Bridging the Gap: Can Large Language Models Match Human Expertise in Writing Neurosurgical Operative Notes?

BACKGROUND: Proper documentation is essential for patient care. The popularity of artificial intelligence (AI) offers the potential for improvements in neurosurgical note-writing. The study aimed to assess how AI can optimize documentation in neurosurgical procedures. METHODS: Thirty-six notes were included. All identifiable data were removed. Essential information, such as perioperative data and diagnosis, was sourced from these notes. ChatGPT 4.0 was trained to draft notes from surgical vignettes using each surgeon's note template. One hundred forty-four surveys, with a surgeon or AI note, were shared with three surgeons to evaluate accuracy, content, and organization using a five-point scale. Accuracy was the factual correctness. Content was the comprehensiveness. Organization was the arrangement of the note. Flesch-Kincaid Grade Level (FKGL) and Flesch Reading Ease (FRE) scores quantified each note's readability. RESULTS: The mean AI accuracy (4.44) was not different from the mean surgeon accuracy (4.33, p = 0.512). The mean AI content (3.73) was lower than the mean surgeon content (4.42, p < 0.001). The mean AI organization (4.54) was greater than the mean surgeon organization (4.24, p = 0.064). The mean AI note's FKGL (13.13) was greater than the mean surgeon FKGL (9.99, p <0.001). The mean AI FRE (21.42) was lower than the mean surgeon FRE (41.70, p <0.001). CONCLUSION: AI notes were on par with surgeon notes in accuracy and organization, but lacked in content. Additionally, AI notes utilized language at an advanced reading level. These findings underscore the potential for ChatGPT to enhance the efficiency of neurosurgery documentation.

Comparing reactive versus empiric cerebrospinal fluid drainage strategies for spinal perfusion pressure optimization in patients with acute traumatic spinal cord injuries.

BACKGROUND: Spinal cord hypoperfusion undermines clinical recovery in acute traumatic spinal cord injuries. New guidelines suggest cerebrospinal fluid (CSF) drainage is an important strategy for preventing spinal cord hypoperfusion in the acute post-injury phase. METHODS: This study included participants presenting to a single level 1 trauma center between 2018 and 2022 with cervical or thoracic traumatic spinal cord injury severity grade A-C, as evaluated by the American spinal injury association impairment scale (AIS). The primary objective of this study was to compare the efficacy of two CSF drainage protocols in preventing spinal cord hypoperfusion; 1) draining CSF only when spinal cord perfusion pressure (SCPP) drops below 65 mmHg (i.e. reactive) versus 2) empiric CSF drainage of 5-10 mL every hour. Intrathecal pressure, spinal cord perfusion pressure (SCPP), mean arterial pressure (MAP), and vasopressor utilization were compared using univariate T-test statistical analysis. RESULTS: While there was no difference in the incidence of sub-optimal SCPP (<65 mmHg; p = 0.1658), reactively drained participants were more likely to exhibit critical hypoperfusion (<50 mmHg; p = 0.0030) despite also having lower average intrathecal pressures (p < 0.001). There were no differences in average SCPP, mean arterial pressure (MAP), or vasopressor utilization between the two groups (p > 0.05). CONCLUSIONS: Empiric (vs reactive) CSF drainage resulted in fewer incidences of critical spinal cord hypoperfusion for patients with acute traumatic spinal cord injuries.

Intradiscal Osteotomy and Bilateral Expandable Transforaminal Interbody Fusion Cages for Iatrogenic Kyphotic Deformity: A Technical Report.

Objectives Expandable transforaminal interbody fusion (TLIF) devices have been developed to introduce more segmental lordosis through a narrow operative corridor, but there are concerns about the degree of achievable correction with a small graft footprint. In this report, we describe the technical nuances associated with placing bilateral expandable cages for correction of iatrogenic deformity. Materials and Methods A 60-year-old female with symptomatic global sagittal malalignment and a severe lumbar kyphotic deformity after five prior lumbar surgeries presented to our institution. We performed multilevel posterior column osteotomies, a L3-4 intradiscal osteotomy, and placed bilateral lordotic expandable TLIF cages at the level of maximum segmental kyphosis. Results We achieve a 21-degree correction of the patient's focal kyphotic deformity and restoration of the patient global sagittal alignment. Conclusion This case demonstrates both the feasibility and utility of placing bilateral expandable TLIF cages at a single disc space in the setting of severe focal sagittal malalignment. This technique expands the implant footprint and, when coupled with an intradiscal osteotomy, allows for a significant restoration of segmental lordosis.

Time of day does not impact spinal serotonin levels in humans.

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 ± $ \pm $ 67.7 nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 ± $ \pm $ 75.8 nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p = .762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

Preinjury Frailty Predicts 1-Year Mortality in Older Adults With Traumatic Spine Fractures.

BACKGROUND AND OBJECTIVES: Nearly 30% of older adults presenting with isolated spine fractures will die within 1 year. Attempts to ameliorate this alarming statistic are hindered by our inability to identify relevant risk factors. The primary objective of this study was to develop a prediction model that identifies feasible targets to limit 1-year mortality. METHODS: This retrospective cohort study included 703 older adults (65 years or older) admitted to a level I trauma center with isolated spine fractures, without neural deficit, from January 2013 to January 2018. Multivariable analysis was used to select for independently significant patient demographics, frailty variables, injury metrics, and management decisions to incorporate into distinct logistic regression models predicting 1-year mortality. Variables were considered significant, if P < .05. RESULTS: Of the 703 older adults, 199 (28.3%) died after hospital discharge, but within 1 year of index trauma. Risk Analysis Index (RAI; odds ratio [OR]: 1.116; 95% CI: 1.087-1.149; P < .001) and ambulation requiring a cane (OR: 2.601; 95% CI: 1.151-5.799; P = .02) or walker (OR: 4.942; 95% CI: 2.698-9.196; P < .001), ie, frailty variables, were associated with increased odds of 1-year mortality. Spine trauma scales were not associated with 1-year mortality. Longer hospital stays (OR: 1.112; 95% CI: 1.034-1.196; P = .004) and nursing home discharge (OR: 3.881; 95% CI: 2.070-7.378; P < .001) were associated with increased odds, while discharge to rehab (OR: 0.361; 95% CI: 0.155-0.799; P = .014) decreased 1-year mortality odds. A "preinjury" regression model incorporating Risk Analysis Index and ambulation status resulted in an area under receiver operating characteristic curve (AUROCC) of 0.914 (95% CI: 0.863-0.965). A "postinjury" model incorporating Glasgow Coma Scale, hospital stay duration, and discharge disposition resulted in AUROCC of 0.746 (95% CI: 0.642-0.849). Combining elements of the preinjury and postinjury models into an "integrated model" produced an AUROCC of 0.908 (95% CI: 0.852-0.965). CONCLUSION: Preinjury frailty measures are most strongly associated with 1-year mortality outcomes in older adults with isolated spine fractures. Incorporating injury metrics or management decisions did not enhance predictive accuracy. Further work is needed to understand how targeting frailty may reduce mortality.

A guide to selecting upper thoracic versus lower thoracic uppermost instrumented vertebra in adult spinal deformity correction.

PURPOSE: Operative treatment of adult spinal deformity (ASD) has been shown to improve patient health-related quality of life (HRQOL). Selection of the uppermost instrumented vertebra (UIV) in either the upper thoracic (UT) or lower thoracic (LT) spine is a pivotal decision with effects on operative and postoperative outcomes. This review overviews the multifaceted decision-making process for UIV selection in ASD correction. METHODS: PubMed was queried for articles using the keywords "uppermost instrumented vertebra", "upper thoracic", "lower thoracic", and "adult spinal deformity". RESULTS: Optimization of UIV selection may lead to superior deformity correction, better patient-reported outcomes, and lower risk of proximal junctional kyphosis (PJK) and failure (PJF). Patient alignment characteristics, including preoperative thoracic kyphosis, coronal deformity, and the magnitude of sagittal correction influence surgical decision-making when selecting a UIV, while comorbidities such as poor body mass index, osteoporosis, and neuromuscular pathology should also be taken in to account. Additionally, surgeon experience and resources available to the hospital may also play a role in this decision. Currently, it is incompletely understood whether postoperative HRQOLs, functional and radiographic outcomes, and complications after surgery differ between selection of the UIV in either the UT or LT spine. CONCLUSION: The correct selection of the UIV in surgical planning is a challenging task, which requires attention to preoperative alignment, patient comorbidities, clinical characteristics, available resources, and surgeon-specific factors such as experience.

Surgical intervention ≤ 24 hours versus > 24 hours after injury for the management of acute traumatic central cord syndrome: a systematic review and meta-analysis.

OBJECTIVE: The objective was to evaluate the efficacy, outcomes, and complications of surgical intervention performed within 24 hours (≤ 24 hours) versus after 24 hours (> 24 hours) in managing acute traumatic central cord syndrome (ATCCS). METHODS: Articles pertinent to the study were retrieved from PubMed, Scopus, Web of Science, and Cochrane. The authors performed a systematic review and meta-analysis of treatment procedures and outcomes according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) guidelines. RESULTS: Seven articles comprising 488 patients were included, with 188 (38.5%) patients in the ≤ 24-hour group and 300 (61.5%) in the > 24-hour group. Significant differences were not found between groups in terms of demographic characteristics, injury mechanism, spinal cord compression level, neuroimaging features, and the American Spinal Injury Association (ASIA) motor score at admission. Both groups had a similar approach to surgery and steroid administration. The surgical complication rate was significantly higher in the > 24-hour group (4.5%) compared to the ≤ 24-hour group (1.2%) (p = 0.05). Clinical follow-up duration was similar at 12 months (interquartile range 3-36) for both groups (p > 0.99). The ≤ 24-hour group demonstrated a not statistically significant greater improvement in ASIA motor score, with a mean difference of 12 (95% CI -20.7 to 44.6) compared to the > 24-hour group. CONCLUSIONS: The present study indicates potential advantages of early (≤ 24 hours) surgery in ATCCS patients, specifically in terms of lower complication rates. However, further research is needed to confirm these findings and their clinical implications.

Associating T1-Weighted and T2-Weighted Magnetic Resonance Imaging Radiomic Signatures With Preoperative Symptom Severity in Patients With Cervical Spondylotic Myelopathy.

BACKGROUND: Preoperative symptom severity in cervical spondylotic myelopathy (CSM) can be variable. Radiomic signatures could provide an imaging biomarker for symptom severity in CSM. This study utilizes radiomic signatures of T1-weighted and T2-weighted magnetic resonance imaging images to correlate with preoperative symptom severity based on modified Japanese Orthopaedic Association (mJOA) scores for patients with CSM. METHODS: Sixty-two patients with CSM were identified. Preoperative T1-weighted and T2-weighted magnetic resonance imaging images for each patient were segmented from C2-C7. A total of 205 texture features were extracted from each volume of interest. After feature normalization, each second-order feature was further subdivided to yield a total of 400 features from each volume of interest for analysis. Supervised machine learning was used to build radiomic models. RESULTS: The patient cohort had a median mJOA preoperative score of 13; of which, 30 patients had a score of >13 (low severity) and 32 patients had a score of ≤13 (high severity). Radiomic analysis of T2-weighted imaging resulted in 4 radiomic signatures that correlated with preoperative mJOA with a sensitivity, specificity, and accuracy of 78%, 89%, and 83%, respectively (P < 0.004). The area under the curve value for the ROC curves were 0.69, 0.70, and 0.77 for models generated by independent T1 texture features, T1 and T2 texture features in combination, and independent T2 texture features, respectively. CONCLUSIONS: Radiomic models correlate with preoperative mJOA scores using T2 texture features in patients with CSM. This may serve as a surrogate, objective imaging biomarker to measure the preoperative functional status of patients.

SUPRASPINAL CONTROL OF MOTONEURONS AFTER PARALYSIS ENABLED BY SPINAL CORD STIMULATION.

Spinal cord stimulation (SCS) restores motor control after spinal cord injury (SCI) and stroke. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Instead, here we show that SCS does not facilitate residual supraspinal inputs but directly triggers motoneurons action potentials. However, supraspinal inputs can shape SCS-mediated activity, mimicking volitional control of motoneuron firing. Specifically, by combining simulations, intraspinal electrophysiology in monkeys and single motor unit recordings in humans with motor paralysis, we found that residual supraspinal inputs transform subthreshold SCS-induced excitatory postsynaptic potentials into suprathreshold events. We then demonstrated that only a restricted set of stimulation parameters enables volitional control of motoneuron firing and that lesion severity further restricts the set of effective parameters. Our results explain the facilitation of voluntary motor control during SCS while predicting the limitations of this neurotechnology in cases of severe loss of supraspinal axons.

Infant Rudimentary Meningocele with Tethering of the Cervical Cord: A Case Report.

Rudimentary meningoceles of the spine with dural extension are very rare and warrant surgical excision to prevent infection and long-term neurological deficits in pediatric patients. We present the case of a 5-month-old infant with a tethered spinal cord secondary to a rudimentary meningocele. The patient presented shortly after birth with a midline cervical dimple that was evaluated for a suspected dermal sinus tract. Magnetic resonance imaging scan of the spine showed a sinus tract with intradural extension to C2-3 and external opening at the level of spinous process C5. En bloc surgical excision and spinal cord release were successfully performed. Histological analysis of the specimen confirmed the presence of two blunt sinus tracts and staining was consistent with a rudimentary meningocele. Intradural rudimentary meningoceles in infants can successfully be managed with surgical intervention. Surgery is indicated to prevent future motor complications from spinal cord tethering and neoplastic growth from the rudimentary meningocele.

Patterns in Follow-Up Imaging Usage for Pediatric Patients with Whiplash-Associated Disorder.

BACKGROUND: A clinical concern exists that pediatric patients with whiplash-associated disorder (WAD) might have missed structural injuries or, alternatively, subsequently develop structural injuries over time, despite initially negative imaging findings. The primary objective of this study is to assess follow-up imaging usage for pediatric patients presenting with WAD. METHODS: A retrospective review of 444 pediatric patients presenting to a level 1 pediatric trauma hospital from January 1, 2010 to December 31, 2019 was performed. Imaging was reviewed at the initial encounter and the 3- and 6-month follow-up appointments. RESULTS: At the initial evaluation, children aged <6 years were more likely to receive radiographs (P = 0.007) and magnetic resonance imaging (P = 0.048) than were children aged 6-11 and 12-18 years. At the 3- and 6-month follow-up appointments, persistent neck pain was rare, representing <15% of patients at either time. Regardless of pain persistence, 80.2% of patients seen at the 3-month follow-up and 100% of patients at the 6-month follow-up underwent additional imaging studies. At the 3-month follow-up, children with persistent neck pain were more likely to undergo magnetic resonance imaging than were patients without persistent pain (P < 0.001). Also, patients with persistent neck pain were also more likely to not undergo any imaging evaluation (P = 0.002). Follow-up imaging studies did not reveal new structural injuries at either time point. CONCLUSIONS: Follow-up imaging for pediatric patients with low-grade WAD did not identify new structural pathology-in patients with or without persistent neck pain.

Top-ten most-cited articles on anterior column release in the context of minimally invasive lumbar interbody fusion.

Introduction: Lateral anterior column release (ACR) is a minimally invasive option for the correction of sagittal plane deformity. To assemble a homogeneous picture of published research on ACR, an advanced bibliometric analysis was conducted to compile the top-ten most-cited articles on the topic of ACR. Methods: A keyword search using the Thomson Reuters Web of Knowledge was conducted to identify articles discussing the role of lateral ACR. The articles were then ranked based on the total number of citations to identify the ten most-cited articles published. A subjective appraisal of the findings of these articles was conducted to provide a ranked literature review and to examine trends in the study of ACR between 2012 and 2019. Results: The earliest published article on ACR was in 2012 by Deukmedjian et al. Three articles were in vitro biomechanical assessments of ACR, and seven articles were on outcome analyses, which were either case series or case controlled. The most-cited article was a biomechanical study authored by Uribe et al. The article with the highest rate of citations/year was authored by Manwaring et al. Uribe and the European Spine Journal were the most frequently cited author and journal, respectively. Conclusions: The lateral ACR approach has enjoyed significant scholarly attention since its advent. Higher-level analyses with robust control groups, larger sample sizes, and long-term follow-up are necessary to improve our understanding of this approach.

Epidural stimulation of the cervical spinal cord for post-stroke upper-limb paresis.

Cerebral strokes can disrupt descending commands from motor cortical areas to the spinal cord, which can result in permanent motor deficits of the arm and hand. However, below the lesion, the spinal circuits that control movement remain intact and could be targeted by neurotechnologies to restore movement. Here we report results from two participants in a first-in-human study using electrical stimulation of cervical spinal circuits to facilitate arm and hand motor control in chronic post-stroke hemiparesis ( NCT04512690 ). Participants were implanted for 29 d with two linear leads in the dorsolateral epidural space targeting spinal roots C3 to T1 to increase excitation of arm and hand motoneurons. We found that continuous stimulation through selected contacts improved strength (for example, grip force +40% SCS01; +108% SCS02), kinematics (for example, +30% to +40% speed) and functional movements, thereby enabling participants to perform movements that they could not perform without spinal cord stimulation. Both participants retained some of these improvements even without stimulation and no serious adverse events were reported. While we cannot conclusively evaluate safety and efficacy from two participants, our data provide promising, albeit preliminary, evidence that spinal cord stimulation could be an assistive as well as a restorative approach for upper-limb recovery after stroke.

GABA Increases Sensory Transmission In Monkeys.

Sensory input flow is central to voluntary movements. For almost a century, GABA was believed to modulate this flow by inhibiting sensory axons in the spinal cord to sculpt neural inputs into skilled motor output. Instead, here we show that GABA can also facilitate sensory transmission in monkeys and consequently increase spinal and cortical neural responses to sensory inputs challenging our understanding of generation and perception of movement.

Retinoic acid receptor alpha activation is necessary and sufficient for plasticity induced by recurrent central apnea.

Reductions in respiratory-related synaptic inputs to inspiratory motor neurons initiate a form of plasticity that proportionally enhances inspiratory motor output, even in the absence of changing blood gases. This form of plasticity is known as inactivity-induced inspiratory motor facilitation (iMF). iMF triggered by brief, recurrent reductions in respiratory neural activity requires local retinoic acid (RA) synthesis, but receptor subtypes activated by RA are unknown. To test the hypothesis that retinoic acid receptor alpha (RARα) is necessary for iMF, RAR subtype-specific inhibitors were delivered intrathecally above the phrenic motor pool in urethane-anesthetized, ventilated rats before 5, ∼1 min central apneas (without hypoxia; separated by 5 min) while monitoring phrenic inspiratory output. Pretreatment with a spinal RARα inhibitor impaired the capacity for recurrent central apnea to trigger long-lasting increases in phrenic inspiratory output, but plasticity was expressed in rats pretreated with an RARß/γ inhibitor. Intrathecal RA application in the absence of reduced respiratory neural activity elicited an increase in phrenic inspiratory output, which was prevented by pretreatment with an RARα inhibitor. These data indicate that spinal RARα activation is necessary for iMF triggered by recurrent reductions in respiratory neural activity, and that RARα activation in/near the phrenic motor pool in the absence of respiratory neural activity deprivation is sufficient to elicit phrenic inspiratory motor facilitation. Understanding cellular cascades underlying plasticity induced by reductions in respiratory neural activity may define avenues for pharmacological intervention in disorders in which endogenous compensatory mechanisms that defend ongoing inspiratory motor output are impaired.NEW & NOTEWORTHY Local mechanisms near phrenic motor neurons respond to reductions in respiratory-related synaptic inputs by triggering a chemoreflex-independent, proportional enhancement in inspiratory output, a form of plasticity called inactivity-induced inspiratory motor facilitation (iMF). Here, we show that activation of spinal retinoic acid receptor alpha (RARα) is necessary to trigger phrenic iMF, and that spinal RARα activation in the absence of respiratory neural activity deprivation is sufficient to elicit phrenic inspiratory facilitation.

Spinal AMP kinase activity differentially regulates phrenic motor plasticity.

Acute intermittent hypoxia (AIH) elicits phrenic motor plasticity via multiple distinct cellular mechanisms. With moderate AIH, phrenic motor facilitation (pMF) requires Gq protein-coupled serotonin type 2 receptor activation, ERK MAP kinase activity, and new synthesis of brain-derived neurotrophic factor. In contrast, severe AIH elicits pMF by an adenosine-dependent mechanism that requires exchange protein activated by cAMP, Akt, and mammalian target of rapamycin (mTOR) activity, followed by new tyrosine receptor kinase B protein synthesis; this same pathway is also initiated by Gs protein-coupled serotonin 7 receptors (5-HT7). Because the metabolic sensor AMP-activated protein kinase (AMPK) inhibits mTOR-dependent protein synthesis, and mTOR signaling is necessary for 5-HT7 but not 5-HT2 receptor-induced pMF, we hypothesized that spinal AMPK activity differentially regulates pMF elicited by these distinct receptor subtypes. Serotonin type 2A receptor [5-HT2A; (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride] or 5-HT7 (AS-19) receptor agonists were administered intrathecally at C4 (3 injections, 5-min intervals) while recording integrated phrenic nerve activity in anesthetized, vagotomized, paralyzed, and ventilated rats. Consistent with our hypothesis, spinal AMPK activation with 2-deoxyglucose or metformin blocked 5-HT7, but not 5-HT2A receptor-induced pMF; in both cases, pMF inhibition was reversed by spinal administration of the AMPK inhibitor compound C. Thus, AMPK differentially regulates cellular mechanisms of serotonin-induced phrenic motor plasticity.NEW & NOTEWORTHY Spinal AMP-activated protein kinase (AMPK) overactivity, induced by local 2-deoxyglucose or metformin administration, constrains serotonin 7 (5-HT7) receptor-induced (but not serotonin type 2A receptor-induced) respiratory motor facilitation, indicating that metabolic challenges might regulate specific forms of respiratory motor plasticity. Pharmacological blockade of spinal AMPK activity restores 5-HT7 receptor-induced respiratory motor facilitation in the presence of either 2-deoxyglucose or metformin, showing that AMPK is an important regulator of 5-HT7 receptor-induced respiratory motor plasticity.

Competing mechanisms of plasticity impair compensatory responses to repetitive apnoea.

KEY POINTS: Intermittent reductions in respiratory neural activity, a characteristic of many ventilatory disorders, leads to inadequate ventilation and arterial hypoxia. Both intermittent reductions in respiratory neural activity and intermittent hypoxia trigger compensatory enhancements in inspiratory output when experienced separately, forms of plasticity called inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively. Reductions in respiratory neural activity that lead to moderate, but not mild, arterial hypoxia occludes plasticity expression, indicating that concurrent induction of iMF and LTF impairs plasticity through cross-talk inhibition of their respective signalling pathways. Moderate hypoxia undermines iMF by enhancing NR2B-containing NMDA receptor signalling, which can be rescued by exogenous retinoic acid, a molecule necessary for iMF. These data suggest that in ventilatory disorders characterized by reduced inspiratory motor output, such as sleep apnoea, endogenous mechanisms of compensatory plasticity may be impaired, and that exogenously activating respiratory plasticity may be a novel strategy to improve breathing. ABSTRACT: Many forms of sleep apnoea are characterized by recurrent reductions in respiratory neural activity, which leads to inadequate ventilation and arterial hypoxia. Both recurrent reductions in respiratory neural activity and hypoxia activate mechanisms of compensatory plasticity that augment inspiratory output and lower the threshold for apnoea, inactivity-induced inspiratory motor facilitation (iMF) and long-term facilitation (LTF), respectively. However, despite frequent concurrence of reduced respiratory neural activity and hypoxia, mechanisms that induce and regulate iMF and LTF have only been studied separately. Here, we demonstrate that recurrent reductions in respiratory neural activity ('neural apnoea') accompanied by cessations in ventilation that result in moderate (but not mild) hypoxaemia do not elicit increased inspiratory output, suggesting that concurrent induction of iMF and LTF occludes plasticity. A key role for NMDA receptor activation in impairing plasticity following concurrent neural apnoea and hypoxia is indicated since recurrent hypoxic neural apnoeas triggered increased phrenic inspiratory output in rats in which spinal NR2B-containing NMDA receptors were inhibited. Spinal application of retinoic acid, a key molecule necessary for iMF, bypasses NMDA receptor-mediated constraints, thereby rescuing plasticity following hypoxic neural apnoeas. These studies raise the intriguing possibility that endogenous mechanisms of compensatory plasticity may be impaired in some individuals with sleep apnoea, and that exogenously activating pathways giving rise to respiratory plasticity may be a novel pharmacological strategy to improve breathing.

Perioperative Neurological Complications Following Anterior Cervical Discectomy and Fusion: Clinical Impact on 317,789 Patients from the National Inpatient Sample.

BACKGROUND: Perioperative neurologic complication after an anterior cervical discectomy and fusion (ACDF) is uncommon but may have significant clinical consequences. OBJECTIVE: We aim to estimate the incidence of perioperative neurologic complications, identify their risk factors, and evaluate their impact on morbidity and mortality after ACDF. METHODS: ACDF cases (n = 317,789 patients) were extracted from the National Inpatient Sample between 1999 and 2011. Based on their Elixhauser-van Walraven score (VWR), patients were classified as low (VWR < 5), moderate (5-14), or high risk (>14) for surgery. The primary outcome was perioperative neurologic complications. Secondary outcomes included morbidity (hospital length of stay >14 days or discharge disposition to a location other than home) and in-hospital mortality. RESULTS: The rate of perioperative neurologic complications, morbidity, and mortality after ACDF was 0.4%, 8.4%, and 0.1%, respectively. Perioperative neurologic complications were highly associated with in-house morbidity (odds ratio [OR], 3.7 [3.1-4.4]) and mortality (OR, 8.0 [4.1-15.5]). The strongest predictors for perioperative neurologic complications were moderate- (OR, 3.1 [2.6-3.7]) and high-risk VWR (OR, 5.4 [3.3-8.9]), postoperative hematoma/seroma formation (OR, 5.4 [3.9-7.4]), and obesity (OR, 1.9 [1.6-2.3]). The rate of perioperative neurologic complications increased from 0.2% to 0.7% from 1999 to 2011, which was temporally associated with the rise in moderate- (P = 0.002) and high-risk patients (P = 0.001) undergoing ACDF. CONCLUSIONS: Perioperative neurologic complications are independent predictors of in-hospital morbidity and mortality after ACDF. Both morbidity and perioperative neurologic complications have increased between 1999 and 2011, which may be due, in part, to increasing numbers of moderate- and high-risk patients undergoing ACDF.

Protein kinase Cδ constrains the S-pathway to phrenic motor facilitation elicited by spinal 5-HT7 receptors or severe acute intermittent hypoxia.

KEY POINTS: Concurrent 5-HT2A (Q pathway) and 5-HT7 (S pathway) serotonin receptor activation cancels phrenic motor facilitation due to mutual cross-talk inhibition. Spinal protein kinase Cδ (PKCδ) or protein kinase A inhibition restores phrenic motor facilitation with concurrent Q and S pathway activation, demonstrating a key role for these kinases in cross-talk inhibition. Spinal PKCδ inhibition enhances adenosine-dependent severe acute intermittent hypoxia-induced phrenic long-term facilitation (S pathway), consistent with relief of cross-talk inhibition. ABSTRACT: Intermittent spinal serotonin receptor activation elicits long-lasting phrenic motor facilitation (pMF), a form of respiratory motor plasticity. When activated alone, spinal Gq protein-coupled serotonin 2A receptors (5-HT2A ) initiate pMF by a mechanism that requires ERK-MAP kinase signalling and new BDNF protein synthesis (Q pathway). Spinal Gs protein-coupled serotonin 7 (5-HT7 ) and adenosine 2A (A2A ) receptor activation also elicits pMF, but via distinct mechanisms (S pathway) that require Akt signalling and new TrkB protein synthesis. Although studies have shown inhibitory cross-talk interactions between these competing pathways, the underlying cellular mechanisms are unknown. We propose the following hypotheses: (1) concurrent 5-HT2A and 5-HT7 activation undermines pMF; (2) protein kinase A (PKA) and (3) NADPH oxidase mediate inhibitory interactions between Q (5-HT2A ) and S (5-HT7 ) pathways. Selective 5-HT2A (DOI hydrochloride) and 5HT7 (AS-19) agonists were administered intrathecally at C4 (three injections, 5-min intervals) in anaesthetized, vagotomized and ventilated male rats. With either spinal 5-HT2A or 5-HT7 activation alone, phrenic amplitude progressively increased (pMF). In contrast, concurrent 5-HT2A and 5-HT7 activation failed to elicit pMF. The 5-HT2A -induced Q pathway was restored by inhibiting PKA activity (Rp-8-Br-cAMPS). NADPH oxidase inhibition did not prevent cross-talk inhibition. Therefore, we investigated alternative mechanisms to explain Q to S pathway inhibition. Spinal protein kinase C (PKC) inhibition with Gö6983 or PKCδ peptide inhibitor restored the 5-HT7 -induced S pathway to pMF, revealing PKCδ as the relevant isoform. Spinal PKCδ inhibition enhanced the S pathway-dependent form of pMF elicited by severe acute intermittent hypoxia. We suggest that powerful constraints between 5-HT2A and 5-HT7 or A2A receptor-induced pMF are mediated by PKCδ and PKA, respectively.

Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia.

BACKGROUND: Cancer cachexia is an insidious process characterized by muscle atrophy with associated motor deficits, including diaphragm weakness and respiratory insufficiency. Although neuropathology contributes to muscle wasting and motor deficits in many clinical disorders, neural involvement in cachexia-linked respiratory insufficiency has not been explored. METHODS: We first used whole-body plethysmography to assess ventilatory responses to hypoxic and hypercapnic chemoreflex activation in mice inoculated with the C26 colon adenocarcinoma cell line. Mice were exposed to a sequence of inspired gas mixtures consisting of (i) air, (ii) hypoxia (11% O2 ) with normocapnia, (iii) hypercapnia (7% CO2 ) with normoxia, and (iv) combined hypercapnia with hypoxia (i.e. maximal chemoreflex response). We also tested the respiratory neural network directly by recording inspiratory burst output from ligated phrenic nerves, thereby bypassing influences from changes in diaphragm muscle strength, respiratory mechanics, or compensation through recruitment of accessory motor pools. RESULTS: Cachectic mice demonstrated a significant attenuation of the hypoxic tidal volume (0.26mL±0.01mL vs 0.30mL±0.01mL; p<0.05), breathing frequency (317±10bpm vs 344±6bpm; p<0.05) and phrenic nerve (29.5±2.6% vs 78.8±11.8%; p<0.05) responses. On the other hand, the much larger hypercapnic tidal volume (0.46±0.01mL vs 0.46±0.01mL; p>0.05), breathing frequency (392±5bpm vs 408±5bpm; p>0.05) and phrenic nerve (93.1±8.8% vs 111.1±13.2%; p>0.05) responses were not affected. Further, the concurrent hypercapnia/hypoxia tidal volume (0.45±0.01mL vs 0.45±0.01mL; p>0.05), breathing frequency (395±7bpm vs 400±3bpm; p>0.05), and phrenic nerve (106.8±7.1% vs 147.5±38.8%; p>0.05) responses were not different between C26 cachectic and control mice. CONCLUSIONS: Breathing deficits associated with cancer cachexia are specific to the hypoxic ventilatory response and, thus, reflect disruptions in the hypoxic chemoafferent neural network. Diagnostic techniques that detect decompensation and therapeutic approaches that support the failing hypoxic respiratory response may benefit patients at risk for cancer cachectic-associated respiratory failure.