Cardiorespiratory Responses to Acute Intermittent Hypoxia in Humans With Chronic Spinal Cord Injury.

Brief exposure to repeated episodes of low inspired oxygen, or acute intermittent hypoxia (AIH), is a promising therapeutic modality to improve motor function after chronic, incomplete spinal cord injury (SCI). Although therapeutic AIH is under extensive investigation in persons with SCI, limited data are available concerning cardiorespiratory responses during and after AIH exposure despite implications for AIH safety and tolerability. Thus, we recorded immediate (during treatment) and enduring (up to 30 min post-treatment) cardiorespiratory responses to AIH in 19 participants with chronic SCI (>1 year post-injury; injury levels C1 to T6; American Spinal Injury Association Impairment Scale A to D; mean age = 33.8 ± 14.1 years; 18 males). Participants completed a single AIH (15, 60-sec episodes, inspired O2 ≈ 10%; 90-sec intervals breathing room air) and Sham (inspired O2 ≈ 21%) treatment, in random order. During hypoxic episodes: (1) arterial oxyhemoglobin saturation decreased to 82.1 ± 2.9% (p < 0.001); (2) minute ventilation increased 3.83 ± 2.29 L/min (p = 0.008); and (3) heart rate increased 4.77 ± 6.82 bpm (p = 0.010). Considerable variability in cardiorespiratory responses was found among subjects; some individuals exhibited large hypoxic ventilatory responses (≥0.20 L/min/%, n = 11), whereas others responded minimally (<0.20 L/min/%, n = 8). Apneas occurred frequently during AIH and/or Sham protocols in multiple participants. All participants completed AIH treatment without difficulty. No significant changes in ventilation, heart rate, or arterial blood pressure were found 30 min post-AIH p > 0.05). In conclusion, therapeutic AIH is well tolerated, elicits variable chemoreflex activation, and does not cause persistent changes in cardiorespiratory control/function 30 min post-treatment in persons with chronic SCI.

APOE4, Age, and Sex Regulate Respiratory Plasticity Elicited by Acute Intermittent Hypercapnic-Hypoxia.

Rationale: Acute intermittent hypoxia (AIH) shows promise for enhancing motor recovery in chronic spinal cord injuries and neurodegenerative diseases. However, human trials of AIH have reported significant variability in individual responses. Objectives: Identify individual factors (eg, genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH). Methods: In 17 healthy individuals (age = 27 ± 5 yr), associations between individual factors and changes in the magnitude of AIHH (15, 1-min O2 = 9.5%, CO2 = 5% episodes) induced changes in diaphragm motor-evoked potential (MEP) amplitude and inspiratory mouth occlusion pressures (P0.1) were evaluated. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity (BDNF, HTR2A, TPH2, MAOA, NTRK2) and neuronal plasticity (apolipoprotein E, APOE) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized (h)ApoE knock-in rats were performed to test causality. Results: AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE4 (i.e., APOE3/4) compared to individuals with other APOE genotypes (P = 0.048) and the other tested SNPs. Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (P = 0.004). Additionally, age was inversely related with change in P0.1 (P = 0.007). In hApoE4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE3 controls (P < 0.05). Conclusions: APOE4 genotype, sex, and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults. Addition to Knowledge Base: AIH is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative disease. Figure 5 Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, AIHH, in healthy humans. We demonstrate that genetics (particularly the lipid transporter, APOE), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.

Thalamic control of sensory processing and spindles in a biophysical somatosensory thalamoreticular circuit model of wakefulness and sleep.

Thalamoreticular circuitry plays a key role in arousal, attention, cognition, and sleep spindles, and is linked to several brain disorders. A detailed computational model of mouse somatosensory thalamus and thalamic reticular nucleus has been developed to capture the properties of over 14,000 neurons connected by 6 million synapses. The model recreates the biological connectivity of these neurons, and simulations of the model reproduce multiple experimental findings in different brain states. The model shows that inhibitory rebound produces frequency-selective enhancement of thalamic responses during wakefulness. We find that thalamic interactions are responsible for the characteristic waxing and waning of spindle oscillations. In addition, we find that changes in thalamic excitability control spindle frequency and their incidence. The model is made openly available to provide a new tool for studying the function and dysfunction of the thalamoreticular circuitry in various brain states.

APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia.

Rationale: Acute intermittent hypoxia (AIH) is a promising strategy to induce functional motor recovery following chronic spinal cord injuries and neurodegenerative diseases. Although significant results are obtained, human AIH trials report considerable inter-individual response variability. Objectives: Identify individual factors ( e.g. , genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH). Methods: Associations of individual factors with the magnitude of AIHH (15, 1-min O 2 =9.5%, CO 2 =5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P 0.1 ) were evaluated in 17 healthy individuals (age=27±5 years) compared to Sham. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity ( BDNF, HTR 2A , TPH 2 , MAOA, NTRK 2 ) and neuronal plasticity (apolipoprotein E, APOE ) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized ( h ) ApoE knock-in rats were performed to test causality. Results: AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE 4 ( i.e., APOE 3/4 ) allele versus other APOE genotypes (p=0.048). No significant differences were observed between any other SNPs investigated, notably BDNFval/met ( all p>0.05 ). Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (p=0.004). Age was inversely related with change in P 0.1 within the limited age range studied (p=0.007). In hApoE 4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE 3 controls (p<0.05). Conclusions: APOE 4 genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults. ADDITION TO KNOWLEDGE BASE: Acute intermittent hypoxia (AIH) is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative diseases. Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH), in healthy humans. We demonstrate that genetics (particularly the lipid transporter, APOE ), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.

Effects of a mixture of Lentilactobacillus hilgardii, Lentilactobacillus buchneri, Pediococcus pentosaceus and fibrolytic enzymes on silage fermentation, aerobic stability, and performance of growing beef cattle.

This study evaluated the effects of novel silage inoculants containing lactic acid bacteria (LAB) and fibrolytic enzymes on ensiling, aerobic stability (AS), and the performance of growing beef cattle. Whole-plant corn forage was either uninoculated (CON) or inoculated with a mixture of LAB containing (cfu g-1 fresh forage) 1.5 × 105 L. hilgardii (CNCM I-4785), 1.5 × 105 L. buchneri (NCIMB 40788) and 1.0 × 105 P. pentosaceus (NCIMB 12455) for a total of 4.0 × 105 cfu g-1 fresh forage LAB (IB), or a combination of IB plus fibrolytic enzymes (xylanase + ß-glucanase) (IC). All treatments were ensiled in mini-silos, whereas CON and IC were also ensiled in silo bags for the growth performance study. Total bacteria (TB) counts were lower (P = 0.02) for IC than CON after 14 d of ensiling, whereas TB counts of IC and IB were greater (P ≤ 0.01) than CON after 60 d of ensiling in mini-silos. The LAB in IC and IB ensiled in mini-silos were greater than CON on d 60 (P ≤ 0.01) and 90 (P ≤ 0.001) of ensiling and after 3 d (P ≤ 0.01) of aerobic exposure (AE). Silage pH of IC ensiled in silo bags was lower than CON on d 3 (P < 0.01), 7 (P < 0.001), and 14 (P = 0.02) of AE. Yeast counts were lower for IC than CON in terminal silage (P < 0.001), and after 3 (P < 0.001) and 7 d (P < 0.01) of AE. Acetate (AC) concentrations were higher (P ≤ 0.02) for IC than CON throughout AE, whereas lactate (LA) concentrations of IC were greater than CON on d 3 (P < 0.001), 7 (P < 0.01), and 14 (P < 0.001) of AE. Greater AC concentration and lower yeast counts resulted in greater (P < 0.001) stability for IC ensiled in silo bags than CON after 14 d of AE. Growth performance of steers was similar (P > 0.05) as the nutrient composition of silage was similar across diets. Improved AS of IC could potentially have a greater impact on DMI, production efficiency, and growth performance in large-scale commercial feedlot operations where silage at the silo face may be exposed to air for longer periods of time.

Acute intermittent hypercapnic-hypoxia elicits central neural respiratory motor plasticity in humans.

Acute intermittent hypoxia (AIH) elicits long-term facilitation (LTF) of respiration. Although LTF is observed when CO2 is elevated during AIH in awake humans, the influence of CO2 on corticospinal respiratory motor plasticity is unknown. Thus, we tested the hypotheses that acute intermittent hypercapnic-hypoxia (AIHH): (1) enhances cortico-phrenic neurotransmission (reflecting volitional respiratory control); and (2) elicits ventilatory LTF (reflecting automatic respiratory control). Eighteen healthy adults completed four study visits. Day 1 consisted of anthropometry and pulmonary function testing. On Days 2, 3 and 4, in a balanced alternating sequence, participants received: AIHH, poikilocapnic AIH, and normocapnic-normoxia (Sham). Protocols consisted of 15, 60 s exposures with 90 s normoxic intervals. Transcranial (TMS) and cervical (CMS) magnetic stimulation were used to induce diaphragmatic motor-evoked potentials and compound muscle action potentials, respectively. Respiratory drive was assessed via mouth occlusion pressure (P0.1 ), and minute ventilation measured at rest. Dependent variables were assessed at baseline and 30-60 min after exposures. Increases in TMS-evoked diaphragm potential amplitudes were observed following AIHH vs. Sham (+28 ± 41%, P = 0.003), but not after AIH. No changes were observed in CMS-evoked diaphragm potential amplitudes. Mouth occlusion pressure also increased after AIHH (+21 ± 34%, P = 0.033), but not after AIH. Ventilatory LTF was not observed after any treatment. We demonstrate that AIHH elicits central neural mechanisms of respiratory motor plasticity and increases resting respiratory drive in awake humans. These findings may have important implications for neurorehabilitation after spinal cord injury and other neuromuscular disorders compromising breathing. KEY POINTS: The occurrence of respiratory long-term facilitation following acute exposure to intermittent hypoxia is believed to be dependent upon CO2 regulation - mechanisms governing the critical role of CO2 have seldom been explored. We tested the hypothesis that acute intermittent hypercapnic-hypoxia (AIHH) enhances cortico-phrenic neurotransmission in awake healthy humans. The amplitude of diaphragmatic motor-evoked potentials induced by transcranial magnetic stimulation was increased after AIHH, but not the amplitude of compound muscle action potentials evoked by cervical magnetic stimulation. Mouth occlusion pressure (P0.1 , an indicator of neural respiratory drive) was also increased after AIHH, but not tidal volume or minute ventilation. Thus, moderate AIHH elicits central neural mechanisms of respiratory motor plasticity, without measurable ventilatory long-term facilitation in awake humans.

Therapeutic acute intermittent hypoxia: A translational roadmap for spinal cord injury and neuromuscular disease.

We review progress towards greater mechanistic understanding and clinical translation of a strategy to improve respiratory and non-respiratory motor function in people with neuromuscular disorders, therapeutic acute intermittent hypoxia (tAIH). In 2016 and 2020, workshops to create and update a "road map to clinical translation" were held to help guide future research and development of tAIH to restore movement in people living with chronic, incomplete spinal cord injuries. After briefly discussing the pioneering, non-targeted basic research inspiring this novel therapeutic approach, we then summarize workshop recommendations, emphasizing critical knowledge gaps, priorities for future research effort, and steps needed to accelerate progress as we evaluate the potential of tAIH for routine clinical use. Highlighted areas include: 1) greater mechanistic understanding, particularly in non-respiratory motor systems; 2) optimization of tAIH protocols to maximize benefits; 3) identification of combinatorial treatments that amplify plasticity or remove plasticity constraints, including task-specific training; 4) identification of biomarkers for individuals most/least likely to benefit from tAIH; 5) assessment of long-term tAIH safety; and 6) development of a simple, safe and effective device to administer tAIH in clinical and home settings. Finally, we update ongoing clinical trials and recent investigations of tAIH in SCI and other clinical disorders that compromise motor function, including ALS, multiple sclerosis, and stroke.

Enhanced Sensing of Weak Anharmonicities through Coherences in Dissipatively Coupled Anti-PT Symmetric Systems.

In the last few years, the great utility of exceptional points in sensing linear perturbations has been recognized. However, physical systems are inherently anharmonic and macroscopic physics is most accurately described by nonlinear models. Considering the multitude of semiclassical and quantum effects ensuing from nonlinear interactions, the sensing of anharmonicities is a prerequisite to the primed control of these effects. Here, we propose an expedient sensing scheme relevant to dissipatively coupled anti parity-time (anti-PT) symmetric systems and customized for the fine-grained estimation of anharmonic perturbations. The sensitivity to anharmonicities is derived from the coherence between two modes induced by a common vacuum. Owing to this coherence, the linear response acquires a pole on the real axis. We demonstrate how this singularity can be exploited for the enhanced sensing of very weak anhamonicities at low pumping rates. Our results are applicable to a wide class of systems, and we specifically illustrate the remarkable sensing capabilities in the context of a weakly anharmonic yttrium iron garnet sphere interacting with a cavity via a tapered fiber waveguide. A small change in the anharmonicity leads to a substantial change in the induced spin current.

Effect of acute intermittent hypoxia on cortico-diaphragmatic conduction in healthy humans.

Acute intermittent hypoxia (AIH) is a strategy to improve motor output in humans with neuromotor impairment. A single AIH session increases the amplitude of motor evoked potentials (MEP) in a finger muscle (first dorsal interosseous), demonstrating enhanced corticospinal neurotransmission. Since AIH elicits phrenic/diaphragm long-term facilitation (LTF) in rodent models, we tested the hypothesis that AIH augments diaphragm MEPs in humans. Eleven healthy adults (7 males, age = 29 ± 6 years) were tested. Transcranial and cervical magnetic stimulation were used to induce diaphragm MEPs and compound muscle action potentials (CMAP) recorded by surface EMG, respectively. Stimulus-response curves were generated prior to and 30-60 min after AIH. Diaphragm LTF was assessed by measurement of integrated EMG burst amplitude and frequency during eupnoeic breathing before and after AIH. Following baseline measurements, AIH was delivered from an oxygen generator connected to a facemask under poikilocapnic conditions (15 one minute episodes of 9% inspired oxygen with one minute room air intervals). There were no detectable changes in MEP (-1.5 ± 12.1%, p = 0.96) or CMAP (+0.1 ± 7.8%, p = 0.97) amplitudes across the stimulus-response curve. At stimulation intensities approximating 50% of the difference between minimum and maximum baseline amplitudes, MEP and CMAP amplitudes were also unchanged (p > 0.05). Further, no AIH effect was observed on diaphragm EMG activity during eupnoea post-AIH (p > 0.05). We conclude that unlike hand muscles, poikilocapnic AIH does not enhance diaphragm MEPs or produce diaphragm LTF in healthy humans.

Conserving purple prairie clover (Dalea purpurea Vent.) as hay and silage had little effect on the efficacy of condensed tannins in modulating ruminal fermentation in vitro.

BACKGROUND: The objective of this study was to determine the effects of forage conservation method and condensed tannins (CT) in conserved forage on rumen fermentation. Purple prairie clover (PPC; Dalea purpurea Vent.) containing 84.5 g kg-1 dry matter (DM) of CT was harvested at full flower and preserved as freeze-dried green chop (F), hay (H) or silage (S). Batch culture incubations were conducted using conserved forages as a substrate and treatments were arranged as 3 × 2 factorial design of forage type (F, H and S) with or without polyethylene glycol (PEG). PEG was used to isolate the effects of CT on fermentation. Incubation was repeated twice with quadruplicate vials for each treatment in each incubation. 15 N-labelled ammonium sulfate was used as microbial N marker and headspace gas was sampled to determine methane production. RESULTS: Concentrations of neutral detergent fiber (NDF) and acid detergent fiber were lower (P < 0.01) in F than in H or S. Ensiling decreased (P < 0.001) total phenolics and extractable CT, but had no effect on total CT, whereas none of these phenolic fractions were altered in H. Hay and silage had lower (P < 0.01) true DM disappearance (TDMD) and NDF disappearance (NDFD) than F. Inclusion of PEG did not affect TDMD or NDFD after 8, 24 or 72 h of incubation. Productions of total gas, methane and total volatile fatty acid and the rate of gas production (c) were also similar, but ammonia was higher (P < 0.05) and microbial N was lower (P < 0.05) with than without PEG after 72 h of incubation. After 72 h, a lower (P < 0.001) proportion of acetate but higher (P < 0.05) proportion of propionate was noted with S, resulting in a lower (P < 0.001) acetate:propionate ratio as compared to F or H after 8 h of incubation. CONCLUSION: Condensed tannins in PPC decreased protein degradation in vitro, but had minimal effects on overall rumen fermentation, and conservation of PPC as hay or silage had little effect on the efficacy of CT in modulating rumen fermentation. © 2020 Her Majesty the Queen in Right of Canada. Journal of The Science of Food and Agriculture © 2020 Society of Chemical Industry.

Optogenetic Stimulation of Basal Forebrain Parvalbumin Neurons Activates the Default Mode Network and Associated Behaviors.

Activation of the basal forebrain (BF) has been associated with increased attention, arousal, and a heightened cortical representation of the external world. In addition, BF has been implicated in the regulation of the default mode network (DMN) and associated behaviors. Here, we provide causal evidence for a role of BF in DMN regulation, highlighting a prominent role of parvalbumin (PV) GABAergic neurons. The optogenetic activation of BF PV neurons reliably drives animals toward DMN-like behaviors, with no effect on memory encoding. In contrast, BF electrical stimulation enhances memory performance and increases DMN-like behaviors. BF stimulation has a correlated impact on peptide regulation in the BF and ACC, enhancing peptides linked to grooming behavior and memory functions, supporting a crucial role of the BF in DMN regulation. We suggest that in addition to enhancing attentional functions, the BF harbors a network encompassing PV GABAergic neurons that promotes self-directed behaviors associated with the DMN.

Effects of inoculation of corn silage with Lactobacillus hilgardii and Lactobacillus buchneri on silage quality, aerobic stability, nutrient digestibility, and growth performance of growing beef cattle.

This study evaluated the effects of inoculation of whole crop corn silage with a mixture of heterofermentative lactic acid bacteria (LAB) composed of Lactobacillus hilgardii and Lactobacillus buchneri on ensiling, aerobic stability, ruminal fermentation, total tract nutrient digestibility, and growth performance of beef cattle. Uninoculated control corn silage (CON) and silage inoculated with 3.0 × 105 cfu g-1 of LAB containing 1.5 × 105 cfu g-1 of L. hilgardii CNCM I-4785 and 1.5 × 105 cfu g-1 of L. buchneri NCIMB 40788 (INOC) were ensiled in silo bags. The pH did not differ (P > 0.05) between the two silages during ensiling but was greater (P < 0.001) for CON than INOC after 14 d of aerobic exposure (AE). Neutral detergent insoluble crude protein (NDICP) content (% of DM and % of CP basis) of terminal INOC silage was greater (P ≤ 0.05) than that of CON. In terminal silage, concentrations of total VFA and acetate were greater (P < 0.001), while water-soluble carbohydrates were lower (P < 0.001) for INOC than CON. Yeast and mold counts were lower for INOC than CON (P ≤ 0.001) in both terminal and aerobically exposed silages. The stability of INOC was greater (P < 0.001) than that of CON after 14 d of AE. Ruminal fermentation parameters and DMI did not differ (P > 0.05) between heifers fed the two silages, while there was a tendency (P ≤ 0.07) for lower CP and starch digestibility for heifers fed INOC than CON. Total nitrogen (N) intake and N retention were lower (P ≤ 0.04) for heifers fed INOC than CON. Dry matter intake as a percentage of BW was lower (P < 0.04) and there was a tendency for improved feed efficieny (G:F; P = 0.07) in steers fed INOC vs. CON silage. The NEm and NEg contents were greater for INOC than CON diets. Results indicate that inoculation with a mixture of L. hilgardii and L. buchneri improved the aerobic stability of corn silage. Improvements in G:F of growing steers fed INOC silage even though the total tract digestibility of CP and starch tended to be lower for heifers fed INOC are likely because the difference in BW and growth requirements of these animals impacted the growth performance and nutrient utilization and a greater proportion of NDICP in INOC than CON.

Effects of inoculation of corn silage with Lactobacillus spp. or Saccharomyces cerevisiae alone or in combination on silage fermentation characteristics, nutrient digestibility, and growth performance of growing beef cattle.

This study evaluated the effects of a novel silage inoculant containing Saccharomyces cerevisiae strain 3 as a direct fed microbial (DFM) on the ensiling, aerobic stability, and nutrient digestibility of whole-crop corn silage and growth performance of beef cattle. Treatments included uninoculated corn silage (CON) or corn silage inoculated with a mixture of 1.1 × 105 cfu g-1 fresh forage Lactobacillus plantarum and Lactobacillus buchneri (INOC1) or 1.0 × 104 cfu g-1 fresh forage S. cerevisiae strain 3 (INOC2) or a mixture of INOC1 and INOC2 (INOC3). Silage in INOC1 had lower (P = 0.03) proportion of lactate, with acetate (Ac) proportion ranking as INOC1 > INOC3 > INOC2 (P < 0.01). In terminal silage, numbers of lactic acid bacteria were greater (P = 0.05) for INOC1 than CON and INOC2, while yeast counts tended (P = 0.08) to be greater for INOC2 than INOC3 on day 3 of aerobic exposure. Aerobic stability of corn silage was not impacted by inoculation with S. cerevisiae strain 3. Heifers fed INOC2 and INOC3 had lower (P < 0.01) ruminal Ac concentration than those fed CON. Apparent total tract digestibilities of DM, OM, ADF, and NDF were greater (P ≤ 0.03) for heifers fed INOC2 than those fed CON. Growth performance was similar across treatments, excepting DMI as percent of BW tended to be lower (P = 0.08) for INOC2 steers compared to CON steers. These results suggest that S. cerevisiae strain 3 has potential as a component in a fourth generation DFM silage inoculant.

Basal forebrain contributes to default mode network regulation.

The default mode network (DMN) is a collection of cortical brain regions that is active during states of rest or quiet wakefulness in humans and other mammalian species. A pertinent characteristic of the DMN is a suppression of local field potential gamma activity during cognitive task performance as well as during engagement with external sensory stimuli. Conversely, gamma activity is elevated in the DMN during rest. Here, we document that the rat basal forebrain (BF) exhibits the same pattern of responses, namely pronounced gamma oscillations during quiet wakefulness in the home cage and suppression of this activity during active exploration of an unfamiliar environment. We show that gamma oscillations are localized to the BF and that gamma-band activity in the BF has a directional influence on a hub of the rat DMN, the anterior cingulate cortex, during DMN-dominated brain states. The BF is well known as an ascending, activating, neuromodulatory system involved in wake-sleep regulation, memory formation, and regulation of sensory information processing. Our findings suggest a hitherto undocumented role of the BF as a subcortical node of the DMN, which we speculate may be important for switching between internally and externally directed brain states. We discuss potential BF projection circuits that could underlie its role in DMN regulation and highlight that certain BF nuclei may provide potential target regions for up- or down-regulation of DMN activity that might prove useful for treatment of DMN dysfunction in conditions such as epilepsy or major depressive disorder.

Anatomy and physiology of phrenic afferent neurons.

Large-diameter myelinated phrenic afferents discharge in phase with diaphragm contraction, and smaller diameter fibers discharge across the respiratory cycle. In this article, we review the phrenic afferent literature and highlight areas in need of further study. We conclude that 1) activation of both myelinated and nonmyelinated phrenic sensory afferents can influence respiratory motor output on a breath-by-breath basis; 2) the relative impact of phrenic afferents substantially increases with diaphragm work and fatigue; 3) activation of phrenic afferents has a powerful impact on sympathetic motor outflow, and 4) phrenic afferents contribute to diaphragm somatosensation and the conscious perception of breathing. Much remains to be learned regarding the spinal and supraspinal distribution and synaptic contacts of myelinated and nonmyelinated phrenic afferents. Similarly, very little is known regarding the potential role of phrenic afferent neurons in triggering or modulating expression of respiratory neuroplasticity.

Histological identification of phrenic afferent projections to the spinal cord.

Limited data are available regarding the spinal projections of afferent fibers in the phrenic nerve. We describe a method that robustly labels phrenic afferent spinal projections in adult rats. The proximal end of the cut phrenic nerve was secured in a microtube filled with a transganglionic tracer (cholera toxin ß-subunit, CT-ß, or Cascade Blue) and tissues harvested 96-h later. Robust CT-ß labeling occurred in C3-C5 dorsal root ganglia cell bodies and phrenic afferent projections were identified in the mid-cervical dorsal horn (laminae I-III), intermediate grey matter (laminae IV, VII) and near the central canal (laminae X). Afferent fiber labeling was reduced or absent when CT-ß was delivered to the intrapleural space or directly to the hemidiaphragm. Soaking the phrenic nerve with Cascade Blue also produced robust labeling of mid-cervical dorsal root ganglia cells bodies, and primary afferent fibers were observed in spinal grey matter and dorsal white matter. Our results show that the 'nerve soak' method effectively labels both phrenic motoneurons and phrenic afferent projections, and show that primary afferents project throughout the ipsilateral mid-cervical gray matter.

Gamma band directional interactions between basal forebrain and visual cortex during wake and sleep states.

The basal forebrain (BF) is an important regulator of cortical excitability and responsivity to sensory stimuli, and plays a major role in wake-sleep regulation. While the impact of BF on cortical EEG or LFP signals has been extensively documented, surprisingly little is known about LFP activity within BF. Based on bilateral recordings from rats in their home cage, we describe endogenous LFP oscillations in the BF during quiet wakefulness, rapid eye movement (REM) and slow wave sleep (SWS) states. Using coherence and Granger causality methods, we characterize directional influences between BF and visual cortex (VC) during each of these states. We observed pronounced BF gamma activity particularly during wakefulness, as well as to a lesser extent during SWS and REM. During wakefulness, this BF gamma activity exerted a directional influence on VC that was associated with cortical excitation. During SWS but not REM, there was also a robust directional gamma band influence of BF on VC. In all three states, directional influence in the gamma band was only present in BF to VC direction and tended to be regulated specifically within each brain hemisphere. Locality of gamma band LFPs to the BF was confirmed by demonstration of phase locking of local spiking activity to the gamma cycle. We report novel aspects of endogenous BF LFP oscillations and their relationship to cortical LFP signals during sleep and wakefulness. We link our findings to known aspects of GABAergic BF networks that likely underlie gamma band LFP activations, and show that the Granger causality analyses can faithfully recapitulate many known attributes of these networks.

Recovery-based services in a psychiatric intensive care unit - the consumer perspective.

OBJECTIVE: To describe the implementation of recovery-based practice into a psychiatric intensive care unit, and report change in seclusion rates over the period when these changes were introduced (2011-2013). METHOD: Recovery-based practices including collaborative care, safety care plans, a comfort room, and debriefing after coercive interventions were introduced. A carer consultant was employed. A restraint and seclusion review committee, chaired by a peer worker, was established. A consumer exit interview was introduced and these data were collected, reviewed by staff and the peer worker and used to improve the ward environment. Rates of seclusion were measured during the period when recovery-based practices were introduced. RESULTS: Consumer feedback indicated that positive aspects of the psychiatric intensive care unit included approachable, helpful staff and completion of a safety care plan. Negative aspects included lack of involvement in decisions about admission and about medications, the non-smoking policy, and being placed in seclusion or restraint. There was a significant reduction in the number of consumers secluded and the total number of seclusions. CONCLUSIONS: Recovery principles can be successfully introduced in a psychiatric intensive care unit environment. Introduction of recovery based practice was associated with a reduction in seclusion.

Tree shrews (Tupaia belangeri) exhibit novelty preference in the novel location memory task with 24-h retention periods.

Novelty preference is pervasive in mammalian species, and describes an inherent tendency to preferentially explore novelty. The novel location memory task studied here assesses the ability of animals to form accurate memories of a spatial configuration, consisting of several identical objects placed within an arena. Tree shrews were first familiarized with a particular object configuration during several sessions, and then an object was displaced during a test session. Tree shrews exhibited enhanced exploration when confronted with this novel configuration. The most reliable indicator associated with novelty preference was an enhancement in directed exploration towards the novel object, although we also observed a non-specific overall increase in exploration in one experiment. During the test session, we also observed an exploration of the location, which had previously been occupied by the displaced object, an effect termed empty quadrant. Our behavioral findings suggest multiple stages of spatial memory formation in tree shrews that are associated with various forms of behavioral responses to novelty. Reduced novelty preference has been linked to major depressive disorder in human patients. Given the established social conflict depression model in tree shrews, we anticipate that the study of the neural circuits of novelty preference and their malfunction during depression may have implications for understanding or treating depression in humans.

Validation of the Intensive Care Delirium Screening Checklist in nonintubated intensive care unit patients in a resource-poor medical intensive care setting in South India.

OBJECTIVE: Delirium is a common, difficult-to-diagnose clinical condition in critical care units. The lack of recognition of delirium often results in increased morbidity and mortality. The study aimed to determine the validity and reliability of the Intensive Care Delirium Screening Checklist (ICDSC) in a resource-poor medical intensive care setting in South India. MATERIALS AND METHODS: Fifty-three patients admitted into the medical intensive care unit of a teaching hospital who were neither mute nor intubated were recruited for the study. Trained residents administered the ICDSC to screen for delirium. A consultant psychiatrist used the International Classification of Diseases, 10th Revision diagnostic criteria for research to determine the presence of delirium. RESULTS: The optimal threshold for screening, as ICDSC total score of 3 or more, was obtained by using a receiver operating characteristic curve. Although a sensitivity and specificity of 75% and 74%, respectively, were obtained at the original cutoff of 4, a sensitivity of 90% and specificity of 61.54% were achieved with a cutoff of 3. In a subsample of 21 patients, interrater reliability was evaluated and found to be 0.947 (95% confidence interval, 0.870-0.979). The ICDSC had good internal consistency, with Cronbach α of .754 and Guttman split-half coefficient of 0.71. Factor analysis revealed a 2-factor structure, namely, altered sensorium/psychopathology and sleep-wake cycle problems. CONCLUSIONS: Our findings indicate that in nonintubated intensive care unit patients, the ICDSC can be used to screen for delirium but should not be used as a diagnostic instrument in this patient population and that residents can be trained in the use of the instrument in resource-poor critical care settings. Using a different threshold for positivity of 3 rather than 4 appeared to offer improved screening characteristics in this resource-poor critical care setting.