Impact of Upper Limb Motor Recovery on Functional Independence After Traumatic Low Cervical Spinal Cord Injury.

Cervical spinal cord injury (SCI) causes devastating loss of upper limb function and independence. Restoration of upper limb function can have a profound impact on independence and quality of life. In low-cervical SCI (level C5-C8), upper limb function can be restored via reinnervation strategies such as nerve transfer surgery. The translation of recovered upper limb motor function into functional independence in activities of daily living (ADLs), however, remains unknown in low cervical SCI (i.e., tetraplegia). The objective of this study was to evaluate the association of patterns in upper limb motor recovery with functional independence in ADLs. This will then inform prioritization of reinnervation strategies focused to maximize function in patients with tetraplegia. This retrospective study performed a secondary analysis of patients with low cervical (C5-C8) enrolled in the SCI Model Systems (SCIMS) database. Baseline neurological examinations and their association with functional independence in major ADLs-i.e., eating, bladder management, and transfers (bed/wheelchair/chair)-were evaluated. Motor functional recovery was defined as achieving motor strength, in modified research council (MRC) grade, of ≥ 3 /5 at one year from ≤ 2/5 at baseline. The association of motor function recovery with functional independence at one-year follow-up was compared in patients with recovered elbow flexion (C5), wrist extension (C6), elbow extension (C7), and finger flexion (C8). A multi-variable logistic regression analysis, adjusting for known factors influencing recovery after SCI, was performed to evaluate the impact of motor function at one year on a composite outcome of functional independence in major ADLs. Composite outcome was defined as functional independence measure score of 6 or higher (complete independence) in at least two domains among eating, bladder management, and transfers. Between 1992 and 2016, 1090 patients with low cervical SCI and complete neurological/functional measures were included. At baseline, 67% of patients had complete SCI and 33% had incomplete SCI. The majority of patients were dependent in eating, bladder management, and transfers. At one-year follow-up, the largest proportion of patients who recovered motor function in finger flexion (C8) and elbow extension (C7) gained independence in eating, bladder management, and transfers. In multi-variable analysis, patients who had recovered finger flexion (C8) or elbow extension (C7) had higher odds of gaining independence in a composite of major ADLs (odds ratio [OR] = 3.13 and OR = 2.87, respectively, p < 0.001). Age 60 years (OR = 0.44, p = 0.01), and complete SCI (OR = 0.43, p = 0.002) were associated with reduced odds of gaining independence in ADLs. After cervical SCI, finger flexion (C8) and elbow extension (C7) recovery translate into greater independence in eating, bladder management, and transfers. These results can be used to design individualized reinnervation plans to reanimate upper limb function and maximize independence in patients with low cervical SCI.

Clinical applications of electrical stimulation for peripheral nerve injury: a systematic review.

Introduction: Peripheral nerve injuries are common neurologic injuries that are challenging to treat with current therapies. Electrical stimulation has been shown to accelerate reinnervation and enhance functional recovery. This study aims to review the literature on clinical application of electrical stimulation for peripheral nerve injury. Methods: PubMed and Embase were sourced from 1995 to August 2022. Selection was based on predetermined inclusion/exclusion criteria. Eight hundred and thirty-five articles were screened with seven being included in this review. Results: Two hundred and twenty-nine patients with peripheral nerve injuries were represented. Six of the studies were randomized controlled trials. A variety of nerve injuries were represented with all being in the upper extremity and supraclavicular region. Electrical stimulation protocols and evaluation varied. Electrodes were implanted in four studies with one also implanting the stimulator. Length of stimulation per session was either 20 mins or 1 h. Median stimulation frequency was 20 Hz. Stimulation intensity varied from 3 to 30V; pulse width ranged from 0.1 to 1.007 ms. Three protocols were conducted immediately after surgery. Patients were followed for an average of 13.5 months and were evaluated using electrophysiology and combinations of motor, sensory, and functional criteria. Discussion: Patients who received electrical stimulation consistently demonstrated better recovery compared to their respective controls. Electrical stimulation for peripheral nerve injury is a novel treatment that has not been well-studied in humans. Our review illustrates the potential benefit in implementing this approach into everyday practice. Future research should aim to optimize protocol for clinical use.

Recurrent Peroneal Intraneural Ganglion Cyst: Management and Review of the Literature.

Intraneural ganglion cysts have been reported to affect the common peroneal nerve. Peroneal intraneural ganglion cysts are managed through surgical intervention. Despite surgical intervention, intraneural ganglion cysts can recur. Common intraneural ganglion cyst recurrence patterns have been proposed based on the initial surgical management of the cyst. These patterns all emphasize the importance of treatment of the proximal tibiofibular (TF) joint to reduce the risk of cyst recurrence. Although joint resection is the favored intervention in the literature, joint arthrodesis is an option for certain patients. Here, we present a case of a peroneal intraneural ganglion cyst and its recurrence in a 36-year-old male who had previously undergone surgical removal of the cyst three months prior, as well as a review of the current literature that aims to add to our current understanding of intraneural cysts.

Association of upper-limb neurological recovery with functional outcomes in high cervical spinal cord injury.

OBJECTIVE: High cervical spinal cord injury (SCI) results in complete loss of upper-limb function, resulting in debilitating tetraplegia and permanent disability. Spontaneous motor recovery occurs to varying degrees in some patients, particularly in the 1st year postinjury. However, the impact of this upper-limb motor recovery on long-term functional outcomes remains unknown. The objective of this study was to characterize the impact of upper-limb motor recovery on the degree of long-term functional outcomes in order to inform priorities for research interventions that restore upper-limb function in patients with high cervical SCI. METHODS: A prospective cohort of high cervical SCI (C1-4) patients with American Spinal Injury Association Impairment Scale (AIS) grade A-D injury and enrolled in the Spinal Cord Injury Model Systems Database was included. Baseline neurological examinations and functional independence measures (FIMs) in feeding, bladder management, and transfers (bed/wheelchair/chair) were evaluated. Independence was defined as score ≥ 4 in each of the FIM domains at 1-year follow-up. At 1-year follow-up, functional independence was compared among patients who gained recovery (motor grade ≥ 3) in elbow flexors (C5), wrist extensors (C6), elbow extensors (C7), and finger flexors (C8). Multivariable logistic regression evaluated the impact of motor recovery on functional independence in feeding, bladder management, and transfers. RESULTS: Between 1992 and 2016, 405 high cervical SCI patients were included. At baseline, 97% of patients had impaired upper-limb function with total dependence in eating, bladder management, and transfers. At 1 year of follow-up, the largest proportion of patients who gained independence in eating, bladder management, and transfers had recovery in finger flexion (C8) and wrist extension (C6). Elbow flexion (C5) recovery had the lowest translation to functional independence. Patients who achieved elbow extension (C7) were able to transfer independently. On multivariable analysis, patients who gained elbow extension (C7) and finger flexion (C8) were 11 times more likely to gain functional independence (OR 11, 95% CI 2.8-47, p < 0.001) and patients who gained wrist extension (C6) were 7 times more likely to gain functional independence (OR 7.1, 95% CI 1.2-56, p = 0.04). Older age (≥ 60 years) and motor complete SCI (AIS grade A-B) reduced the likelihood of gaining independence. CONCLUSIONS: After high cervical SCI, patients who gained elbow extension (C7) and finger flexion (C8) had significantly greater independence in feeding, bladder management, and transfers than those with recovery in elbow flexion (C5) and wrist extension (C6). Recovery of elbow extension (C7) also increased the capability for independent transfers. This information can be used to set patient expectations and prioritize interventions that restore these upper-limb functions in patients with high cervical SCI.

Surgical Management of a Spinal Dural Arteriovenous Fistula.

Spinal dural arteriovenous fistulas (SDAVFs) may have subtle clinical presentations and are often misdiagnosed. Clinical status gradually deteriorates following symptom onset making prompt identification and management essential. Here we present a case of a 67-year-old patient with rapidly progressing motor and sensory deficits to eventual right hemiplegia. Following imaging and surgical intervention, a thoracic SDAVF was identified and resected. This case report highlights a unique SDAVF with a stroke-like presentation. For patients with such presentation, without a clear source of intracranial pathology, spinal causes such as SDAVF could be considered.

Spinal Epidermoid Tumor: A Case Report.

Spinal epidermoid tumors are rare tumors with typical symptoms including low back pain, radiculopathy, weakness, sensory disturbances, and bowel/bladder dysfunction. Here we present a rare case of a spinal epidermoid tumor in a 44-year-old female patient with a previous surgical history of epidural anesthesia with two cesarean sections. Our report aims to highlight the rare development of this type of tumor following epidural anesthesia, a routine part of labor management.

Systematic review of the therapeutic use of Schwann cells in the repair of peripheral nerve injuries: Advancements from animal studies to clinical trials.

Objective: To systematically evaluate the literature on the therapeutic use of Schwann cells (SC) in the repair of peripheral nerve injuries. Methods: The Cochrane Library and PubMed databases were searched using terms [("peripheral nerve injury" AND "Schwann cell" AND "regeneration") OR ("peripheral nerve injuries")]. Studies published from 2008 to 2022 were eligible for inclusion in the present study. Only studies presenting data from in-vivo investigations utilizing SCs in the repair of peripheral nerve injuries qualified for review. Studies attempting repair of a gap of ≥10 mm were included. Lastly, studies needed to have some measure of quantifiable regenerative outcome data such as histomorphometry, immunohistochemical, electrophysiology, or other functional outcomes. Results: A search of the PubMed and Cochrane databases revealed 328 studies. After screening using the abstracts and methods, 17 studies were found to meet our inclusion criteria. Good SC adherence and survival in conduit tubes across various studies was observed. Improvement in morphological and functional outcomes with the use of SCs in long gap peripheral nerve injuries was observed in nearly all studies. Conclusion: Based on contemporary literature, SCs have demonstrated clear potential in the repair of peripheral nerve injury in animal studies. It has yet to be determined which nerve conduit or graft will prove superior for delivery and retention of SCs for nerve regeneration. Recent developments in isolation and culturing techniques will enable further translational utilization of SCs in future clinical trials.

An updated management algorithm for incorporating minimally invasive techniques to treat thoracolumbar trauma.

OBJECTIVE: Minimally invasive surgery (MIS) techniques can effectively stabilize and decompress many thoracolumbar injuries with decreased morbidity and tissue destruction compared with open approaches. Nonetheless, there is limited direction regarding the breadth and limitations of MIS techniques for thoracolumbar injuries. Consequently, the objectives of this study were to 1) identify the range of current practice patterns for thoracolumbar trauma and 2) integrate expert opinion and literature review to develop an updated treatment algorithm. METHODS: A survey describing 10 clinical cases with a range of thoracolumbar injuries was sent to 12 surgeons with expertise in spine trauma. The survey results were summarized using descriptive statistics, along with the Fleiss kappa statistic of interrater agreement. To develop an updated treatment algorithm, the authors used a modified Delphi technique that incorporated a literature review, the survey results, and iterative feedback from a group of 14 spine trauma experts. The final algorithm represented the consensus opinion of that expert group. RESULTS: Eleven of 12 surgeons contacted completed the case survey, including 8 (73%) neurosurgeons and 3 (27%) orthopedic surgeons. For the 4 cases involving patients with neurological deficits, nearly all respondents recommended decompression and fusion, and the proportion recommending open surgery ranged from 55% to 100% by case. Recommendations for the remaining cases were heterogeneous. Among the neurologically intact patients, MIS techniques were typically recommended more often than open techniques. The overall interrater agreement in recommendations was 0.23, indicating fair agreement. Considering both literature review and expert opinion, the updated algorithm indicated that MIS techniques could be used to treat most thoracolumbar injuries. Among neurologically intact patients, percutaneous instrumentation without arthrodesis was recommended for those with AO Spine Thoracolumbar Classification System subtype A3/A4 (Thoracolumbar Injury Classification and Severity Score [TLICS] 4) injuries, but MIS posterior arthrodesis was recommended for most patients with AO Spine subtype B2/B3 (TLICS > 4) injuries. Depending on vertebral body integrity, anterolateral corpectomy or mini-open decompression could be used for patients with neurological deficits. CONCLUSIONS: Spine trauma experts endorsed a range of strategies for treating thoracolumbar injuries but felt that MIS techniques were an option for most patients. The updated treatment algorithm may provide a foundation for surgeons interested in safe approaches for using MIS techniques to treat thoracolumbar trauma.

Dose Adjustment Associated Complications of Bone Morphogenetic Protein: A Longitudinal Assessment.

OBJECTIVE: Bone morphogenetic protein (BMP) is a growth factor that aids in osteoinduction and promotes bone fusion. There is a lack of literature regarding recombinant human BMP-2 (rhBMP-2) dosage in different spine surgeries. This study aims to investigate the trends in rhBMP-2 dosage and the associated complications in spinal arthrodesis. METHODS: A retrospective study was conducted investigating spinal arthrodesis using rhBMP-2. Variables including age, procedure type, rhBMP-2 size, complications, and postoperative imaging were collected. Cases were grouped into the following surgical procedures: anterior lumbar interbody fusion/extreme lateral interbody fusion (ALIF/XLIF), posterior lumbar interbody fusion/transforaminal lumbar interbody fusion (PLIF/TLIF), posterolateral fusion (PLF), anterior cervical discectomy and fusion (ACDF), and posterior cervical fusion (PCF). RESULTS: A total of 1209 patients who received rhBMP-2 from 2006 to 2020 were studied. Of these, 230 were categorized as ALIF/XLIF, 336 as PLIF/TLIF, 243 as PLF, 203 as ACDF, and 197 as PCF. PCF (P < 0.001), PLIF/TLIF (P < 0.001), and PLF (P < 0.001) demonstrated a significant decrease in the rhBMP-2 dose used per level, with major transitions seen in 2018, 2011, and 2013, respectively. In our sample, 129 complications following spinal arthrodesis were noted. A significant relation between rhBMP-2 size and complication rates (χ2= 73.73, P = 0.0029) was noted. rhBMP-2 dosage per level was a predictor of complication following spinal arthrodesis (odds ratio = 1.302 [1.05-1.55], P < 0.001). CONCLUSIONS: BMP is an effective compound in fusing adjacent spine segments. However, it carries some regional complications. We demonstrate a decreasing trend in the dose/vertebral level. A decrease rhBMP-2 dose per level correlated with a decrease in complication rates.

The Interdisciplinary Stem Cell Institute's Use of Food and Drug Administration-Expanded Access Guidelines to Provide Experimental Cell Therapy to Patients With Rare Serious Diseases.

The U.S. Food and Drug Administration (FDA) provides guidance for expanded access to experimental therapies, which in turn plays an important role in the Twenty-first Century Cures Act mandate to advance cell-based therapy. In cases of incurable diseases where there is a lack of alternative treatment options, many patients seek access to cell-based therapies for the possibility of treatment responses demonstrated in clinical trials. Here, we describe the use of the FDA's expanded access to investigational new drug (IND) to address rare and emergency conditions that include stiff-person syndrome, spinal cord injury, traumatic brain stem injury, complex congenital heart disease, ischemic stroke, and peripheral nerve injury. We have administered both allogeneic bone marrow-derived mesenchymal stem cell (MSC) and autologous Schwann cell (SC) therapy to patients upon emergency request using Single Patient Expanded Access (SPEA) INDs approved by the FDA. In this report, we present our experience with 10 completed SPEA protocols.

A Retrospective Pilot Study for Preoperative Screening to Prevent Iatrogenic Cervical Spinal Cord Injury.

PURPOSE: The preoperative medical clearance process is well established to screen for medical comorbidities and therefore must be thorough. However, screening for potential cervical spine disease is often overlooked. In older surgical candidates, the presence of cervical spondylosis can increase risk of iatrogenic cervical spine injury during prolonged neck extension in non-spinal surgeries. We present a standard protocol for cervical spine clearance and a novel sustained neck extension maneuver through a retrospective case series. METHODS: Sixty-three consecutive cases that underwent preoperative cervical clearance between April 2012 and December 2019 were reviewed. Referral for clearance occurred through the department of anesthesiology after concerning radiographic or physical exam findings were noted. A standard preoperative screening protocol with a sustained one-minute neck extension maneuver was implemented. Recommendations were made for standard neck precautions with or without neuromonitoring or for cervical spine decompression surgery prior to the planned procedure. RESULTS: There were 25 patients with symptoms of myelopathy, 11 with radiculopathy and 13 with neck pain at baseline. Cervical spondylosis was observed in 51 patients, cervical canal stenosis in 29 and cervical myelomalacia in six. Fifty-seven patients underwent neck extension exam and 25 exhibited new or worsening symptoms. Myelopathic symptoms and radicular pain at baseline and positive Hoffman's and Spurling's sign, independently, were significantly associated with a positive neck extension exam (p<0.05). Fourteen patients were recommended for cervical decompression prior to planned procedure. CONCLUSIONS: Our preoperative cervical spine clearance protocol is safe and may aid in identifying patients susceptible to iatrogenic cervical spine injury.

Supraclavicular Resection of a Cervical Rib Causing Thoracic Outlet Syndrome: 2-Dimensional Operative Video.

Presence of a cervical rib results from overdevelopment of the seventh cervical vertebrae.1-3 The cervical rib along with scalene muscles can cause neurogenic thoracic outlet syndrome.4,5 Rib resection is typically done via anterior approach, using either supraclavicular or transaxillary route.6,7 We present an operative video detailing supraclavicular resection of a cervical rib causing neurogenic thoracic outlet syndrome with direct decompression of the lower trunk of the brachial plexus. The patient presented with severe symptoms including hand atrophy. We were able to directly visualize the rib and resect it, along with scalene musculature. We present 3-mo follow-up data noting clinical improvement in neuropathic symptoms.

The Pre-Registry Commercial Driver Medical Examination: Screening Sensitivity and Certification Lengths for Two Safety-Related Medical Conditions.

OBJECTIVE: Use independent diagnostic data to analyze the screening effectiveness of the pre-Registry commercial driver medical examination (CDME) for obstructive sleep apnea (OSA), and its sensitivity for hypertension; analyze certification lengths where relevant. METHODS: CDME screening results for 1668 drivers were compared to polysomnogram diagnostic test results, and CDME screening results were evaluated for 1155 drivers with at least one insurance claim with a hypertension diagnostic code. Any CDME documentation of the medical condition was considered as detection by screening. RESULTS: CDME sensitivity was 20.7% for moderate OSA (AHI ≥ 15). While sensitivity was 77.5% for hypertension, 93.3% of drivers with Stage 3 hypertension were certified, contrary to Federal Motor Carrier Safety Administration standards. CONCLUSIONS: The pre-Registry CDME was ineffective in screening commercial drivers for OSA. Screening was better for hypertension; incorrect certifications were given to many hypertensive drivers.

Employer-mandated obstructive sleep apnea treatment and healthcare cost savings among truckers.

OBJECTIVE: To evaluate the effect of an employer-mandated obstructive sleep apnea (OSA) diagnosis and treatment program on non-OSA-program trucker medical insurance claim costs. METHODS: Retrospective cohort analysis; cohorts constructed by matching (randomly, with replacement) Screen-positive Controls (drivers with insurance screened as likely to have OSA, but not yet diagnosed) with Diagnosed drivers (n = 1,516; cases = 1,224, OSA Negatives = 292), on two factors affecting exposure to medical claims: experience level at hire and weeks of job tenure at the Diagnosed driver's polysomnogram (PSG) date (the "matching date"). All cases received auto-adjusting positive airway pressure (APAP) treatment and were grouped by objective treatment adherence data: any "Positive Adherence" (n = 932) versus "No Adherence" (n = 292). Bootstrap resampling produced a difference-in-differences estimate of aggregate non-OSA-program medical insurance claim cost savings for 100 Diagnosed drivers as compared to 100 Screen-positive Controls before and after the PSG/matching date, over an 18-month period. A two-part multivariate statistical model was used to set exposures and demographics/anthropometrics equal across sub-groups, and to generate a difference-in-differences comparison across periods that identified the effect of OSA treatment on per-member per-month (PMPM) costs of an individual driver, separately from cost differences associated with adherence choice. RESULTS: Eighteen-month non-OSA-program medical claim costs savings from diagnosing (and treating as required) 100 Screen-positive Controls: $153,042 (95% CI: -$5,352, $330,525). Model-estimated effect of treatment on those adhering to APAP: -$441 PMPM (95% CI: -$861, -$21). CONCLUSIONS: Results suggest a carrier-based mandatory OSA program generates substantial savings in non-OSA-program medical insurance claim costs.

Synovial Sarcoma of the Nerve-Clinical and Pathological Features: Case Series and Systematic Review.

BACKGROUND: Synovial sarcoma of the nerve is a rare entity with several cases and case series reported in the literature. Despite an improved understanding of the biology, the clinical course is difficult to predict. OBJECTIVE: To compile a series of patients with synovial sarcoma of the peripheral nerve (SSPN) and assess clinical and pathological factors and their contribution to survival and recurrence. METHODS: Cases from 2 institutions collected in patients undergoing surgical intervention for SSPN. Systematic review including PubMed and Scopus databases were searched for related articles published from 1970 to December 2018. Eligibility criteria: (1) case reports or case series reporting on SSPN, (2) clinical course and/or pathological features of the tumor reported, and (3) articles published in English. RESULTS: From patients treated at our institutions (13) the average follow-up period was 3.2 yr. Tumor recurrence was seen in 4 cases and death in 3. Systematic review of the literature yielded 44 additional cases with an average follow-up period of 3.6 yr. From pooled data, there were 10 recurrences and 7 deaths (20% and 14%, respectively). Adjuvant treatment used in 62.5% of cases. Immunohistochemical markers used in diagnosis varied widely; the most common are the following: Epithelial membrane antigen (EMA), cytokeratin, vimentin, cluster of differentiation (CD34), and transducin-like enhancer of split 1 (TLE1). Statistical analysis illustrated tumor size and use of chemotherapy to be negative predictors of survival. No other factors, clinically or from pathologist review, were correlated with recurrence or survival. CONCLUSION: By combining cases from our institution with historical data and performing statistical analysis we show correlation between tumor size and death.

Nonadherence with Employer-Mandated Sleep Apnea Treatment and Increased Risk of Serious Truck Crashes.

STUDY OBJECTIVES: To evaluate the effect of an employer-mandated obstructive sleep apnea (OSA) program on the risk of serious preventable truck crashes. METHODS: Data are from the first large-scale, employer-mandated program to screen, diagnose, and monitor OSA treatment adherence in the US trucking industry. A retrospective analysis of cohorts was constructed: polysomnogram-diagnosed drivers (OSA positive n = 1,613, OSA negative n = 403) were matched to control drivers unlikely to have OSA (n = 2,016) on two factors affecting crash risk, experience-at-hire and length of job tenure; tenure was matched on the date of each diagnosed driver's polysomnogram. Auto-adjusting positive airway pressure (APAP) treatment was provided to all cases (i.e. OSA positive drivers); treatment adherence was objectively monitored. Cases were grouped by treatment adherence: "Full Adherence" (n = 682), "Partial Adherence" (n = 571), or "No Adherence" (n = 360). Preventable Department-of-Transportation-reportable crashes/100,000 miles were compared across study subgroups. Robustness was assessed. RESULTS: After the matching date, "No Adherence" cases had a preventable Department of Transportation-reportable crash rate that was fivefold greater (incidence rate ratio = 4.97, 95% confidence interval: 2.09, 10.63) than that of matched controls (0.070 versus 0.014 per 100,000 miles). The crash rate of "Full Adherence" cases was statistically similar to controls (incidence rate ratio = 1.02, 95% confidence interval: 0.48, 2.04; 0.014 per 100,000 miles). CONCLUSIONS: Nontreatment-adherent OSA-positive drivers had a fivefold greater risk of serious preventable crashes, but were discharged or quit rapidly, being retained only one-third as long as other subjects. Thus, the mandated program removed risky nontreatment-adherent drivers and retained adherent drivers at the study firm. Current regulations allow nonadherent OSA cases to drive at another firm by keeping their diagnosis private. COMMENTARY: A commentary on this article appears in this issue on page 961.

Finite sampling corrected 3D noise with confidence intervals.

When evaluated with a spatially uniform irradiance, an imaging sensor exhibits both spatial and temporal variations, which can be described as a three-dimensional (3D) random process considered as noise. In the 1990s, NVESD engineers developed an approximation to the 3D power spectral density for noise in imaging systems known as 3D noise. The goal was to decompose the 3D noise process into spatial and temporal components identify potential sources of origin. To characterize a sensor in terms of its 3D noise values, a finite number of samples in each of the three dimensions (two spatial, one temporal) were performed. In this correspondence, we developed the full sampling corrected 3D noise measurement and the corresponding confidence bounds. The accuracy of these methods was demonstrated through Monte Carlo simulations. Both the sampling correction as well as the confidence intervals can be applied a posteriori to the classic 3D noise calculation. The Matlab functions associated with this work can be found on the Mathworks file exchange ["Finite sampling corrected 3D noise with confidence intervals," https://www.mathworks.com/matlabcentral/fileexchange/49657-finite-sampling-corrected-3d-noise-with-confidence-intervals.].