Journal of Addiction & Addictive Disorders Category: Clinical Type: Review Article

Why Functional Non-Invasive Near-Infrared Spectroscopy Coupled with 31P-Nuclear Magnetic Resonance Spectroscopy should be used to Predict, Diagnose and Manage Substance Abuse-Induced Strokes and Deaths: A Personal Perspective

Burton M Altura1*, Asefa Gebrewold2, Anthony Carella3 and Bella T Altura4
1 Department Of Physiology And Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York, United States
2 Department Of Physiology And Pharmacology, SUNY Downstate Medical Center, New York, United States
3 Department Of Physiology And Pharmacology, Suny Downstate Medical Center, New York, United States
4 Magnesium For Health Foundation, Patterson, California, United States

*Corresponding Author(s):
Burton M Altura
Department Of Physiology And Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York, United States
Tel:+1 7182702194,
Email:burton.altura@downstate.edu

Received Date: Dec 14, 2019
Accepted Date: Jan 13, 2020
Published Date: Jan 20, 2020

Abstract

For more than 40 years, it has been known that substances of abuse (i.e., alcohol, psychedelics, cocaine, amphetamines heroin, etc.) can induce brain-vascular damage, inflammatory responses in the brain, and strokes in several different areas of the human brain. However, it has been difficult to precisely investigate the mechanisms of action or the precise developmental changes occurring with chronic abuse. We have found that a combination of Near-Infrared Spectroscopy (NIRS) and 31P-Nuclear Magnetic Resonance Spectroscopy (31P-NMRS) has allowed us to gain considerable , precise knowledge about the biochemical, physiological and metabolic actions of numerous substances of abuse, enabling us to demonstrate , at discrete brain micro-areas of the brain, quantitative changes in reduced vs. oxygenated hemoglobin, mitochondrial alterations in reduced vs. oxygenated cytochrome oxidase aa3 , intracellular pH, ATP, ADP, PCr, free inorganic phosphorous , blood flows, and intracellular free Mg. This technology, as reviewed herein, has allowed us, at least in experimental animals, to gain considerable insights into what biochemical, biophysical, physiological and metabolic alterations probably are responsible for substance abuse-induced brain damage, blackouts, functional neuronal deficits, and strokes. We believe these emerging technologies can be utilized, clinically, to predict impending doom, cell death and strokes and should be used in major hospitals-trauma centers to better diagnose, manage and prevent strokes.

INTRODUCTION

For close to 50 years, our laboratories have been interested in how various substances of abuse induce brain damage, strokes and death [1-74]. The biggest problem we have faced in this area is, how to detect substance abuse-induced vascular and functional changes in the brain, at discrete, localized areas of the brain, without opening the cranium? Clinical and experimental studies have now, unequivocally, established that ingestion, intravenously-administered, or sometimes snorting cocaine, amphetamines, heroin, morphine-derivatives, fentanyl, or psychedelic drugs (i.e., LSD, phencyclidine and derivatives, mescaline, psilocybin, etc.) can produce a variety of dangerous effects in different areas of the brain, including profound vascular damage, inflammatory responses, hallucinations, euphoria, reductions in blood flows, diverse forms of programmed cell death, and strokes [4,10,14-16,18,20,22,27,30,33-35,39,40,48,59,61,64,65,75-89]. These actions include atrophy of cortical, subcortical, and prefrontal cortical, hippocampal, medullary and cerebral areas of the brain associated with headaches, blackouts, functional neuronal deficits and psychoses which could lead to dementias. Clinically, it is known that all substances of abuse can lead to strokes and/or sudden-death.

DIRECT IN-SITU MICROVASCULAR OBSERVATIONS AND IN-VITRO STUDIES ON ISOLATED BLOOD VESSELS USING DIVERSE SUBSTANCES OF ABUSE

Previous studies from our laboratories, using image-splitting in-vivo television microscopy, at very high magnifications (up to 6,500 x normal) , on opened craniums in anesthetized mammals (e.g., rats, mice, guinea-pigs, rabbits and monkeys), have shown that alcohol, cocaine, cocaine derivatives, amphetamines, heroin, heroin derivatives, fentanyl combinations, and a variety of psychedelic drugs produced graded concentration-dependent spasms of cerebral and medullary arterioles, small arteries, and venules in the intact brains causing rupture of venular postcapillaries (microvessels<60um in diameter) [2,8,10,14,16,18,20, 22,26,28,30,40,53,61,64,70,71,unpublished findings]. Our laboratories were the first to demonstrate that most substances of abuse can induce intense contractions of isolated cerebral and basilar arteries from rats, mice, rabbits, guinea-pigs, monkeys, sheep, and baboons via direct actions on the vascular smooth muscle cells as well as on isolated human umbilical-placental blood arteries and veins [4,11,15,19,34,35,66,72, unpublished findings]. Further investigations by our group revealed the probable mechanisms whereby most substances of abuse cause the intense vasospasms and rupture of postcapillary microvessels [4,12,15,32,33,35,36,38,39,40,44,48,51,52,61,66,68,71-74, unpublished findings].

LIMITATIONS OF CURRENT STRUCTURAL AND FUNCTIONAL IMAGING METHODS FOR STUDYING BRAIN-VASCULAR ACTIONS OF DRUGS OF ABUSE IN UNOPENED CRANIUMS

Since the mid-1970’s, it has been known that substances of abuse can cause serious brain -vascular damage and strokes, both hemorrhagic and ischemic [see 75-89, for reviews]. However, up until recently, it has been difficult to gain specific information on exact target sites and mechanisms of action in the living, unopened human brain.

Obviously, we cannot follow either the brain-vascular or metabolic actions after ingestion, intravenous injections, or snorting substances of abuse by opening craniums. In view of this dilemma, non-invasive methods for studying unopened brains, in-situ, had to be devised. As of this writing, the available techniques used for diagnostic brain imaging can be classified into structural and functional methods. Structural imaging of the brain is utilized to acquire anatomical information (e.g., X-ray Computed Tomography [CT], Magnetic Resonance Imaging [MRI], and ultrasound imaging) while the goal of functional imaging of the brain is to acquire information on the physiological state of cerebral and other brain areas (e.g., blood flows, oxygen consumption, metabolic activities, neuronal activities, etc.). These latter methods include functional MRIs (fMFRIs), Electroencephalography (EEG), Magneto Encephalography (MEG), Positron Emission Tomography (PET), and Single Photon Emission Computed Tomography (SPECT).

USE OF NEAR-INFRARED SPECTROSCOPY

Near-Infrared Spectroscopy (NIRS) was designed to measure concentration changes in hemoglobin (oxygenated vs. deoxygenated) and mitochondrial cytochromes in the brain (e.g., cytochrome oxidase aa3), noninvasively [90]. NIRS, although primarily utilized to assess brain tissue oxygenation, has also demonstrated considerable potential for neuroimaging (e.g., functional NIRS) [91,92]. Approximately 20 years ago, Villinger and Chance used noninvasive approaches employing near-infrared light to interrogate the human cortex through the intact scalp and skull [93]. It is now thus, possible, as we have found in lab animals to utilize visible light to illuminate discrete areas of the intact brain to measure, mitochondrial levels of cytochrome oxidase aa3 (reduced vs. oxidized), tissue oxygenation, and reduced vs. oxygenated hemoglobin concentrations before and after administration of drugs of abuse [17,40,48,69,94, unpublished data]. By combining these NIRS measurements with high-resolution 31P-nuclear magnetic resonance spectroscopy (31P-NMRS), we have been able to probe discrete areas of the unopened brain for intracellular levels of pH, ATP, ADP, phosphocreatine (PCr), inorganic phosphate, and metabolic controlling cations such as magnesium (Mg2+), thus allowing us to get a pretty- good, quantitative picture of discrete localized cerebral, cortical, medullary, and frontal brain blood flows, tissue oxygenation and cellular energy metabolism [30,32,33,40,42,46,48,54,59,60,94]. In addition, our quantitative brain measurements allow us to predict whether discrete cellular areas are on the verge of dysfunction and cellular death by the intracellular level of inorganic phosphate; the higher the intracellular level of free inorganic phosphate, the greater the chance of irreversible cell death [33].

Tissue sections of brains of rats, and primary cultured cerebral vascular muscle cells, administered stroke-doses of either alcohol, cocaine, amphetamines, or heroin-fentanyl combinations indicated at least four different forms of programmed cell death on cerebral vascular smooth muscle cells, viz., apoptosis, necroptosis, pyroptosis, and ferroptosis, similar to what we have seen on coronary arteries and cardiac muscle cells excised from animals fed Mg-deficient diets [73,74,95-97]. Whether any of these forms of programmed forms of cell death are found on cerebral vascular smooth muscle cells in human brains impacted with substances of abuse remains to be investigated.

PROOF OF PRINCIPLE WITH NIRS AND 31P-NMR SPECTROSCOPY WITH SUBSTANCES OF ABUSE IN LIVE EXPERIMENTAL ANIMALS

For almost the past 30 years, our laboratories have utilized NIRS and 31P-NMRS to evaluate whether a combination of these technologies could yield quantitative information on the vascular and metabolic states of the effects of diverse substances of abuse in discrete, localized areas in brains of lightly -anesthetized rodents. So far, our experiments have shown that administration of cocaine, cocaine derivatives, amphetamines (including methamphetamines), alcohols (including methanol), heroin, heroin-derivatives, fentanyl-mixtures, marijuana-cannabis products, and psychedelic drugs (including LSD, PCP, mescaline, peyote, and psilocybin) suppress the firing of pyramidal cells in freely -moving animals, and increase levels of deoxyhemoglobin and reduced cytochrome oxidase aa3 in discrete areas of the brain (i.e., frontal cortex, cerebral hemispheres, and medulla) in a concentration-dependent manner; the greater the doses of the substances of abuse, the greater the degrees of localized ischemia [10,14,16,17,18,19,20,26,28,30,32,33,37,40,42,45,54,59,60,62,69,94, unpublished observations]. Application of 31P-NMRS technology, utilizing specialized holders for the anesthetized animals concomitant with a magnet of 9.4 tesla strength, one of the strongest magnets available, allowed us to show that administration of the diverse substances of abuse caused profound reductions in intracellular pH, ATP, ADP , phosphocreatine (PCr), and Mg2+ with concomitant rises in intracellular inorganic phosphate (Pi) levels; the higher the doses of the substances of abuse, the greater the lowering of intracellular ATP, ADP, PCr, Mg2+, and pH while the Pi kept rising towards severe vascular damage followed by hemorrhagic strokes (observed on autopsies) and death [32,33,42,54,55,59,60,94]. Collectively, our intracellular Pi measurements on more than 350 animals leads us to believe that a fast- rising intracellular level of Pi may be a clear diagnostic and prognostic biomarker of impending strokes followed by death unless steps for intervention are rapidly taken.

CONCLUSION AND FUTURE THOUGHTS

It is now known that substances of abuse (viz.; alcohol, psychedelics, cocaine and derivatives, amphetamines and derivatives, morphine-derivatives, heroin and derivatives, fentanyl, and designer substances of abuse) can all induce brain-vascular damage, inflammatory responses, and strokes in different areas of the human brain. However, until now, it has been difficult to investigate the mechanism (s) of action in the living intact brain without opening the cranium.

Although various biophysical and brain-imaging techniques have been devised to get some semi-quantitative biochemical and metabolic information, the reliable data, for the most part, centers on mostly structural alterations. Over the past 30 years, in collaboration with several scientists, we have found that a combination of Near-Infrared Spectroscopy (NIRS) with 31P-nuclear magnetic resonance spectroscopy (31P-NMRS) has allowed us to gain a considerable amount of knowledge about the biochemical, physiological and metabolic actions of numerous substances of abuse, thus enabling us to:

  1. Demonstrate, at discrete brain micro-areas, quantitative changes in reduced vs. oxygenated hemoglobin , mitochondrial alterations in reduced vs. oxygenated cytochrome aa3, intracellular pH, ATP, ADP, PCr, free inorganic phosphorus (Pi), blood flows, and intracellular levels of free Mg2+. This technology has allowed us, at least in experimental animals, to gain insights into what biochemical, biophysical, physiological, and metabolic alterations probably are responsible for substance abuse-induced brain damage, blackouts, functional neuronal deficits, and strokes;
  2. Predict impending doom, cell death, and strokes. In view of our experiments, so far, we believe a combination of NIRS and 31P-NMRS should be used in hospitals to better determine the state of the human brain after ingestion, intravenous administration, or snorting a substance of abuse in order to be able to better diagnose, manage and treat patients.

ACKNOWLEDGEMENT

Much of our investigative studies have been supported by research grants awarded to us (BMA and BTA) by various branches of The National Institutes of Health (i.e., The National Heart, Lung and Blood Institute; The National Institute on Drug Abuse; The National Institute of Mental Health; and The National Institute on Alcoholism and Alcohol Abuse) as well as unrestricted grants-in-aid from a number of pharmaceutical companies (i.e., The Up John Co., Sandoz Pharmaceuticals, The CIBA-GEIGY Corp, The Bayer Corp., Novartis Pharmaceuticals, and Pfizer Pharmaceuticals). Some of our studies were carried out while two of us (BMA, BTA) were on the faculty of The Albert Einstein College of Medicine of Yeshiva University. Most of our studies could not have been done without the outstanding help provided by Professor Raj K. Gupta of The Albert Einstein College of Medicine, Professor Lawrence M. Resnick (now deceased) of the Cornell University College of Medicine, and Professor Randall L. Barbour of SUNY Downstate Medical Center.

REFERENCES

  1. Altura BM, Altura BT, Carella A (1980) Effects of ketamine on vascular smooth muscle function. Br J Pharmacol 70: 257-267.
  2. Altura BT, Gebrewold A, Altura BM (1980) Are there opiate receptors in the microcirculation? In: Vascular Neuroeffector Mechanisms, Bevan JA (eds). Raven Press, New York, USA. Pg no: 338-340.
  3. Turlapaty PDMV, Altura BM (1980) Magnesium deficiency produces spasms of coronary arteries: Relationship to sudden death ischemic heart disease. Science 208: 198-200.
  4. Altura BT, Altura BM (1981) Phencyclidine, lysergic acid diethylamide, and mescaline: Cerebral artery spasms and hallucinogenic activity. Science 212: 1051-1053.
  5. Altura BM, Altura BT (1980) Vascular smooth muscle and general anesthetics. Federation Proc 39: 1584-1591.
  6. Weinberg J, Altura BM (1980) Morphine pretreatment influences reactivity of isolated rat arterial smooth muscle. Subst Alcohol Actions Misuse 1: 71-82.
  7. Altura BM (1981) Pharmacology of venules: Some current concepts and clinical potential. J Cardiovasc Pharmacol 3: 1413-1428.
  8. Altura BM (1981) Pharmacology of the microcirculation. In: The Microcirculation, Effros EM, Ditzel J, Schmid-Schoinbein H (eds). Academic Press, Massachusetts, USA. Pg no: 51-105.
  9. Altura BM, Altura BT (1981) General anesthetics and magnesium ions as calcium antagonists. In: New Perspectives on Calcium Antagonists, Weiss GB (eds). The American Physiological Society, Maryland, USA. Pg no: 131-145.
  10. Altura BM, Altura BT (1981) Alcohol induces cerebral arterial and arteriolar vasospasm by a direct action. Circulation 64: 284.
  11. Altura BM, Altura BT, Carella A, Chatterjee M, Halevy S, et al. (1982) Alcohol produces spasms of human umbilical blood vessels: Relationship to fetal alcohol syndrome. Eur J Pharmacol 86: 311-312
  12. Altura BM, Altura BT, Carella A 1983) Ethanol produces coronary vasospasm: Evidence for a direct action of ethanol on vascular muscle. Br J Pharmacol 78: 260-262.
  13. Altura BM, Altura BT, Carella A (1983) Magnesium deficiency-induced spasms of umbilical vessels: Relation to preeclampsia, hypertension, growth retardation. Science 221: 376-378.
  14. Altura BM, Altura BT (1983) Peripheral vascular actions of ethanol and its interaction with neurohumoral substances. Neurobhav Toxicol Teratol 5: 211-220.
  15. Altura BT, Quirion R, Pert CB, Altura BM (1983) Phencyclidine (angel dust) analogs and sigma-opiate benzomorphans cause cerebral arterial spasm. Proc Natl Acad Sci USA 80: 865-869.
  16. Altura BM, Altura BT, Carella A (1983) Alcohol-induced spasms of cerebral blood vessels: Relation to cerebrovascular accidents and sudden death. Science 220: 331-333.
  17. Altura BM, Altura BT (1983) Pharmacologic inhibition of cerebral vasospasm in ischemia, hallucinogen ingestion, and hypomagnesemia: Barbiturates, calcium antagonists, and magnesium. Am J Emerg Med 1: 80-190.
  18. Altura BT, Altura BM (1983) Cerebrovasospasms induced by phencyclidine are prevented by calcium antagonists and magnesium ions. Magnesium: Exp and Clin Res 2: 52-56.
  19. Altura BT, Altura BM (1984) Effects of barbiturates, phencyclidine, ketamine and analogs on cerebral circulation and cerebrovascular muscle. Microcirc Endothelium Lymphatics 1: 169-184.
  20. Altura BM, Altura BT (1984) Alcohol, the cerebral circulation and strokes. Alcohol 1: 325-331.
  21. Altura BT, Altura BM, Quirion R (1984) Identification of benzomorphan-K-opiate receptors in cerebral arteries which subserve relaxation. Br J Pharmacol 82: 459-466.
  22. Altura BM, Altura BT (1985) Alcohol, cerebral circulation, and vascular diseases. In: Progress in Alcohol Research, volume 1: Alcohol, Nutrition and The Nervous System, Parvez H (eds). NVU Science Press, Amsterdam, The Netherlands. Pg no: 311-326.
  23. Altura BM (1987) Pharmacology of the pulmonary circulation: An overview. In: The Pulmonary Circulation in Health and Disease, Will J (eds). Academic Press, New York, USA. Pg no: 79-95.
  24. Monuszko E, Halevy S, Freese K, Liu-Barnett M, Altura BM (1989) Vasoactive actions of local anesthetics on isolated human umbilical arteries and veins. Br J Pharmacol 97: 319-328.
  25. Altura BM, Altura BT (1989) Cardiovascular functions in alcoholism and after acute administration of alcohol: Heart and blood vessels. In: Alcoholism: Biochemical and Genetic Aspects, Goedde HW, Agarwal DP (eds). Pergamon Press, Elmsford, USA. Pg no: 167-227.
  26. Huang QF, Gebrewold A, Altura BT, Altura BM (1990) Mg2+ protects against PCP-induced cerebrovasospasms and vascular damage in rat brain. Magnes Trace Elem 9: 44-46.
  27. Huang QF, Gebrewold A, AlturaBT, Altura BM (1990) Cocaine-induced cerebral vascular damage can be ameliorated by Mg2+ in rat brain. Neurosci Lett 109: 113-116.
  28. Huang Q-F, Gebrewold A, Altura BT, Altura BM (1990) Magnesium ions prevent phencyclidine-induced cerebrovasospasms and rupture of cerebral microvessels: Direct in-vivo microcirculatory studies on the brain. Neurosci Lett 113: 115-119.
  29. Mathew R, Altura BM (1991) Pulmonary circulation, Pharmacology. In: Encyclopedia of Human Biology, volume 6. Academic Press, New York, USA. Pg no: 345-355.
  30. Altura BM, Altura BT (1984) Alcohol, stroke and the cerebral circulation. Alcohol 1: 325-331.
  31. Zou LY, Wu F, Altura BT, Barbour RL, Altura BM (1992) Beneficial effects of high magnesium on alcohol-induced cardiac failure. Magnes Trace Elem 10: 409-419.
  32. Altura BM, Gupta RK (1992) Cocaine induces intracellular free Mg deficits, ischemia and stroke as observed by in-vivo 31P-NMR of the brain. Biochim Biophys Acta 1111: 271-274.
  33. Altura BM, Altura BT, Gupta RK (1992) Alcohol intoxication results in rapid loss in free magnesium in brain and disturbances in brain bioenergetics: Relation to cerebrovasospasm, alcohol-induced strokes, and barbiturate-anesthesia induced deaths. Magnesium Trace Elem 10: 122-135.
  34. He GQ, Zhang A, Altura BT, Altura BM (1992) Cocaine-induced cerebral arterial vasospasm: Possible relation to stroke and sudden death. FASEB J 6: 986.
  35. Zhang A, Altura BT, Altura BM (1993) Ethanol-induced contraction of cerebral arteries in diverse mammals and its mechanism of action. Eur J Pharmacol 248: 229-236.
  36. Altura BM, Zhang A, Cheng TP, Altura BT (1993) Cocaine induces rapid loss of intracellular free Mg2+ in cerebral vascular smooth muscle cells. Eur J Pharmacol 246: 299-301.
  37. Barbour RL, Gebrewold A, Altura BM (1993) Optical spectroscopy and cerebral vascular effects of alcohol in the intact brain: Effects on tissue deoxyhemoglobin, blood content, and reduced cytochrome oxidase. Alcohol Clin Exp Res 17: 1319-1324.
  38. Altura BM, Zhang A, Cheng TP, Altura BT (1993) Ethanol promotes rapid depletion of intracellular free Mg in cerebral vascular smooth muscle cells: Possible relation to alcohol-induced behavioral and stroke-like effects. Alcohol 10: 563-566.
  39. He GQ Zhang A, Altura BT, Altura BM (1994) Cocaine-induced cerebrovasospasm and its mechanism of action. J Pharmacol Exp Ther 268:1532-1539.
  40. Altura BM, Altura BT (1994) Role of magnesium and calcium in alcohol-induced hypertension and strokes as probed by in-vivo television microscopy, digital mage microscopy, optical spectroscopy, 31P-NMR spectroscopy and a unique magnesium ion-selective electrode. Alcohol Clin Exp Res 18: 1057-1068.
  41. Memon ZI, Altura BT, Benjamin JL, Cracco RQ, Altura BM (1995) Predictive value of serum ionized but not total magnesium levels n head injuries. Scand J Clin Lab Invest 55: 671-677.
  42. Altura BM, Gebrewold A, Altura BT, Gupta RK (1995) Role of brain [Mg2+]i in alcohol-induced hemorrhagic stroke in a rat model: A 31P-NMR in-vivo study. Alcohol 12: 131-136.
  43. Altura BM, Zhang A, Cheng TP, Altura BT (1995) Alcohols induce rapid depletion of intracellular free Mg2+ in cerebral vascular muscle cells: Relation to chain length and partition coefficient. Alcohol 12: 247-250.
  44. Babu A, Cheng TP, Zhang A, Altura BT, Altura BM (1999) Low concentrations of ethanol deplete type-2 astrocytes of intracellular free magnesium. Brain Res Bull 50: 59-62.
  45. Ludvig N, Altura BT, Fox SE, Altura BM (1995) The suppressant effect of ethanol, delivered via intrahippocampal microdialysis, on the firing of local pyramidal cells in freely behaving rats. Alcohol 12: 417-421.
  46. Altura BM, Altura BT (199) Alcohol-associated acute head trauma in human subjects is associated with early deficits in serum ionized magnesium and calcium. Alcohol 12: 433-436.
  47. Zhang A, Fan SH, Cheng TP, Altura BT, Wong RKS, et al. (1996) Extracellular Mg2+ modulates intracellular Ca2+ in acutely isolated CA1 pyramidal cells of the guinea-pig brain. Brain Res 728: 204-208.
  48. Altura BM, Altura BT (1996) Effects of alcohol on overall brain metabolism. In: The Pharmacology of Alcohol and Alcohol Dependence, Begleiter H, Kissin B (eds). Oxford Univ Press, New York, USA. Pg no: 181-206.
  49. Altura BM, Zhang A, Altura BT (1996) Alcohol, myocardial bioenergetics, phospholipids, and ionic balance. In: Alcohol and Cardiovascular System, Zakhari S, Assef M (eds). NIAAA Research Monograph, USA Govt Printing Office, Bethesda, USA. Pg no: 279-315.
  50. Altura BM, Zou LY, Altura BT, Jelicks LA, Wittenberg BA, et al. (1996) Beneficial vs. detrimental actions of ethanol on heart and coronary vascular muscle: Roles of Mg2+ and Ca2+. Alcohol 13: 499-513.
  51. Zhang A, Cheng TP, Altura BT, Altura BM (1996) Acute cocaine results in rapid rises in intracellular free calcium concentration in canine cerebral vascular smooth muscle cells: Possible relation to etiology of stroke. Neuroscience Lett 215: 57-59.
  52. Altura BM, Zhang A, Cheng TP, Altura BT (1996) Exposure of piglet coronary arterial smooth muscle cells to low alcohol results in elevation of intracellular free Ca2+: Relevance to fetal alcohol syndrome. Eur J Pharmacol 314: 9-11.
  53. Altura BM, Gebrewold A (1996) Alpha-tocopherol attenuates alcohol-induced cerebral vascular damage: Possible role of oxidants in alcohol brain pathology and strokes. Neurosci Lett 220: 207-210.
  54. Altura BM, Gebrewold A, Altura BT, Gupta RK (1997) Magnesium protects against cocaine-induced hemorrhagic stroke in a rat model: A 31P-NMR in-vivo study. Frontiers in Bioscience 2: 9-12.
  55. Altura BM, Gebrewold A, Zhang A, Altura BT, Gupta RK (1997) Short-term reduction in dietary intake of magnesium causes deficits in brain intracellular free Mg2+ and [H+]I but not high-energy phosphates as observed by in-vivo 31P-NMR . Biochim Biophys Acta 1358: 1-5.
  56. Altura BM, Zhang A, Altura BT (1997) Exposure of piglet coronary arterial muscle cells to low concentrations of Mg2+ found in blood of ischemic heart disease patients results in rapid elevation of cytosolic Ca2+: Relevance to sudden infant death syndrome. Eur J Pharmacol 338: R7-R9.
  57. Altura BT, Memon ZS, Zhang A, Cheng TP, Slverman R, et al (1997) Low levels of serum ionized magnesium are found in stroke patients early after stroke which results in rapid elevation in cytosolic free calcium and spasm in cerebral vascular muscle cells. Neurosci Lett 230: 37-40.
  58. Morrill GA, Gupta RK, Kostellow AB, Ma GY, Zhang A, et al. (1997) Mg2+ modulates membrane lipids in vascular smooth muscle: A link to atherogenesis. FEBS Lett 408: 191-194.
  59. Altura BM, Weaver C, Gebrewold A, Altura BT, Gupta RK (1998) Continuous osmotic mini-pump infusion of alcohol into brain decreases brain [Mg2+] and brain bioenergetics and enhances susceptibility to hemorrhagic stroke: An in-vivo 31P-NMR study. Alcohol 15: 113-117.
  60. Altura BM, Gebrewold A, Zhang A, Altura BT, Gupta RK (1998) Magnesium deficiency exacerbates brain injury and stroke mortality induced by alcohol: A 31P-NMR study. Alcohol 15: 181-183.
  61. Altura BM, Gebrewold A (1998) Pyrrolidine dithiocarbamate attenuates alcohol-induced leukocyte-endothelial cell interaction and cerebral vascular damage in rats: Possible role of activation of transcription factor NF-kappa B in alcohol brain pathology. Alcohol 16: 25-28.
  62. Ludvig N, Fox SE, Kubie JL, Altura BM, Altura BT (1998) Application of the combined single-cell recording /intracerebral microdialysis method to alcohol research in freely moving animals. Alcohol Clin Exp Res 22: 41-50.
  63. Zheng T, Li W, Zhang A, Altura BM, Altura BT (1998) Staurosporine and H7 attenuate ethanol-induced elevation in [Ca2+]I in cultured canine cerebral vascular smooth muscle cells. Neurosci Lett 241: 139-142.
  64. Ema M, Gebrewold A, Altura BT, Zhang A, Altura BM (1998) Alcohol-induced vascular damage of brain is ameliorated by administration of magnesium. Alcohol 15: 95-103.
  65. Altura BM, Altura BT (1999) Association of alcohol in brain injury, headaches, and stroke with brain-tissue and serum levels of magnesium: A review of recent findings mechanisms of action. Alcohol 19:119-130.
  66. Yang ZW, Wang J, Zheng T, Altura BT, Altura BM (2001) Ethanol-induced contractions of cerebral arteries: role of tyrosine and mitogen-activated protein kinases. Stroke 32: 249-257.
  67. Altura BM, Zhang A, Cheng TP, Altura BT (2001) Extracellular magnesium regulates nuclear and perinuclear free ionized calcium in cerebral vascular smooth muscle cells: Possible relation to alcohol and central nervous system injury. Alcohol 23: 83-90.
  68. Yang ZW, Wang J, Zhang A, Altura BT, Altura BM (2001) Importance of PKC and PI3Ks in ethanol-induced contraction of cerebral arterial smooth muscle. Am J Physiol Heart Circ Physiol 280: 2144-2152.
  69. Barbour RL, Gebrewold A, Altura BT, Altura BM (2002) Optical spectroscopy and prevention of deleterious cerebral vascular effects of ethanol by magnesium ions. Eur J Pharmacol 447: 79-86.
  70. Altura BM, Gebrewold A, Zheng T, Altura BT (2002) Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact rat brain: Insight into mechanisms and possible relation to brain injury. Brain Res Bull 58: 271-278.
  71. Altura BM, Gebrewold A, Zhang A, Altura BT (2002) Role of leukocytes in ethanol-induced microvascular injury in the rat brain situ: Potential role in alcohol brain pathology and stroke. Eur J Pharmacol 448: 89-94.
  72. Yang ZW, Wang J, Zheng T, Altura BT, Altura BM (2002) Roles of tyrosine kinase-, 1-phosphatidylinositol 3-kinase-, and mitogen-activated protein kinase-signaling pathways in ethanol-induced contractions of rat aortic smooth muscle: Possible relation to alcohol-induced hypertension. Alcohol 28: 17-28.
  73. Su J, Li JF, Li W, Altura BT, Altura BM (2003) Cocaine induces apoptosis in cerebral vascular muscle cells: Potential roles in strokes and brain damage. Eur J Pharmacol 482: 61-66.
  74. Su J, Li JF, Li W, Altura BT, Altura BM (2004) Cocaine induces apoptosis in primary cultured rat aortic smooth muscle cells: Possible relationship to aortic dissection, atherosclerosis and hypertension. Int J Toxicol 23: 233-237.
  75. Kaku DA (1990) Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Int Med 113: 821-827.
  76. Levine SR, Brust JC, Futrell N, Ho KL, Blake D, et al. (1990) Cerebrovascular complications of the use of the crack form of alkaloidal cocaine. N Engl J Med 323: 699-704.
  77. Levine SR, Brust JC, Futrell N, Brass LM, Blake D, et al. (1991) A comparative study of the cerebrovascular complications of cocaine: alkaloidal versus hydrochloride: A review. Neurology 41: 1173.
  78. Sloan MA, Kittner SJ, Rigamonti D, Price TR (1991) Occurrence of stroke associated with use/abuse of drugs. Neurology 41: 1358-1364.
  79. Brust JCM (1995) Stroke and substance abuse. In: Stroke: Pathophysiology, Diagnosis, and Management. Churchill-Livingstone, New York, USA. Pg no: 979-1000.
  80. Brust JC (2004) Neurological Aspects of Substance Abuse. Butterworth-Heinemann, London, UK.
  81. Brust JCM, Ritcher R (1977) Stroke associated with cocaine abuse. NY State J Med 77: 1471.
  82. Cahill DW, Knipp H, Mosser J (1981) Intracranial hemorrhage wkth amphetamine abuse. Neurol 31: 1058-1059.
  83. Perez Jr JA, Arsura EL, Strategos S (1999) Methamphetamine-related stroke: Four cases. J Emerg Med 17: 469-471.
  84. Esse K, Fossati-Bellani M, Traylor A, Martin-Schild S (2011) Epidemic of illicit use, mechanisms of action/addiction and stroke as a health hazard. Brain Behav 1: 44-54.
  85. Altura BM, Zhang A, Shah NC, Shah GJ, Gebrewold A, et al. (2016) Euphoria from drinking alcoholic beverages may be due to reversible constriction of cerebral blood vessels: Potential roles of unrecognized ionized hypomagnesemia, and release of ceramides and platelet-activating factor. Clin Res and Trials 2: 242-245.
  86. Lappin JM, Darke S, Farrell M (2017) Stroke and methamphetamine use in young adults. Neurol, Neurosurg , and Psychiatr 88: 1079-1091.
  87. Altura BM, Gebrewold A, Carella A, Shah NC, Shah GJ, et al. (2018) Increased risk of stroke using marijuana-cannabis products: Evidence for dangerous effects on brain circulation and the unrecognized roles of magnesium. Drugs and Alcohol Addiction 1: 1-6.
  88. Altura BM, Carella A, Gebrewold A, Shah NC, Shah GJ, et al. (2019) Why there is an increased number of deaths from heroin mixed with fentanyl in the USA: Potential roles of unrecognized hypomagnesemia and elevated levels of ceramides and platelet-activating factor particularly in brain stem and potential relationship to Euphoria and hallucinations. Acta Scientific Pharmac Sci 3: 55-62.
  89. Altura BM, Gebrewold A, Carella A, Shah NC, Shah GJ, et al. (2019) Stroke, headaches and hallucinations: Real dangers of the recreational use of amphetamines and ecstasy-like drugs: Unrecognized role of hypomagnesemia. EC Pharmacol 7: 646-652.
  90. Hampson NB, Caatporesi EM, Stolp BW, Moon RE, Shook JE, et al. (1990) Cerebral oxygen availability by NIR spectroscopy during transient hypoxia in humans. J Appl Physiol 69: 907-913.
  91. Al-Rawi PG, Kirkpatrick PJ (2004) Tissue oxygen index: Thresholds for cerebral ischemia using near-infraredspectroscopy. Stroke 37: 2720-2725.
  92. Cuccia DJ, Abookasis D, Frostig RD, Tromberg BJ (2009) Quantitative in vivo imaging of tissue absorption, scattering, and hemoglobin concentration in rat cortex using spatially modulated structural light, Chapter 12. In: In vivo Optical Imaging of Brain Function, 2nd Ed, Frostig RD, ed. CRC Press, Boca Raton (Fl).
  93. Villinger A, Chance B (1997) Non-invasive optical spectroscopy and imaging of human brain function. Trends in Neurosci 20: 435-442.
  94. Altura BM, Gebrewold A, Barbour RL, Wu F, Altura BT (2019) Optical spectroscopy and prevention of deleterious brain-damaging cerebral vascular effects of cocaine by magnesium ions: Effects on brain mitochondrial oxidase, deoxyhemoglobin, ceramide and sphingomyelin levels and their potential application to human substance abuse. Int j Cardiol and Res 6: 137-143.
  95. Altura BM, Shah NC, Shah GJ, Altura BT (2017) Regulated RIPK3 necroptosis is produced in cardiovascular tissues and cells in dietary magnesium deficiency: Roles of cytokines and their potential importance in inflammation and atherogenesis. J Med SurgPathol 2: 1000e104.
  96. Altura BM, Gebrewold A, Carella A, Zhang A, Shah NC, et al. (2018) Regulated ferroptosis is produced in cardiovascular tissues and cells in dietary magnesium deficiency: Initiation of roles of glutathione, mitochondrial alterations and lipid peroxidation in inflammation and atherogenesis. EC Pharmacol and Toxicol 6: 535-541.
  97. Altura BM, Gebrewold A, Carella A, Zhang A, Shah NC, et al. (2019) Regulated pyroptosisis produced in cardiovascular tissues and cells in dietary magnesium deficiency: Cross-talk with cytokines, PAF, telomerases and aging. EC Pharmacol and Toxicol 7: 25-30.

Citation: Altura BM, Gebrewold A, Carella A, Altura BT (2020) Why Functional Non-Invasive Near-Infrared Spectroscopy Coupled with 31P-Nuclear Magnetic Resonance Spectroscopy should be used to Predict, Diagnose and Manage Substance Abuse-Induced Strokes and Deaths: A Personal Perspective. J Addict Addictv Disord 7: 32.

Copyright: © 2020  Burton M Altura, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

© 2022, Copyrights Herald Scholarly Open Access. All Rights Reserved!