular-vascular uncoupling at rest, and during exercise in response to baroreceptor unloading by performing bilateral carotid occlusions in chronically instrumented conscious canines. We observed in healthy subjects that baroreceptor unloading caused significant increases in effective arterial elastance (Ea) at rest (1.2 ± 0.3 mmHg/ml) and during exercise (1.3 ± 0.2 mmHg/ml) that coincided with significant increases in stroke work (SW) (1.5 ± 0.2 mmHg/ml) and (1.6 ± 0.2 mmHg/ml) suggesting maintained ventricular-vascular coupling. Heart Failure significantly increased the effect of baroreceptor unloading on Ea at rest (3.1 ± 0.7 mmHg/ml) and during exercise (2.3 ± 0.5 mmHg/ml) whereas no significant increases in stroke work occurred, thus signifying further ventricular-vascular uncoupling. We believe that the enhanced ventricular-vascular uncoupling observed during baroreceptor unloading only worsens the already challenged orthostatic and exercise tolerance and thereby contributes to poor exercise performance and quality of life for heart failure patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mannozzi, Al-Hassan, Kaur, Lessanework, Alvarez, Massoud, Bhatti and O’Leary.)

The ventricular-vascular relationship assesses the efficacy of energy transferred from the left ventricle to the systemic circulation and is quantified as the ratio of effective arterial elastance to maximal left ventricular elastance. This relationship is maintained during exercise via reflex increases in cardiovascular performance raising both arterial and ventricular elastance in parallel. These changes are, in part, due to reflexes engendered by activation of metabosensitive skeletal muscle afferents-termed the muscle metaboreflex. However, in heart failure, ventricular-vascular uncoupling is apparent and muscle metaboreflex activation worsens this relationship through enhanced systemic vasoconstriction markedly increasing effective arterial elastance which is unaccompanied by substantial increases in ventricular function. This enhanced arterial vasoconstriction is, in part, due to significant reductions in cardiac performance induced by heart failure causing over-stimulation of the metaboreflex due to under perfusion of active skeletal muscle, but also as a result of reduced baroreflex buffering of the muscle metaboreflex-induced peripheral sympatho-activation. To what extent the arterial baroreflex modifies the metaboreflex-induced changes in effective arterial elastance is unknown. We investigated in chronically instrumented conscious canines if removal of baroreflex input via sino-aortic baroreceptor denervation (SAD) would significantly enhance effective arterial elastance in normal animals and whether this would be amplified after induction of heart failure. We observed that effective arterial elastance (E a ), was significantly increased during muscle metaboreflex activation after SAD (0.4 ± 0.1 mmHg/mL to 1.4 ± 0.3 mmHg/mL). In heart failure, metaboreflex activation caused exaggerated increases in E a and in this setting, SAD significantly increased the rise in E a elicited by muscle metaboreflex activation (1.3 ± 0.3 mmHg/mL to 2.3 ± 0.3 mmHg/mL). Thus, we conclude that the arterial baroreflex does buffer muscle metaboreflex induced increases in E a and this buffering likely has effects on the ventricular-vascular coupling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mannozzi, Kim, Sala-Mercado, Al-Hassan, Lessanework, Alvarez, Massoud, Bhatti, Aoun and O’Leary.)

The spinal cord is an important integrative center for blood pressure control. Spinal sensory fibers send projections to sympathetic preganglionic neurons of the thoracic spinal cord and drive sympathetically-mediated increases in blood pressure. While these reflexes responses occur in able-bodied individuals, they are exaggerated following interruption of descending control - such as occurs following spinal cord injury. Similar reflex control of blood pressure may exist in disease states, other than spinal cord injury, where there is altered input to sympathetic preganglionic neurons. This review primarily focuses on mechanisms wherein visceral afferent information traveling via spinal nerves influences sympathetic nerve activity and blood pressure. There is an abundance of evidence for the widespread presence of this spinal reflex arch originating from virtually every visceral organ and thus having a substantial role in blood pressure control. Additionally, this review highlights specific endogenous eicosanoid species, which modulate the activity of afferent fibers involved in this reflex, through their interactions with transient receptor potential (TRP) cation channels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Minic, O’Leary and Reynolds.)

Background: We investigated how low marijuana (MJ) use levels, the typical use pattern in most adolescent users, affect cognitive maturation and schizophrenia risk., Methods: In two complementary adolescent samples where the majority reported minimal MJ use, we compared cognitive performances before and after MJ use initiation. The Iowa sample (40 first-degree relatives and 54 second-degree relatives of patients with schizophrenia and 117 control subjects with no schizophrenia family history) underwent a battery of standardized neuropsychological tests at 0, 18, and 36 months. Based on self-administered Timeline Followback interviews, 26.5% of adolescents had emergent MJ use (eMJ) during follow-up. The second sample ( n  = 3463), derived from a birth cohort, received substance use and sustained attention assessments between ages 10 and 15 years. Mixed linear models and regression analyses tested the effects of eMJ on longitudinal changes in cognitive performance., Results: In the Iowa sample, longitudinal changes in 5 of 8 cognitive domains were significantly associated with eMJ. On sustained attention, visuospatial working memory, and executive sequencing, adolescents with eMJ showed less age-expected improved performance. In addition, first-degree relatives with eMJ were less improved on processing speed and executive reasoning than first-degree relatives without eMJ. In the birth cohort, greater intraindividual variability in reaction times (indicative of poorer sustained attention) was significantly associated with more frequent MJ use and with recreational use levels., Conclusions: Nonheavy MJ use disrupts normal adolescent maturation and compounds aberrant adolescent maturation associated with familial schizophrenia risk. These findings underscore the importance of reducing adolescent MJ access in the context of increased availability to high-potency MJ., (© 2022 The Authors.)

Aim: The current study examined the longitudinal effects of standard binge drinking (4+/5+ drinks for females/males in 2 hours) and extreme binge drinking (8+/10+ drinks for females/males in 2 hours) on resting-state functional connectivity., Method: 119 college students (61 males) were recruited in groups of distinct bingeing patterns at baseline: non-bingeing controls, standard and extreme bingers. Resting-state scans were first obtained when participants were freshmen/sophomores and again approximately two years later. Associations between longitudinal bingeing (reported during this two-year gap) and network connectivity were examined. Network connectivity was calculated by aggregating all edges affiliated with the same network (an edge is a functional connection between two brain regions). The relationship between longitudinal bingeing and connectivity edges was also studied using connectome-based predictive modeling (CPM)., Results: Greater standard bingeing was negatively associated with change in connectivity between Default Mode Network and Ventral Attention Network (DMN-VAN; False Discovery Rate corrected), controlling for initial binge groups, longitudinal network changes, motions, scanner, SES, sex, and age. The correlations between change in DMN-VAN connectivity and change in cognitive performance (Stroop, Digit Span, Letter Fluency, and Trail Making) were also tested, but the results were not significant. Lastly, CPM failed to identify a generalizable predictive model of longitudinal bingeing from change in connectivity edges., Conclusions: Binge drinking is associated with abnormality in networks implicated in attention and self-focused processes, which, in turn, have been implicated in rumination, craving, and relapse. More extensive alterations in functional connectivity might be observed with heavier or longer binge drinking pattern., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex-induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express transient receptor potential vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultrapotent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1-sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4-L6) of RTX (2 µg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex-induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min), and stroke work (2.27 ± 0.2 L·mmHg vs. 1.01 ± 0.2 L·mmHg). Effects were maintained until 78 ± 14 days post-RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 µg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre-RTX vs. +19.7 ± 3.1 mmHg post-RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.

Deep learning methods hold strong promise for identifying biomarkers for clinical application. However, current approaches for psychiatric classification or prediction do not allow direct interpretation of original features. In the present study, we introduce a sparse deep neural network (DNN) approach to identify sparse and interpretable features for schizophrenia (SZ) case-control classification. An L 0 -norm regularization is implemented on the input layer of the network for sparse feature selection, which can later be interpreted based on importance weights. We applied the proposed approach on a large multi-study cohort with gray matter volume (GMV) and single nucleotide polymorphism (SNP) data for SZ classification. A total of 634 individuals served as training samples, and the classification model was evaluated for generalizability on three independent datasets of different scanning protocols (N = 394, 255, and 160, respectively). We examined the classification power of pure GMV features, as well as combined GMV and SNP features. Empirical experiments demonstrated that sparse DNN slightly outperformed independent component analysis + support vector machine (ICA + SVM) framework, and more effectively fused GMV and SNP features for SZ discrimination, with an average error rate of 28.98% on external data. The importance weights suggested that the DNN model prioritized to select frontal and superior temporal gyrus for SZ classification with high sparsity, with parietal regions further included with lower sparsity, echoing previous literature. The results validate the application of the proposed approach to SZ classification, and promise extended utility on other data modalities and traits which ultimately may result in clinically useful tools., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

New Findings: What is the central question of this study? Does the muscle metaboreflex affect the ratio of left ventricular contraction/relaxation rates and does heart failure impact this relationship. What is the main finding and its importance? The effect of muscle metaboreflex activation on the ventricular relaxation rate was significantly attenuated in heart failure. Heart failure attenuates the exercise and muscle metaboreflex-induced changes in the contraction/relaxation ratio. In heart failure, the reduced ability to raise cardiac output during muscle metaboreflex activation may not solely be due to attenuation of ventricular contraction but also alterations in ventricular relaxation and diastolic function., Abstract: The relationship between contraction and relaxation rates of the left ventricle varies with exercise. In in vitro models, this ratio was shown to be relatively unaltered by changes in sarcomere length, frequency of stimulation, and β-adrenergic stimulation. We investigated whether the ratio of contraction to relaxation rate is maintained in the whole heart during exercise and muscle metaboreflex activation and whether heart failure alters these relationships. We observed that in healthy subjects the ratio of contraction to relaxation increases from rest to exercise as a result of a higher increase in contraction relative to relaxation. During muscle metaboreflex activation the ratio of contraction to relaxation is significantly reduced towards 1.0 due to a large increase in relaxation rate matching contraction rate. In heart failure, contraction and relaxation rates are significantly reduced, and increases during exercise are attenuated. A significant increase in the ratio was observed from rest to exercise although baseline ratio values were significantly reduced close to 1.0 when compared to healthy subjects. There was no significant change observed between exercise and muscle metaboreflex activation nor was the ratio during muscle metaboreflex activation significantly different between heart failure and control. We conclude that heart failure reduces the muscle metaboreflex gain and contraction and relaxation rates. Furthermore, we observed that the ratio of the contraction and relaxation rates during muscle metaboreflex activation is not significantly different between control and heart failure, but significant changes in the ratio in healthy subjects due to increased relaxation rate were abolished in heart failure., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

The purinergic receptor ligand, ATP, may participate in reflex induced vasoconstriction through sympathetic efferent and sensory afferent mechanisms. However, the role of the purinergic system in contributing to autonomic dysreflexia following spinal cord injury is unclear. The present study investigates the involvement of P2X receptors in contributing to pressor responses during autonomic dysreflexia. Twenty rats were subjected to spinal cord injury and 24 h later hemodynamic responses to colorectal distension were recorded. Animals were randomized to receive intravenous administration of the P2X receptor antagonist, NF023, or vehicle control. The data indicate that NF023 attenuates pressor responses to colorectal distension., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autonomic alterations at the onset of exercise are critical to redistribute cardiac output towards the contracting muscles while preventing a fall in arterial pressure due to excessive vasodilation within the contracting muscles. Neural mechanisms responsible for these adjustments include central command, the exercise pressor reflex, and arterial and cardiopulmonary baroreflexes. The exercise pressor reflex evokes reflex increases in sympathetic activity to the heart and systemic vessels and decreases in parasympathetic activity to the heart, which increases blood pressure (BP), heart rate, and total peripheral resistance through vasoconstriction of systemic vessels. In this review, we discuss recent advancements in our understanding of exercise pressor reflex function in health and disease. Specifically, we discuss emerging evidence suggesting that sympathetic vasoconstrictor drive to the contracting and non-contracting skeletal muscle is differentially controlled by central command and the metaboreflex in healthy conditions. Further, we discuss evidence from animal and human studies showing that cardiovascular diseases, including hypertension, diabetes, and heart failure, lead to an altered exercise pressor reflex function. We also provide an update on the mechanisms thought to underlie this altered exercise pressor reflex function in each of these diseases. Although these mechanisms are complex, multifactorial, and dependent on the etiology of the disease, there is a clear consensus that several mechanisms are involved. Ultimately, approaches targeting these mechanisms are clinically significant as they provide alternative therapeutic strategies to prevent adverse cardiovascular events while also reducing symptoms of exercise intolerance., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: Binge drinking is common during college, and studies have shown that many college students drink in quantities that far exceed the standard binge drinking threshold. Previous research has noted personality differences in individuals who engage in binge drinking, but few studies have examined neurobiological differences in both standard bingers (4/5 drinks in two hours for females/males; sBinge) and extreme binge drinkers (8+/10+ drinks in two hours for females/males; eBinge)., Method: The current study of 221 college students used functional magnetic resonance imaging (fMRI) to study neural activation on a stop signal task (SST) to assess behavioral inhibition and a monetary incentive delay (MID) task to assess activation to rewards and losses. Non-bingeing controls, sBinge, and eBinge freshmen and sophomores were recruited. In addition, because binge/extreme binge drinking is often associated with marijuana (MJ) use, MJ + sBinge and MJ + eBinge groups were also included., Results: All five groups showed strong activation in expected key cortical and striatal regions on both the SST and the MID. However, there were no significant differences between groups either at the whole-brain level or in specific regions of interest. Behavioral performance on the fMRI tasks also did not differ between groups., Conclusions: These results suggest that our sample of individuals who engage in binge or extreme binge drinking with or without MJ co-use do not differ in brain activity on reward and inhibitory tasks. Neural differences may be present on other cognitive tasks or may emerge later after more sustained use of alcohol, MJ, and other drugs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Dynamic exercise elicits robust increases in sympathetic activity in part due to muscle metaboreflex activation (MMA), a pressor response triggered by activation of skeletal muscle afferents. MMA during dynamic exercise increases arterial pressure by increasing cardiac output via increases in heart rate, ventricular contractility, and central blood volume mobilization. In heart failure, ventricular function is compromised, and MMA elicits peripheral vasoconstriction. Ventricular-vascular coupling reflects the efficiency of energy transfer from the left ventricle to the systemic circulation and is calculated as the ratio of effective arterial elastance ( E a ) to left ventricular maximal elastance ( E max ). The effect of MMA on E a in normal subjects is unknown. Furthermore, whether muscle metaboreflex control of E a is altered in heart failure has not been investigated. We utilized two previously published methods of evaluating E a [end-systolic pressure/stroke volume ( E aPV )] and [heart rate × vascular resistance ( E aZ )] during rest, mild treadmill exercise, and MMA (induced via partial reductions in hindlimb blood flow imposed during exercise) in chronically instrumented conscious canines before and after induction of heart failure via rapid ventricular pacing. In healthy animals, MMA elicits significant increases in effective arterial elastance and stroke work that likely maintains ventricular-vascular coupling. In heart failure, E a is high, and MMA-induced increases are exaggerated, which further exacerbates the already uncoupled ventricular-vascular relationship, which likely contributes to the impaired ability to raise stroke work and cardiac output during exercise in heart failure.

Background: Schizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined., Methods: Hippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed., Results: This study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = -0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = -0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (β = 10.8, p < 5 × 10-8, 95% CI 7.0-14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume., Conclusions: This study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.

Whole body exercise tolerance is the consummate example of integrative physiological function among the metabolic, neuromuscular, cardiovascular, and respiratory systems. Depending on the animal selected, the energetic demands and flux through the oxygen transport system can increase two orders of magnitude from rest to maximal exercise. Thus, animal models in health and disease present the scientist with flexible, powerful, and, in some instances, purpose-built tools to explore the mechanistic bases for physiological function and help unveil the causes for pathological or age-related exercise intolerance. Elegant experimental designs and analyses of kinetic parameters and steady-state responses permit acute and chronic exercise paradigms to identify therapeutic targets for drug development in disease and also present the opportunity to test the efficacy of pharmacological and behavioral countermeasures during aging, for example. However, for this promise to be fully realized, the correct or optimal animal model must be selected in conjunction with reproducible tests of physiological function (e.g., exercise capacity and maximal oxygen uptake) that can be compared equitably across laboratories, clinics, and other proving grounds. Rigorously controlled animal exercise and training studies constitute the foundation of translational research. This review presents the most commonly selected animal models with guidelines for their use and obtaining reproducible results and, crucially, translates state-of-the-art techniques and procedures developed on humans to those animal models.

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Blood flow restriction training (BFRT) is an increasingly widespread method of exercise that involves imposed restriction of blood flow to the exercising muscle. Blood flow restriction is achieved by inflating a pneumatic pressure cuff (or a tourniquet) positioned proximal to the exercising muscle before, and during, the bout of exercise (i.e., ischemic exercise). Low-intensity BFRT with resistance training promotes comparable increases in muscle mass and strength observed during high-intensity exercise without blood flow restriction. BFRT has expanded into the clinical research setting as a potential therapeutic approach to treat functionally impaired individuals, such as the elderly, and patients with orthopedic and cardiovascular disease/conditions. However, questions regarding the safety of BFRT must be fully examined and addressed before the implementation of this exercise methodology in the clinical setting. In this respect, there is a general concern that BFRT may generate abnormal reflex-mediated cardiovascular responses. Indeed, the muscle metaboreflex is an ischemia-induced, sympathoexcitatory pressor reflex originating in skeletal muscle, and the present review synthesizes evidence that BFRT may elicit abnormal cardiovascular responses resulting from increased metaboreflex activation. Importantly, abnormal cardiovascular responses are more clearly evidenced in populations with increased cardiovascular risk (e.g., elderly and individuals with cardiovascular disease). The evidence provided in the present review draws into question the cardiovascular safety of BFRT, which clearly needs to be further investigated in future studies. This information will be paramount for the consideration of BFRT exercise implementation in clinical populations.

Objective: Youth with a family history of alcohol use disorder (family history positive [FHP]) are at increased risk for developing maladaptive substance use relative to family history negative (FHN) peers. Building on earlier studies demonstrating morphological differences and distinct patterns of neural activation in FHP, the purpose of the present study was to investigate differential intrinsic functional connectivity among brain networks indexing premorbid risk of developing alcohol use disorder (AUD)., Method: The current study examined intrinsic functional connectivity using resting state functional magnetic resonance imaging in 191 adolescents 13 to 18 years of age with and without family history of AUD via independent component analysis, a method enabling data-driven investigation of internetwork and intranetwork connectivity among brain regions at rest., Results: Analyses revealed significantly lower intranetwork connectivity in FHP compared to FHN participants between the dorsal premotor cortex and other sensorimotor network regions. Reduced intranetwork connectivity in this region was further correlated with the number of biological family members with AUD and mood disorders. Robust differences were also evident in internetwork connectivity as a function of age. However, there was no evidence for family history by age interactions., Conclusion: Intra- but not internetwork connectivity appears to differentiate FHP and FHN adolescents, whereas age differences within adolescence are marked by differences in internetwork connectivity., (Copyright © 2019. Published by Elsevier Inc.)

Autonomic dysreflexia (AD) often occurs in individuals living with spinal cord injury (SCI) and is characterized by uncontrolled hypertension in response to otherwise innocuous stimuli originating below the level of the spinal lesion. Visceral stimulation is a predominant cause of AD in humans and effectively replicates the phenotype in rodent models of SCI. Direct assessment of sympathetic responses to viscerosensory stimulation in spinalized animals is challenging and requires invasive surgical procedures necessitating the use of anesthesia. However, administration of anesthesia markedly affects viscerosensory reactivity, and the effects are exacerbated following spinal cord injury (SCI). Therefore, the major goal of the present study was to develop a decerebrate rodent preparation to facilitate quantification of sympathetic responses to visceral stimulation in the spinalized rat. Such a preparation enables the confounding effect of anesthesia to be eliminated. Sprague-Dawley rats were subjected to SCI at the fourth thoracic segment. Four weeks later, renal sympathetic nerve activity (RSNA) responses to visceral stimuli were quantified in urethane/chloralose-anesthetized and decerebrate preparations. Visceral stimulation was elicited via colorectal distension (CRD) for 1 min. In the decerebrate preparation, CRD produced dose-dependent increases in mean arterial pressure (MAP) and RSNA and dose-dependent decreases in heart rate (HR). These responses were significantly greater in magnitude among decerebrate animals when compared with urethane/chloralose-anesthetized controls and were markedly attenuated by the administration of urethane/chloralose anesthesia after decerebration. We conclude that the decerebrate preparation enables high-fidelity quantification of neuronal reactivity to visceral stimulation in spinalized rats. NEW & NOTEWORTHY In animal models commonly used to study spinal cord injury, quantification of sympathetic responses is particularly challenging due to the increased susceptibility of spinal reflex circuits to the anesthetic agents generally required for experimentation. This constitutes a major limitation to understanding the mechanisms mediating regionally specific neuronal responses to visceral activation in chronically spinalized animals. In the present study, we describe a spinalized, decerebrate rodent preparation that facilitates quantification of sympathetic reactivity in response to visceral stimuli following spinal cord injury. This preparation enables reliable and reproducible quantification of viscero-sympathetic reflex responses resembling those elicited in conscious animals and may provide added utility for preclinical evaluation of neuropharmacological agents for the management of autonomic dysreflexia.

Underperfusion of active skeletal muscle causes metabolites to accumulate and stimulate group III and IV skeletal muscle afferents, which triggers a powerful pressor response termed the muscle metaboreflex. Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in healthy individuals increases arterial pressure mainly via substantial increases in cardiac output (CO). The increases in CO occur via the combination of tachycardia and increased ventricular contractility. Importantly, MMA also elicits substantial central blood volume mobilization, which allows the ventricular responses to sustain the increases in CO. Otherwise preload would fall and the increases in CO could not be maintained. In subjects with systolic heart failure (HF), the ability to increase CO during exercise and MMA is markedly reduced, which has been attributed to impaired ventricular contractility. Whether the ability to maintain preload during MMA in HF is preserved is unknown. Using a conscious chronically instrumented canine model, we observed that MMA in HF is able to raise central blood volume similarly as in normal subjects. Therefore, the loss of the ability to raise CO during MMA in HF is not because of the loss of the ability to mobilize blood volume centrally. NEW & NOTEWORTHY In normal subjects during dynamic exercise muscle metaboreflex activation elicits large increases in cardiac output that occur via increases in heart rate, ventricular contractility, and, importantly, marked central blood volume mobilization that acts to maintain ventricular preload, thereby allowing the changes in cardiac function to maintain the increases in cardiac output. In subjects with heart failure, the ability to raise cardiac output during muscle metaboreflex activation is impaired. We investigated whether this is because of the inability to maintain ventricular preload. We found that this reflex is still able to elicit large increases in central blood volume, and therefore the limited ability to raise cardiac output likely stems from ventricular dysfunction and not the ability to maintain preload.

Background: Binge drinking is common in college students, and many drink in quantities greater than the standard definition of bingeing. Combined use of additional substances, particularly marijuana, is also common. Objectives: Increased impulsivity and sensation seeking are risk factors for bingeing, and this study was designed to characterize their association with extreme compared to standard bingeing, as well as with combined bingeing and marijuana use. Negative consequences of alcohol use were also investigated. Methods: Self-report personality measures and a measure of the negative consequences of alcohol use were given to a sample of 221 college students (109 females) sorted into a control and 4 binge groups based upon their patterns of bingeing and marijuana use. Narrowly defined, non-overlapping measures of impulsivity and sensation seeking were analyzed to assess the association of these personality measures with substance-use patterns and negative consequences of bingeing. Results: Standard bingers did not differ from non-bingeing controls on either impulsivity or sensation seeking, whereas extreme bingers had significantly higher impulsivity and sensation seeking scores than controls and also significantly higher sensation seeking than standard bingers. Exploratory analyses of a broader set of personality scales showed that a disinhibition scale was also significant predictor of substance use group. A number of personality traits significantly predicted substance use patterns as well as specific negative consequences of bingeing. Conclusions: Impulsivity, sensation seeking and disinhibition are significant associates of substance use patterns and the negative consequences of use in college students.

During both static and dynamic exercise hypertensive subjects can experience robust increases in arterial pressure to such an extent that heavy exercise is often not recommended in these patients due to the dangerously high levels of blood pressure sometimes observed. Currently, the mechanisms mediating this cardiovascular dysfunction during exercise in hypertension are not fully understood. The major reflexes thought to mediate the cardiovascular responses to exercise in normotensive healthy subjects are central command, arterial baroreflex and responses to stimulation of skeletal muscle mechano-sensitive and metabo-sensitive afferents. This review will summarize our current understanding of the roles of these reflexes and their interactions in mediating the altered cardiovascular responses to exercise observed in hypertension. We conclude that much work is needed to fully understand the mechanisms mediating excessive pressor response to exercise often seen in hypertensive patients.

Background: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group., Methods: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide., Results: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset., Conclusions: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aims: To provide quantitative conversions between commonly used scales for the assessment of negative symptoms in schizophrenia., Method: Linear regression analyses generated conversion equations between symptom scores from the Scale for the Assessment of Negative Symptoms (SANS), the Schedule for the Deficit Syndrome (SDS), the Positive and Negative Syndrome Scale (PANSS), or the Negative Symptoms Assessment (NSA) based on a cross sectional sample of 176 individuals with schizophrenia. Intraclass correlations assessed the rating conversion accuracy based on a separate sub-sample of 29 patients who took part in the initial study as well as an independent sample of 28 additional subjects with schizophrenia., Results: Between-scale negative symptom ratings were moderately to highly correlated (r = 0.73-0.91). Intraclass correlations between the original negative symptom rating scores and those obtained via using the conversion equations were in the range of 0.61-0.79., Conclusions: While there is a degree of non-overlap, several negative symptoms scores reflect measures of similar constructs and may be reliably converted between some scales. The conversion equations are provided at http://www.converteasy.org and may be used for meta- and mega-analyses that examine negative symptoms., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Adenosine operating in the nucleus of the solitary tract (NTS) may inhibit or facilitate neurotransmitter release from nerve terminals and directly inhibit or facilitate central neurons via A 1 and A 2a pre- and postsynaptic receptors, respectively. However, adenosine A 2a receptors, may also activate GABA-ergic neurons/terminals which in turn inhibit glutamatergic transmission in the NTS network. Our previous studies showed that adenosine operating via both A 1 (inhibitor) and A 2a (activator) receptors powerfully inhibits the cardiopulmonary chemoreflex (CCR) at the level of the caudal NTS. A 1 receptors most likely inhibit glutamate release in the CCR network, whereas A 2a receptors facilitate NTS GABA-ergic mechanisms which in turn inhibit CCR glutamatergic transmission. Therefore, we hypothesized that A 2a receptors are located on NTS GABA-ergic neurons/terminals whereas A 1 receptors may be located on NTS glutamatergic neurons/terminals. We investigated this hypothesis using double immunofluorescent staining for A 2a or A 1 adenosine receptors and GABA synthesizing enzyme, GAD67, in 30 μm thick, floating, medullary rat sections. We found that A 2a adenosine receptors are localized within the GABA-ergic cells in the caudal NTS, whereas A 1 adenosine receptors are absent from these neurons. Instead, A 1 receptors were located on non-GABA-ergic (likely glutamatergic) neurons/terminals in the caudal NTS. These data support our functional findings and the hypothesis that adenosine A 2a, but not A 1 receptors are located on GABA-ergic neurons., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Two powerful reflexes controlling cardiovascular function during exercise are the muscle metaboreflex and arterial baroreflex. In heart failure (HF), the strength and mechanisms of these reflexes are altered. Muscle metaboreflex activation (MMA) in normal subjects increases mean arterial pressure (MAP) primarily via increases in cardiac output (CO), whereas in HF the mechanism shifts to peripheral vasoconstriction. Baroreceptor unloading increases MAP via peripheral vasoconstriction, and this pressor response is blunted in HF. Baroreceptor unloading during MMA in normal animals elicits an enormous pressor response via combined increases in CO and peripheral vasoconstriction. The mode of interaction between these reflexes is intimately dependent on the parameter (e.g., MAP and CO) being investigated. The interaction between the two reflexes when activated simultaneously during dynamic exercise in HF is unknown. We activated the muscle metaboreflex in chronically instrumented dogs during mild exercise (via graded reductions in hindlimb blood flow) followed by baroreceptor unloading [via bilateral carotid occlusion (BCO)] before and after induction of HF. We hypothesized that BCO during MMA in HF would cause a smaller increase in MAP and a larger vasoconstriction of ischemic hindlimb vasculature, which would attenuate the restoration of blood flow to ischemic muscle observed in normal dogs. We observed that BCO during MMA in HF increases MAP by substantial vasoconstriction of all vascular beds, including ischemic active muscle, and that all cardiovascular responses, except ventricular function, exhibit occlusive interaction. We conclude that vasoconstriction of ischemic active skeletal muscle in response to baroreceptor unloading during MMA attenuates restoration of hindlimb blood flow. NEW & NOTEWORTHY We found that baroreceptor unloading during the muscle metaboreflex in heart failure results in occlusive interaction (except for ventricular function) with significant vasoconstriction of all vascular beds. In addition, restoration of blood flow to ischemic active muscle, via preferentially larger vasoconstriction of nonischemic beds, is significantly attenuated in heart failure.

This study assessed genetic contributions to six cognitive domains, identified by the MATRICS Cognitive Consensus Battery as relevant for schizophrenia, cognition-enhancing, clinical trials. Psychiatric Genomics Consortium Schizophrenia polygenic risk scores showed significant negative correlations with each cognitive domain. Genome-wide association analyses identified loci associated with attention/vigilance (rs830786 within HNF4G), verbal memory (rs67017972 near NDUFS4), and reasoning/problem solving (rs76872642 within HDAC9). Gene set analysis identified unique and shared genes across cognitive domains. These findings suggest involvement of common and unique mechanisms across cognitive domains and may contribute to the discovery of new therapeutic targets to treat cognitive deficits in schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Cognitive impairment is a feature of many psychiatric diseases, including schizophrenia. Here we aim to identify multimodal biomarkers for quantifying and predicting cognitive performance in individuals with schizophrenia and healthy controls. A supervised learning strategy is used to guide three-way multimodal magnetic resonance imaging (MRI) fusion in two independent cohorts including both healthy individuals and individuals with schizophrenia using multiple cognitive domain scores. Results highlight the salience network (gray matter, GM), corpus callosum (fractional anisotropy, FA), central executive and default-mode networks (fractional amplitude of low-frequency fluctuation, fALFF) as modality-specific biomarkers of generalized cognition. FALFF features are found to be more sensitive to cognitive domain differences, while the salience network in GM and corpus callosum in FA are highly consistent and predictive of multiple cognitive domains. These modality-specific brain regions define-in three separate cohorts-promising co-varying multimodal signatures that can be used as predictors of multi-domain cognition.

Anthropogenic climate change is having significant impacts on montane and high-elevation areas globally. Warmer winter temperatures are driving reduced snowpack in the western USA with broad potential impacts on ecosystem dynamics of particular concern for protected areas. Vegetation phenology is a sensitive indicator of ecological response to climate change and is associated with snowmelt timing. Human monitoring of climate impacts can be resource prohibitive for land management agencies, whereas remotely sensed phenology observations are freely available at a range of spatiotemporal scales. Little work has been done in regions dominated by evergreen conifer cover, which represents many mountain regions at temperate latitudes. We used moderate resolution imaging spectroradiometer (MODIS) data to assess the influence of snowmelt timing and elevation on five phenology metrics (green up, maximum greenness, senescence, dormancy, and growing season length) within Crater Lake National Park, Oregon, USA from 2001 to 2012. Earlier annual mean snowmelt timing was significantly correlated with earlier onset of green up at the landscape scale. Snowmelt timing and elevation have significant explanatory power for phenology, though with high variability. Elevation has a moderate control on early season indicators such as snowmelt timing and green up and less on late-season variables such as senescence and growing season length. PCA results show that early season indicators and late season indicators vary independently. These results have important implications for ecosystem dynamics, management, and conservation, particularly of species such as whitebark pine (Pinus albicaulis) in alpine and subalpine areas.

Background: Individuals with a family history (FH+) of alcohol use disorder (AUD) have a higher risk for developing an AUD than those with no family history (FH-) of AUD. In addition, FH+ individuals tend to perform worse on neuropsychological measures and show heightened impulsivity, which may be due to underlying differences in brain structure such as cortical thickness. The primary aim of this study was to investigate differences in cortical thickness in FH+ compared to FH- adolescents. Secondary aims were to (i) investigate differences in executive functioning and impulsivity, and (ii) examine associations between brain structure and behavior., Methods: Brain scans of 95 FH- and 93 FH+ subjects aged 13 to 18 were obtained using magnetic resonance imaging. FH+ subjects were required to have at least 1 biological parent with a history of an AUD. FH+ and FH- individuals had limited or no past alcohol use, thereby minimizing potential effects of alcohol. Subjects were evaluated on impulsivity and executive functioning tasks. Thicknesses of cortical lobes and subregions were analyzed using FreeSurfer. Regions showing group differences were examined for group-by-age interactions and correlations with neuropsychological and personality measures., Results: FH+ adolescents had thinner cortices in frontal and parietal lobes, notably in the medial orbitofrontal, lateral orbitofrontal, and superior parietal cortices. The difference in cortical thickness between family history groups was strongest among the youngest subjects. FH+ subjects were also more impulsive and had poorer performance on a spatial memory task., Conclusions: These findings demonstrate frontal and parietal structural differences in FH+ adolescents that might underlie cognitive and behavioral characteristics associated with AUD risk., (Copyright © 2017 by the Research Society on Alcoholism.)