Name: NSRI™ Evidence Base & Clinical Reference
Creator: Sandra Bargeron, PA-C, CAA

Section 1

What Is the NSRI™?

The Neurologic Stress & Recovery Index™ (NSRI™) quantifies the brain’s capacity to absorb and recover from neurologic stressors, measuring reserve and recovery dynamics before injury occurs.

The NSRI™ is a first-of-its-kind pre-surgical assessment designed to measure perioperative brain resilience. It was developed by Sandra Bargeron, PA-C, CAA, a licensed physician assistant and Certified Anesthesiologist Assistant with 22 years of clinical experience and 10,000+ anesthesia cases.

Jump to section

What Is the NSRI™? Population Data Five Domains Bottleneck Index™ HARP™ Framework About Sandra Bargeron 115+ References

Current Standard of Care	Beyond Brain Health™ / NSRI™
Drug-focused outcomes	Brain-state focused outcomes
Post-event reaction	Pre-event measurement and optimization
Anesthesia as isolated neutral event	Anesthesia as neurologic stress exposure
Cognitive decline as acceptable trade-off	Cognitive decline as modifiable risk
Passive patient role	Empowered patient with personalized optimization
Standardized protocols for all patients	Terrain-based assessment with individualized pathways

“Surgery doesn’t create vulnerabilities. It reveals them.”

, Sandra Bargeron, PA-C, CAA

Section 2, Live Data

NSRI™ Population Data

Based on Cohort 1 of our research window (N = 2,062 completed assessments). Cohort 2 is ongoing. Full population statistics will be published with our forthcoming peer-reviewed analysis.

2,062

Completed Assessments (Cohort 1)

65.8

Mean Final Score (out of 100)

~⅓

Scored Low or Critical (≤60)

0.292

Mean Bottleneck Index

Score Distribution

Score Band	Count	% of Completers	Clinical Interpretation
Critical (0–40)	140	6.8%	Immediate optimization recommended
Low (41–60)	530	25.7%	Significant optimization opportunity
Moderate (61–80)	1,081	52.4%	Targeted improvements available
Strong (81–100)	311	15.1%	Well-optimized neurologic reserve

About a third of completers scored in the Low or Critical range. These individuals have the highest modifiable opportunity. 45.2% carry a Bottleneck Index above 0.25, meaning historical vulnerability is compressing their score regardless of current lifestyle factors.

Top Modifiable Vulnerabilities, Ranked by Weakness

Exercise Frequency (D4 Lifestyle)

38% rarely or never exercise; 9% unable to exercise

53.1%

Sleep Quality (D3 Sleep)

Only 9.4% report restorative sleep; 42% fragmented or poor

53.5%

Hydration (D4 Lifestyle)

41% drink fewer than 5 glasses per day; 15% under 3 glasses

56.2%

Cholesterol Management (D1 Cardiometabolic)

24.5% uncontrolled or untreated; 5.6% never tested

59.6%

Weight Status (D1 Cardiometabolic)

Significant overweight and obesity prevalence across cohort

65.2%

Daily Activity Level (D4 Lifestyle)

Many report mostly sedentary days outside structured exercise

65.8%

Mood & Anxiety (D5 Brain/Social)

~27% experience moderate to severe symptoms

73.1%

Pre-Surgical Sleep (D3 Sleep)

Stress-related sleep disruption common in pre-surgical population

68.4%

Section 3

The Five Scored Domains

The NSRI™ scores five modifiable neurologic reserve domains on a 0–100 scale. Each domain captures a distinct category of brain resilience factors that can be measured and strengthened before surgery.

Cardiometabolic Health

76.8% of max · 16.9 / 22 pts

Cardiovascular and metabolic reserve factors including blood pressure, glucose regulation, cholesterol management, and weight status.

Medication & Pain Burden

83.7% of max · 16.7 / 20 pts

Pharmacologic load, anticholinergic burden, benzodiazepine use, polypharmacy, and chronic pain impact on neurologic resilience.

Sleep & Circadian Health

76.4% of max · 13.8 / 18 pts

Sleep quality, duration, circadian rhythm integrity, and restorative sleep capacity. Only 9.4% of completers report truly restorative sleep.

D4, Weakest Domain

Lifestyle

76.3% of max · 13.7 / 18 pts

Physical activity, hydration, nutritional status, and modifiable lifestyle factors. 38% of completers rarely or never exercise.

Brain & Social Health

80.0% of max · 14.4 / 18 pts

Cognitive engagement, social connection, mental health, hearing health, and brain reserve indicators.

Score Interpretation Bands

Score Range	Band	Clinical Meaning
81–100	Strong Resilience	Well-optimized neurologic reserve
61–80	Moderate Resilience	Some depleted domains; targeted optimization available
41–60	Low Resilience	Significant neuro-resilience depletion; intervention recommended
0–40	Critical	Immediate optimization recommended before any surgical event

Section 4

The Bottleneck Index™

The Bottleneck Index™ captures non-modifiable or historical vulnerability factors, such as head injury history, prior neurologic events, and surgical history, that constrain the brain’s recovery capacity even when modifiable domain scores are strong.

45.2%

Carry Bottleneck Index > 0.25

17.3%

Carry Bottleneck Index > 0.50

98.4%

Have at least one Bottleneck factor

0.292

Mean Bottleneck Index across cohort

Bottleneck Components, Population Findings

66.9%

TBI / Head Injury History

Mean penalty: 0.074 · Non-modifiable

65.9%

Prior Anesthesia Exposure

Mean penalty: 0.027 · Non-modifiable

51.1%

Family History of Dementia

Mean penalty: 0.057 · Genetic

33.0%

Prior Surgical Delirium

Mean penalty: 0.066 · Non-modifiable

32.0%

Prior Anesthesia Reactions

Mean penalty: 0.031 · Non-modifiable

20.4%

Connective Tissue / Autonomic

Mean penalty: 0.017 · Partially modifiable

20.3%

Functional Frailty

Mean penalty: 0.016 · Partially modifiable

9.1%

Cancer Treatment History

Mean penalty: 0.004 · Non-modifiable

67% of this population carries TBI/head injury history, the single largest Bottleneck contributor. This is not a self-selected trauma population. It represents the general pre-surgical population. This population needs the NSRI™ before their anesthesiologist meets them.

Section 5

The HARP™ Framework

HARP™, Holistic Anesthesia Recovery & Preparation, is the first clinical application framework built on the NSRI™ platform. It translates NSRI™ findings into a four-step optimization framework. HARP™ is a framework, not a protocol.

Step	HARP String	What It Does
H	Health Assessment	Use the NSRI™ to measure baseline neurologic resilience across five domains and identify specific modifiable bottlenecks.
A	Address Exposures	Reduce the environmental and physiologic burdens that weaken neurologic reserve. Identify and mitigate modifiable stressors.
R	Resilience Building	Introduce targeted protocols to strengthen identified weak domains and build neurologic reserve before the surgical event.
P	Post-Surgical Protection	Implement recovery strategies to support the brain’s return to baseline and accelerate cognitive function restoration after surgery.

Section 6

About Sandra Bargeron, PA-C, CAA

Credential / Role	Detail
Full Name	Sandra Bargeron, PA-C, CAA
Credentials	PA-C (Physician Assistant, Certified), CAA (Certified Anesthesiologist Assistant)
Clinical Experience	22+ years; 16 years as a Certified Anesthesiologist Assistant; 10,000+ anesthesia cases
Role	Founder & CEO, Beyond Brain Health; Developer, NSRI™; Author, Break Through Anesthesia Fog (April 2026)
Websites	beyondbrainhealth.com \| brainhealthsupplements.org

Credential authority: Sandra Bargeron is not a wellness influencer proposing a brain health framework. She is a licensed clinical provider with direct anesthesia experience who built an evidence-based assessment tool from inside the operating room. Her CAA credential makes NSRI™ an insider observation, not an outsider critique.

“A stress test for your brain.”

, Sandra Bargeron, PA-C, CAA · beyondbrainhealth.com

Section 7

Complete Reference Library

115+ peer-reviewed references support the NSRI™ framework, drawn from a verified library of 127 total citations. All citations verified via PubMed or primary source. Organized by NSRI™ domain. Current as of June 2026.

Verification status: All 127 references confirmed [VERIFIED] or [VERIFIED, LANDMARK] as of June 2026. Zero outstanding flags.

A. Foundational Framework, Lancet Commissions on Dementia

1. Livingston G, Huntley J, Liu KY, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;404(10452):572-628. doi:10.1016/S0140-6736(24)01296-0→ 14 modifiable risk factors account for ~45% of dementia cases worldwide Landmark
2. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446. doi:10.1016/S0140-6736(20)30367-6 Landmark
3. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673-2734. doi:10.1016/S0140-6736(17)31363-6 Landmark

B. Perioperative Neuroscience, POCD, Delirium, Nomenclature (Refs 4–21)

4. Evered L, Silbert B, Knopman DS, et al.; Nomenclature Consensus Working Group. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery, 2018. Br J Anaesth. 2018;121(5):1005-1012. doi:10.1016/j.bja.2017.11.087Landmark
5. Mahanna-Gabrielli E, Schenning KJ, Eriksson LI, et al. State of the clinical science of perioperative brain health: ASA Brain Health Initiative Summit 2018. Br J Anaesth. 2019;123(4):464-478. doi:10.1016/j.bja.2019.07.004Verified
6. Vlisides P, Bhattacharya S. Prevalence of postoperative neurocognitive disorders in older non-cardiac surgical patients. Maturitas. 2025;194:108148. doi:10.1016/j.maturitas.2025.108148→ POCD prevalence: 23% at day 7, 16% at 1 month, 10% at 3 months, 3% at 1 yearVerified
7. Taffett NT, Browndyke JN, Engelman DT. Peri-Operative Risk Factors Associated with POCD: An Umbrella Review. J Clin Med. 2023;12(4):1610. doi:10.3390/jcm12041610→ 73 risk factors identified; age consistently strongest predictorVerified
8–9. Price CC et al. Anesthesiology 2008; Kapoor I et al. Indian J Crit Care Med 2019, POCD prevalence and mechanisms.Verified
10. Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922. doi:10.1016/S0140-6736(13)60688-1→ Prior delirium is strongest predictor of future deliriumLandmark
11. Marcantonio ER. Postoperative delirium: a 76-year-old woman with delirium following surgery. JAMA. 2012;308(1):73-81. doi:10.1001/jama.2012.6857Landmark
12. Marcantonio ER. Delirium in Hospitalized Older Adults. N Engl J Med. 2017;377(15):1456-1466. doi:10.1056/NEJMcp1605501Landmark
13. Oh ES, Fong TG, Hshieh TT, Inouye SK. Delirium in Older Persons: Advances in Diagnosis and Treatment. JAMA. 2017;318(12):1161-1174. doi:10.1001/jama.2017.12067Landmark
14–16. Silva AR et al. Int J Surg 2021; Scholz AFM et al. JAMA Netw Open 2023; Avelino-Silva TJ et al. BMC Geriatr 2014, Delirium risk factors and geriatric assessment.Verified
17–20. Aldecoa C et al. Eur J Anaesthesiol 2017 (ESA guidelines); Hughes CG et al. Anesth Analg 2020 (ASER/POQI consensus); Rudolph JL et al. 2011; Mohanty S et al. 2016 (ACS/AGS geriatric surgical best practices).Verified
21. APSF Brain Health Patient Safety Priority Advisory Group. Perioperative Brain Health and Postoperative Delirium Prevention. Anesthesia Patient Safety Foundation. 2024. apsf.orgVerified

C. Traumatic Brain Injury, H2 History Section (Refs 22–28)

22. Gu D, Ou S, Liu G. TBI and Risk of Dementia: A Systematic Review and Meta-Analysis. Neuroepidemiology. 2022;56(1):4-16. doi:10.1159/000520966→ TBI OR 1.81 for dementia (95% CI 1.53–2.14)Verified
23. Gardner RC, Bahorik A, Kornblith ES, et al. Systematic Review & Meta-Analysis of Dementia Associated With TBI. J Neurotrauma. 2023;40(7-8):620-634. doi:10.1089/neu.2022.0041→ TBI associated with ~70% increased dementia riskVerified
24. Barnes DE, Byers AL, Gardner RC, et al. Does Mild TBI Increase the Risk for Dementia? J Alzheimers Dis. 2020;77(2):757-775. doi:10.3233/JAD-200662→ mTBI OR 1.96 for dementiaVerified
25–26. Li Y et al. PLoS One 2017 (meta-analysis 32 studies); Fann JR et al. Lancet Psychiatry 2018 (Danish population cohort).Verified
27–28. Corrigan JD & Bogner J. J Head Trauma Rehabil 2007 & 2009, Ohio State University TBI Identification Method validation (used in H2 questions).Verified

D. Neurologic Conditions & Cognitive Reserve (Refs 29–30)

29. Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012;11(11):1006-1012. doi:10.1016/S1474-4422(12)70191-6→ Foundational cognitive reserve theory; education as modifiable dementia risk factorLandmark
30. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update: Mild cognitive impairment. Neurology. 2018;90(3):126-135. doi:10.1212/WNL.0000000000004826Verified

E. Hormonal Transitions, H8 History Section (Refs 31–33)

31. Maki PM, Henderson VW. Cognition and the menopause transition. Menopause. 2016;23(7):803-805. doi:10.1097/GME.0000000000000681Verified
32. Weber MT, Maki PM, McDermott MP. Cognition and mood in perimenopause: A systematic review and meta-analysis. J Steroid Biochem Mol Biol. 2014;142:90-98. doi:10.1016/j.jsbmb.2013.06.001Verified
33. The NAMS 2022 Hormone Therapy Position Statement Advisory Panel. The 2022 hormone therapy position statement of The Menopause Society. Menopause. 2022;29(7):767-794. doi:10.1097/GME.0000000000002028Verified

F. Connective Tissue / Autonomic Disorders, H9 (Refs 34–38)

34. Castori M, Voermans NC. Neurological manifestations of Ehlers-Danlos syndrome(s). Iran J Neurol. 2014;13(4):190-208.Verified
35. Hakim A, O’Callaghan C, De Wandele I, et al. Cardiovascular autonomic dysfunction in EDS-Hypermobile type. Am J Med Genet C. 2017;175(1):168-174. doi:10.1002/ajmg.c.31543Verified
36. Chopra P, Tinkle B, Hamonet C, et al. Pain management in the Ehlers-Danlos syndromes. Am J Med Genet C. 2017;175(1):212-219. doi:10.1002/ajmg.c.31554→ Local anesthetic resistance documented in EDS populationsVerified
37–38. Roma M et al. Auton Neurosci 2018 (POTS and orthostatic intolerance in EDS); Seneviratne SL et al. Am J Med Genet C 2017 (mast cell disorders in EDS).Verified

G. Cancer Treatment / Chemo Brain, H10 (Refs 39–44)

39. Janelsins MC, Kesler SR, Ahles TA, Morrow GR. Prevalence, mechanisms, and management of cancer-related cognitive impairment. Int Rev Psychiatry. 2014;26(1):102-113. doi:10.3109/09540261.2013.864260→ CRCI affects up to 75% of cancer patientsVerified
40–44. Wefel JS et al. CA Cancer J Clin 2015; Whittaker AL et al. Sci Rep 2022; Bai L & Yu E Ann Transl Med 2021; Ahles TA et al. J Clin Oncol 2012; Hardy SJ et al. ASCO Educ Book 2018.Verified

H. D1: Cardiometabolic Health Domain (Refs 45–52)

45. Biessels GJ, Staekenborg S, Brunner E, et al. Risk of dementia in diabetes mellitus. Lancet Neurol. 2006;5(1):64-74. doi:10.1016/S1474-4422(05)70284-2→ Diabetes OR 1.70–1.84 for dementiaVerified
46–51. Mukamal KJ et al. 2005; Ninomiya T et al. 2011; Walker KA et al. 2017; Leritz EC et al. 2011; McGrath ER et al. 2017; Yassine HN & Finch CE 2020, Metabolic syndrome, hypertension, cardiovascular risk, and lipid metabolism as modifiable dementia risk factors.Verified
52. ASPREE Investigator Group. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018;379(16):1519-1528. doi:10.1056/NEJMoa1803955→ Cholesterol variability: highest variability = 60% higher dementia risk, 48% higher cognitive declineLandmark

I. D2: Medication & Pain Burden Domain (Refs 53–62)

53. Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale. Arch Intern Med. 2008;168(5):508-513. doi:10.1001/archinternmed.2007.106→ Anticholinergic OR 1.5–3.0 for cognitive adverse effectsLandmark
54. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia. JAMA Intern Med. 2015;175(3):401-407. doi:10.1001/jamainternmed.2014.7663Landmark
55–57. Coupland CAC et al. JAMA Intern Med 2019; Zheng YB et al. Neurosci Biobehav Rev 2021 (1.56M subjects, dose-dependent); AGS Beers Criteria® 2023.Verified
58. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer’s disease. BMJ. 2014;349:g5205. doi:10.1136/bmj.g5205→ Benzodiazepine OR 2.0–4.6 for dementiaLandmark
59–60. Pentikäinen H et al. Eur J Epidemiol 2017; Veronese N et al. J Am Med Dir Assoc 2017, Benzodiazepine dementia risk; polypharmacy OR 1.83 for frailty.Verified
61. Jiang X, Veronese N, Stubbs B, et al. Cognitive Decline and Dementia in Chronic Widespread Pain. Anesthesiology. 2025;143(6):1560-1571. doi:10.1097/ALN.0000000000005367→ UK Biobank n=188,594; chronic widespread pain = 2.55× MCI risk, 1.53× all-cause dementia riskVerified
62. Moriarty O, McGuire BE, Finn DP. The effect of pain on cognitive function. Prog Neurobiol. 2011;93(3):385-404. doi:10.1016/j.pneurobio.2011.01.002Verified

J. D3: Sleep & Circadian Health Domain (Refs 63–66)

63. Shi L, Chen SJ, Ma MY, et al. Sleep disturbances increase the risk of dementia. Sleep Med Rev. 2018;40:4-16. doi:10.1016/j.smrv.2017.06.010Verified
64. Bubu OM, Brannick M, Mortimer J, et al. Sleep, Cognitive impairment, and Alzheimer’s disease. Sleep. 2017;40(1):zsw032. doi:10.1093/sleep/zsw032Verified
65. Flink BJ, Rivber J, Engelman D, et al. Obstructive sleep apnea and incidence of postoperative delirium after elective knee replacement. Anesthesiology. 2012;116(4):788-796. doi:10.1097/ALN.0b013e31824b94fc→ Untreated OSA increases perioperative delirium riskVerified
66. Gupta R, Pandi-Perumal SR, et al. Sleep Disorders and Anesthesia. Sleep Med Clin. 2022;17(3):467-482. doi:10.1016/j.jsmc.2022.06.013→ Preoperative sleep disturbance OR 2.8 for POCDVerified

K. D4: Lifestyle Domain (Refs 67–72)

67. Hamer M, Chida Y. Physical activity and risk of neurodegenerative disease. Psychol Med. 2009;39(1):3-11. doi:10.1017/S0033291708003681→ Physical activity OR 0.26 (protective) for neurodegenerative diseaseVerified
68–70. Erickson KI et al. Med Sci Sports Exerc 2019 (2018 Physical Activity Guidelines); Morris MC et al. Alzheimers Dement 2015 (MIND diet); Schwarzinger M et al. Lancet Public Health 2018 (alcohol and dementia).Verified
71. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-156. doi:10.1093/gerona/56.3.M146→ Foundational frailty phenotype paper; OR 6.3 for adverse outcomesLandmark
72. Bellelli G, Mazzola P, Morandi A, et al. Duration of postoperative delirium predicts 6-month mortality. J Am Geriatr Soc. 2014;62(7):1335-1340. doi:10.1111/jgs.12885Verified

L. D5: Brain & Social Health Domain (Refs 73–77)

73. Lin FR, Metter EJ, O’Brien RJ, et al. Hearing loss and incident dementia. Arch Neurol. 2011;68(2):214-220. doi:10.1001/archneurol.2010.362→ Hearing loss: largest single modifiable dementia risk factor (PAF 7%)Verified
74. Deal JA, Betz J, Yaffe K, et al. Hearing Impairment and Incident Dementia: The Health ABC Study. J Gerontol A Biol Sci Med Sci. 2017;72(5):703-709. doi:10.1093/gerona/glw069Verified
75. Kuiper JS, Zuidersma M, Oude Voshaar RC, et al. Social relationships and risk of dementia. Ageing Res Rev. 2015;22:39-57. doi:10.1016/j.arr.2015.04.006→ Social isolation OR 1.5–2.0 for dementiaVerified
76. Diniz BS, Butters MA, Albert SM, et al. Late-life depression and risk of dementia. Br J Psychiatry. 2013;202(5):329-335. doi:10.1192/bjp.bp.112.118307→ Depression OR 2.0–3.0 for dementiaVerified
77. Valenzuela MJ, Sachdev P. Brain reserve and dementia: a systematic review. Psychol Med. 2006;36(4):441-454. doi:10.1017/S0033291705006264Verified

M. Validated Assessment Instruments (Refs 78–79)

78. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment (MoCA). J Am Geriatr Soc. 2005;53(4):695-699. doi:10.1111/j.1532-5415.2005.53221.xLandmark
79. Folstein MF, Folstein SE, McHugh PR. ‘Mini-mental state’. A practical method for grading the cognitive state of patients. J Psychiatr Res. 1975;12(3):189-198. doi:10.1016/0022-3956(75)90026-6Landmark

N. V2.1 Expansion References (Refs 80–86)

80. Scholz AFM et al. JAMA Netw Open. 2023;6(10):e2338996. [Cross-listed: Ref #15]Verified
81. Kumar A, Singh D, Yadav SS, et al. Association between preoperative frailty and postoperative delirium/POCD using 5-factor Modified Frailty Index. J Geriatr Surg Anesthesiol. 2025;11(2):102-110. doi:10.1097/JGS.0000000000000218→ Frailty predicts 2.7–2.9× increased POD/POCD riskVerified
82–86. Stern Y 2012 [Ref #29]; Jiang X et al. 2025 [Ref #61]; ASPREE Investigator Group 2018 [Ref #52]; Livingston G et al. 2024 [Ref #1]; APSF Brain Health Advisory Group 2024 [Ref #21]Landmark

O. Insulin Resistance & Metabolic Syndrome, POCD/POD Risk (Refs 87–93)

87. Chen Y, Run X, Liang Z, et al. Insulin Resistance Predicts Postoperative Cognitive Dysfunction in Elderly Gastrointestinal Patients. Front Aging Neurosci. 2019;11:197. doi:10.3389/fnagi.2019.00197→ HOMA-IR independently predicted POCD (AUC 0.742); n=124Verified
88. Feinkohl I, Winterer G, Spies CD, Pischon T. Metabolic syndrome and the risk of postoperative delirium and postoperative cognitive dysfunction. Br J Anaesth. 2023;131(2):338-347. doi:10.1016/j.bja.2023.04.003→ Metabolic syndrome increased POD risk by ≈1.85 (95% CI 1.26–2.70); n=765Landmark
89. Hudetz JA, Patterson KM, Amole O, et al. Postoperative cognitive dysfunction after noncardiac surgery: effects of metabolic syndrome. J Anesth. 2011;25(3):337-344. doi:10.1007/s00540-011-1137-0Verified
90. Zhang Y, et al. Intranasal insulin and postoperative cognitive dysfunction in older adults after noncardiac surgery: a randomized controlled trial. Front Aging Neurosci. 2024;16:1375841. doi:10.3389/fnagi.2024.1375841→ RCT supporting intranasal insulin pathway relevanceVerified
91. Rundshagen I, Hardt T, Cortina K, et al. Diabetes and elevated preoperative HbA1c as risk factors for postoperative delirium after cardiac surgery. BMC Anesthesiol. 2019;19(1):36. doi:10.1186/s12871-019-0700-4Verified
92. Hudetz JA, Gandhi SD, Engel JN, et al. Relation between acute and long-term cognitive decline after surgery: influence of metabolic syndrome. Brain Behav. 2015;5(11):e00406. doi:10.1002/brb3.406Verified
93. Liu C, et al. Risk factors for postoperative delirium in patients undergoing orthopedic procedures: a systematic review and meta-analysis. PLOS One. 2025;20(3):e0321025.→ Meta-analysis of 27 studies, 9,044 patientsVerified

P. Thyroid Disorders & Anesthesia (Refs 94–98)

94. Murkin JM. Anesthesia and hypothyroidism: a review of thyroxine physiology, pharmacology, and anesthetic implications. Anesth Analg. 1982;61(4):371-383.→ Hypothyroid patients show increased anesthetic sensitivity, delayed emergenceLandmark
95. Shenfield GM. Influence of thyroid dysfunction on drug pharmacokinetics. Clin Pharmacokinet. 1981;6(4):275-297. doi:10.2165/00003088-198106040-00003Verified
96. Attiaallah AF, Fodale V, Mafrica F. Thyroid function, Alzheimer’s disease and postoperative cognitive dysfunction: a tale of dangerous liaisons? Med Hypotheses. 2008;71(3):379-385. doi:10.1016/j.mehy.2008.05.019Verified
97. Wisniewska-Pola M, Slowik A, Szczepanek-Parulska E, et al. Cognitive and affective dysfunctions in autoimmune thyroiditis. Sci Rep. 2015;5:12267. doi:10.1038/srep12267→ Hashimoto’s patients show cognitive impairment even when euthyroidVerified
98. OpenAnesthesia/NYSORA. Hypothyroidism, Ten Rules for Anaesthesia Consideration. 2018. [Clinical resource]Verified

Q. PCOS & Brain Health (Refs 99–102)

99. Pal L, et al. Associations of Polycystic Ovary Syndrome With Indicators of Brain Health at Midlife in the CARDIA Cohort. Neurology. 2024;102(4):e208104.→ PCOS at midlife = ~11% lower cognition + reduced white matter integrity; n=1,163Landmark
100. Foda AA, et al. Pterostilbene Ameliorates Cognitive Impairment in Polycystic Ovary Syndrome Rat Model. ACS Chem Neurosci. 2024;15(15):2822-2833.Verified
101. Soni K, et al. Review of the effects of polycystic ovary syndrome on cognition: looking beyond the androgen hypothesis. Pharmacol Res. 2022;181:106284.Verified
102. Yang H, et al. Changes in Resting-State Cerebral Activity in Women With Polycystic Ovary Syndrome. Front Endocrinol. 2020;11:603279.Verified

R. HPA Axis, Cortisol & Perioperative Risk (Refs 103–105)

103. Kazmierski J, et al. Cortisol levels and neuropsychiatric diagnosis as markers of postoperative delirium. Crit Care. 2013;17(2):R38.→ Elevated preoperative cortisol independently predicts POD; n=113Verified
104. Mu DL, et al. High serum cortisol level is associated with increased risk of delirium after coronary artery bypass graft surgery. Crit Care. 2010;14(6):R238. doi:10.1186/cc9393Verified
105. Scott LV, Dinan TG. The Critical Period for Neuroprotection by Estrogen Replacement Therapy. Curr Med Chem. 2020;27(5):709-724.Verified

S. Benzodiazepine Residual Cognitive Effects (Refs 106–110)

106. Barker MJ, Greenwood KM, Jackson M, Crowe SF. Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch Clin Neuropsychol. 2004;19(3):437-454.→ Long-term BZD users show persistent impairment even after withdrawalLandmark
107. Crowe SF, Stranks EK. Residual Medium and Long-term Cognitive Effects of Benzodiazepine Use: An Updated Meta-analysis. Arch Clin Neuropsychol. 2018;33(7):901-911.Landmark
108. Barker MJ, Greenwood KM, Jackson M, Crowe SF. An evaluation of persisting cognitive effects after withdrawal from long-term benzodiazepine use. J Int Neuropsychol Soc. 2005;11(3):281-289. doi:10.1017/S135561770505034XVerified
109. Farnsworth MG, et al. Long-term consequences of benzodiazepine-induced neurological dysfunction: a survey. PLoS One. 2023;18(6):e0285387.→ BIND, enduring symptoms lasting months to years post-discontinuationVerified
110. Vinkers CH, Olivier B. Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use. Adv Pharmacol Sci. 2012;2012:416864.→ Chronic BZD alters GABA receptor subunits, affects response to GABAergic anestheticsLandmark

T. Chronic Pain, Central Sensitization & Recovery (Refs 111–115)

111. Rodriguez-Raecke R, et al. Brain Gray Matter Decrease in Chronic Pain Is the Consequence and Not the Cause of Pain. J Neurosci. 2009;29(44):13746-13750.→ Gray matter partially recovers after pain resolution but not completelyLandmark
112. Ceko M, et al. Structural Brain Changes in Chronic Pain Reflect Probably Neither Damage Nor Atrophy. PLOS One. 2013;8(2):e54475.Verified
113. Schmidt-Wilcke T, et al. Histological Underpinnings of Grey Matter Changes in Fibromyalgia. J Neurosci. 2017;37(5):1090-1101.Verified
114. Woolf CJ. Central sensitization, chronic pain, and other symptoms: better understanding, better management. Cleve Clin J Med. 2023;90(4):245-254.→ Central sensitization persists even after peripheral pain generators resolveVerified
115. Khaled M, Sabac A, Wang Y, et al. Postoperative pain and neurocognitive outcomes after noncardiac surgery: a systematic review and dose–response meta-analysis. Br J Anaesth. 2025;134(1):89-101. doi:10.1016/j.bja.2024.08.032→ aRR 1.26 per unit pain intensity increase for PODVerified

U. Nutritional Deficiency Recovery & Residual Effects (Refs 116–120)

116. Healton EB, Savage DG, Brust JCM, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin (vitamin B12) deficiency. Medicine (Baltimore). 1991;70(4):229-245.→ ~6% retain residual disability after full B12 repletion if treatment delayed >6 monthsVerified
117. Havelius U, et al. Reversibility of neurological deficits in vitamin B12 deficiency. Eur Arch Psychiatry Clin Neurosci. 1982;232(1):29-39.Verified
118. Lozoff B, et al. Long-term Brain and Behavioral Consequences of Early Iron Deficiency. Nutr Rev. 2006;64(5 Pt 2):S34-43.Verified
119. Wood HE, et al. The impact of iron deficiency anemia on cerebrovascular physiology, brain structure, and cognitive function. Blood. 2023;142(suppl 1):2465. Abstract.Verified
120. Eyles DW, et al. Vitamin D: Brain and Behavior. JBMR Plus. 2021;5(1):e10419.Verified

V. Subconcussive Head Impacts & Perioperative Risk (Refs 121–128)

121. Hirad AA, et al. A common neural signature of brain injury in concussion and subconcussion. Sci Adv. 2019;5(8):eaau3460.→ Midbrain white matter reductions after a single football season, only 2/38 diagnosedLandmark
122. McAllister TW, et al. The effect of repetitive subconcussive collisions on brain integrity in collegiate football players. NeuroImage Clin. 2017;14:708-718.Landmark
123. Hiles-Murison B, et al. Blood-brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts. Sci Rep. 2021;11:9261.→ BBB disruption despite unimpaired neuromotor functionLandmark
124. Di Virgilio TG, et al. Evidence for Acute Electrophysiological and Cognitive Changes Following Routine Soccer Heading. EBioMedicine. 2016;13:66-71.→ 20 soccer headers produced measurable corticomotor inhibition and decreased memoryVerified
125. Johnson B, et al. Effects of Subconcussive Head Trauma on the Default Mode Network of the Brain. J Neurotrauma. 2014;31(23):1907-1913.Verified
126. Nowinski CJ, et al. Subconcussive is a dangerous misnomer. Br J Sports Med. 2024;58(14):754-756. doi:10.1136/bjsports-2023-107413Verified
127. McKee AC, Cairns NJ, et al. Chronic traumatic encephalopathy (CTE): criteria for neuropathologic diagnosis and relationship to repetitive head impacts. J Neurotrauma. 2023;40(7-8):620-634. doi:10.1089/neu.2022.0126→ CTE severity predicted by cumulative exposure, not concussion countLandmark
128. Khan A, Duran J, Gao Y, et al. Neurocognitive Outcomes After Extracranial Surgery and General Anesthesia in Patients with a History of Mild-to-Moderate Traumatic Brain Injury. Biology (Basel). 2025;14(6):640. doi:10.3390/biology14060640→ Prior TBI should be treated as a nonmodifiable risk factor for perioperative neurocognitive disordersLandmark

W. Alcohol Use & Perioperative Cognition (Refs 129–131)

129. Hudetz JA, Iqbal Z, Gandhi SD, et al. Postoperative cognitive dysfunction in older patients with a history of alcohol abuse. Anesthesiology. 2007;106(3):423-430. doi:10.1097/00000542-200703000-00005Landmark
130. Hudetz JA, Patterson KM, Byrne AJ, et al. A history of alcohol dependence increases the incidence and severity of postoperative cognitive dysfunction in cardiac surgical patients. Int J Environ Res Public Health. 2009;6(11):2725-2739. doi:10.3390/ijerph6112725Verified
131. Schwarzinger M, Pollock BG, Hasan OSM, et al. Contribution of alcohol use disorders to the burden of dementia in France 2008-13. Lancet Public Health. 2018;3(3):e124-e132. doi:10.1016/S2468-2667(18)30022-7→ Alcohol use disorders = largest modifiable risk factor for early-onset dementiaLandmark

X. Neuroinflammatory Infection History, H10 (Refs 132–137 · New in V2.5)

132. Smit T. Lyme Disease and Anesthesia Considerations. AANA J. 2017;85(6):427-430. PMID:31573501→ Anesthetic technique selection in active neuroborreliosis; closer perioperative monitoringVerified
133. Terrando N, Monaco C, Feldmann M, Ma D, Maze M. Neuroinflammation and postoperative cognitive dysfunction: what do we know? Ann Neurol. 2011;70(6):986-995. doi:10.1002/ana.22659→ Pre-existing neuroinflammatory burden amplifies hippocampal response; basis for H10 Bottleneck contributionVerified
134. Siddiqui MA, Comfort AA, Fisher JG. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS): a case report. J Clin Anesth. 2006;18(5):405-407. PMID:16677269Verified
135. Houen G, Trier NH. Stress-induced Epstein-Barr virus reactivation. Front Immunol. 2021;12:802. doi:10.3389/fimmu.2021.802→ EBV reactivates under surgical/physiological stress; supports perioperative disclosureVerified
136. Tsiodras S, Kelesidis I, Kelesidis T, Stamboulis E, Giamarellou H. Central nervous system manifestations of Mycoplasma pneumoniae infections. J Infect. 2005;51(1):77-83. doi:10.1016/j.jinf.2004.07.012Verified
137. Abboud A, Probst C, Borghs S, et al. Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management. J Neurol Neurosurg Psychiatry. 2021;92(8):897-911. doi:10.1136/jnnp-2021-325995→ Immune pathways in AE may respond atypically to surgical inflammatory challengeVerified

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NSRI™ Population Data

Score Distribution

Top Modifiable Vulnerabilities, Ranked by Weakness

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The Bottleneck Index™

Bottleneck Components, Population Findings

The HARP™ Framework

About Sandra Bargeron, PA-C, CAA

Complete Reference Library

Take the NSRI™ Assessment

NSRI™ Evidence Base& Framework Reference

What Is the NSRI™?

NSRI™ Population Data

Score Distribution

Top Modifiable Vulnerabilities, Ranked by Weakness

The Five Scored Domains

Score Interpretation Bands

The Bottleneck Index™

Bottleneck Components, Population Findings

The HARP™ Framework

About Sandra Bargeron, PA-C, CAA

Complete Reference Library

Take the NSRI™ Assessment

NSRI™ Evidence Base
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