Identification, diagnosis, and treatment of neuropathologies, neurotoxicities, tumors, and brain and spinal cord injuries using electrodes with microvoltammetry

Abstract

The present invention relates to devices and methods of use thereof for detection of biomolecules, in vitro, in vivo, or in situ. The invention relates to methods of diagnosing and/or treating a subject as having or being at risk of developing a disease or condition that is associated with abnormal levels of one or more biomolecules including, but not limited to, inter alia, epilepsy, diseases of the basal ganglia, athetoid, dystonic diseases, neoplasms, Parkinson's disease, brain injuries, spinal cord injuries, and cancer. The invention also provides methods of differentiating white matter from gray matter. In some embodiments, regions of the brain to be resected or targeted for pharmaceutical therapy are identified using sensors. The invention further provides methods of measuring the neurotoxicity of a material by comparing microvoltammograms of a neural tissue in the presence and absence of the material using the inventive sensors.

1 . A sensor comprising: 
 a) a construction; and    b) an indicator.    
     
     
         2 . The sensor of  claim 1 , wherein the sensor is partially or fully encased in an encasement, and the encasement is a hollow three-dimensional surface.  
     
     
         3 . The sensor of  claim 2 , wherein the hollow three-dimensional surface has an end face in any geometric shape.  
     
     
         4 . The sensor of  claim 3 , wherein the geometric shape comprises: a circle, a triangle, a quadrilateral, a rhombus, a parallelogram, a rectangle, or a polygon.  
     
     
         5 . The sensor of  claim 2 , wherein the encasement comprises conducting material, semi-conducting material, non-reactive material, or non-reactive polymers, or combinations thereof.  
     
     
         6 . The sensor of  claim 5 , wherein the encasement comprises: metals, polymers, or blends thereof, polytetrafluoroethylene, fluorinated ethylene-propylene, perfluoroalkoxy polymer resin, polymethylmethacrylate, polyethylethacrylate, steel, stainless steel, silicon, germanium, silver, platinum, gold, or combinations thereof.  
     
     
         7 . The sensor of  claim 1 , wherein the construction comprises: a conducting material, semi-conducting material, conducting metal, or a semi-conducting metal, or combinations thereof.  
     
     
         8 . The sensor of  claim 7 , wherein the construction comprises: steel, stainless steel, silicon, germanium, silver, platinum, or gold, or combinations thereof.  
     
     
         9 . The sensor of  claim 1 , wherein the indicator comprises: 
 a) at least one form of carbon, or combinations thereof; and    b) at least one lipid or an entity having a lipid, or combinations thereof.    
     
     
         10 . The sensor of  claim 9 , wherein the carbon comprises: graphite, fullerenes, cylindrical fullerenes, buckminsterfullerenes, buckyballs, nanotubes, probingtubes, cold form carbon steel, white carbons, dioxosilane, or diamonds, or combinations thereof.  
     
     
         11 . The sensor of  claim 9 , wherein the lipid comprises: lipids, fats, oils, animal fats or oils, plant fats or oils, mineral oils, glycerol containing lipids, membrane lipids, soaps or detergents, waxes, cells, cell components, stem cells, electroplaques, lipoproteins; or combinations thereof.  
     
     
         12 . The sensor of  claim 11 , wherein the lipid comprises: lipids, entities having lipids, fats, oils, animal fats or oils, plant fats or oils, mineral oils, nujol oil, glycerol containing lipids, membrane lipids, soaps or detergents, waxes, cells, cell components, stem cells, electroplaques, lipoproteins, fatty acids, glycerides, monoglycerides, diglycerides, triglycerides, artificial or synthesized fats or oils, heifer fats, ox-depot fats,  Valeria indica  fats, tallow, red tallow, Malabar tallow, vegetable tallow, cocoa butter, soybean oil, safflower oil, sesame oil, peanut oil, coconut oil, linoleic acid, linoleic acid in vegetable oil, soybean oil, cottonseed oil, corn oil, or poppyseed oil, lauric acid, lauric acid in coconut oil, cholesterol, phosphotidylcholine, phosphotidylethanolamine, sphingomyelin, lecithin, lysolecithin, steroids, isoprenoids, eicosenoids, sodium alkyl benzene sulfonate, sodium lauryl sulfate, jejoba wax comprised of gadoleic acid, N-stearoylcerebroside, N-stearoylsphingosine, cardiolipin, or combinations thereof.  
     
     
         13 . The sensor of  claim 1 , wherein the indicator is pre-treated, inserted, or coated with at least one biomolecule, or combinations thereof.  
     
     
         14 . The sensor of  claim 13 , wherein the biomolecule comprises: a pharmaceutical compound, neurotransmitters, neuromodulators, nucleic acids, hormones, vitamins, surfactants, soaps, detergents, stabilizing proteins, amyloid proteins, or combinations thereof.  
     
     
         15 . The sensor of  claim 14 , wherein the biomolecule comprises: pharmaceutical compounds, pharmaceutical compounds specific for neurodegenerative or neuropsychiatric diseases, disorders, and conditions, neurotransmitters, neuromodulators, hormones, surfactants, soaps, detergents, pramipexole, topiramate, clozapine, dopamine, serotonin, norepinephrine, acetylcholine, adenosine, estrogen, vitamins, vitamin A, vitamin E, brain lipids, phosphotidylethanolamine, tallow, sodium lauryl sulfate, N-acetyl-aspartate, choline, lactate, uric acid, stabilizing proteins, amyloid proteins, ascorbic acid, γ-aminobutyric acid, glutamate, neurotensin, somatostatin, dynorphin, homovanillic acid, nucleic acids, tryptophan, tyrosine, nitrous oxide, nitric oxide, or combinations thereof.  
     
     
         16 . A method for microvoltammetric imaging of changes in biomolecule concentrations in response to diagnostic challenge or therapeutic treatment comprising: exposing a neural cell, body, blood, or urine to a diagnostic challenge or therapeutic treatment; contacting said cell, body, blood, or urine with a sensor of  claim 1;  applying a potential to the sensor; and monitoring a temporally resolved microvoltammogram.  
     
     
         17 . A diagnostic method for monitoring neural functions in a mammal comprising: contacting neural cell, body, blood, or urine of said mammal with a sensor of  claim 1;  applying a potential to said sensor; and generating a temporally resolved microvoltammogram, wherein the microvoltammogram indicates the status of neural function in the mammal.  
     
     
         18 . A method of diagnosing and/or monitoring a neurological disease, disorder, or condition, comprising: generating a temporally resolved microvoltammogram of a subject; determining from said microvoltammogram the presence and concentration of at least one biomolecule; and comparing said biomolecule concentration(s) to specific threshold values of each biomolecule or biomolecules to determine the presence of statistically significant concentration differences, wherein said threshold values are derived from the sensor microvoltammogram(s) of at least one healthy individual, wherein the microvolatammogram uses the sensor of  claim 1 .  
     
     
         19 . The method of  claim 18 , wherein the number of biomolecules is at least two.  
     
     
         20 . The method of  claim 18 , wherein the biomolecule comprises: pharmaceutical compounds, pharmaceutical compounds specific for neurodegenerative or neuropsychiatric diseases, disorders, and conditions, neurotransmitters, neuromodulators, hormones, surfactants, soaps, detergents, pramipexole, topiramate, clozapine, dopamine, serotonin, norepinephrine, acetylcholine, adenosine, estrogen, vitamins, vitamin A, vitamin E, brain lipids, phosphotidylethanolamine, tallow, sodium lauryl sulfate, N-acetyl-aspartate, choline, lactate, uric acid, stabilizing proteins, amyloid proteins, ascorbic acid, γ-aminobutyric acid, glutamate, neurotensin, somatostatin, dynorphin, homovanillic acid, nucleic acids, tryptophan, tyrosine, nitrous oxide, nitric oxide, surfactants, or combinations thereof.  
     
     
         21 . The method of  claim 18 , wherein the biomolecule detects conditions, diseases, or disorders of: the basal ganglia, athetoid, dystonic diseases, Parkinson's disease, Huntington's disease, epilepsy, Lesch-Nyhan disease, controlled-substance addictions, cerebral ischemia, white matter disease, stroke cerebral hemorrhage, head trauma, multiple sclerosis, central nervous system infection, hydrocephalus, Leukodystrophies, and neoplasms.  
     
     
         22 . The method of  claim 21  wherein the controlled substance addiction is an addiction to a controlled substance comprising opiates, stimulants, or depressants.  
     
     
         23 . A method for detecting a site of nerve or neuronal damage or blockage in a mammal having or being at risk of developing nerve damage or blockage comprising: generating a temporally resolved microvoltammogram of a tissue of said mammal; simultaneously monitoring movement behavior of said mammal; and comparing said microvoltammogram and movement behavior to a reference microvoltammogram of corresponding tissue of a healthy individual and concurrent reference movement behavior of said healthy individual, wherein the microvoltammogram uses the sensor of  claim 1 .  
     
     
         24 . The method of  claim 23  wherein the nerve damage or blockage is a physical injury or blockage.  
     
     
         25 . The method of  claim 24  wherein the physical injury or blockage is a spinal cord injury or blockage.  
     
     
         26 . The method of  claim 24  wherein the nerve damage or blockage is a chemically-induced injury or blockage.  
     
     
         27 . A diagnostic method for brain or spinal cord injury comprising: generating a temporally resolved microvoltammogram of a tissue of a mammal having or being at risk of developing a brain or spinal cord injury; simultaneously monitoring movement behavior of said mammal; and comparing said microvoltammogram and movement behavior to a reference microvoltammogram of corresponding tissue of a healthy individual and concurrent reference movement behavior of said healthy individual, wherein the microvoltammogram uses the sensor of  claim 1 .  
     
     
         28 . The method of  claim 27  wherein the movement behavior is ambulation, fine motor movement, or combinations thereof.  
     
     
         29 . A diagnostic method for brain cancer comprising: generating a temporally resolved microvoltammogram of cancerous brain cells or tissue; determining from said voltammogram the presence and concentration of at least two biomolecules, wherein said biomolecule comprises: pharmaceutical compounds, neurotransmitters, neuromodulators, hormones, surfactants, soaps, detergents, dopamine, serotonin, norepinephrine, acetylcholine, adenosine, estrogen, vitamins, vitamin A, vitamin E, brain lipids, phosphotidylethanolamine, tallow, sodium lauryl sulfate, N-acetyl-aspartate, choline, lactate, uric acid, stabilizing proteins, amyloid proteins, ascorbic acid, γ-aminobutyric acid, glutamate, neurotensin, somatostatin, dynorphin, homovanillic acid, nucleic acids, tryptophan, tyrosine, nitrous oxide, nitric oxide, or combinations thereof, and comparing said biomolecule concentrations to specific threshold values of each of the biomolecules to determine the presence of statistically significant concentration differences, wherein said threshold values are derived from the microvoltammogram(s) of healthy cells or tissue and said step of comparing said biomolecules distinguishes whether the cancerous cells are present in gray matter or white matter, wherein the microvolatammogram uses the sensor of  claim 1 .  
     
     
         30 . The method of  claim 29 , wherein the brain cancer comprises: malignant gliomas, astrocytomas, oligodendogliomas, ependymomas, gliosarcoma, meningioma, hammartomas, ganglioglioneurocytomas, primitive neuroectodermal tumors (pnet), medulloblastomas, neurofibromas, schwannomas, neuromas, teratomas, pituitary adenomas, or metastatic tumors.  
     
     
         31 . The method of  claim 29  wherein said biomolecules are at least norepinephrine and dopamine.  
     
     
         32 . The method of  claim 29  wherein at least one of said biomolecules is serotonin.  
     
     
         33 . The method of  claim 29  wherein said markers are at least norepinephrine and serotonin and said comparing indicates gray matter if the catecholamine peak is about half the amplitude of the catecholamine reference peak of white matter and the serotonin peak is about double the amplitude of the serotinin reference peak of white matter.  
     
     
         34 . A method of measuring the neurotoxicity of a substance comprising: comparing a temporally resolved microvoltammogram of neural tissue in the absence of said material with a temporally resolved microvoltammogram of tissue in the presence of said material, wherein the microvolatammogram uses the sensor of  claim 1 .  
     
     
         35 . A method of diagnosing epilepsy comprising: generating a temporally resolved microvoltammogram of a tissue of a subject; and comparing said microvoltammogram to at least one reference microvoltammogram; wherein said reference microvoltammogram is of the corresponding tissue of an individual, comprising: a healthy individual, an individual having mesial temporal lobe epilepsy, an individual having neocortical temporal lobe epilepsy, an individual having parietal lobe epilepsy, an individual having frontal lobe epilepsy, an individual having jacksonian epilepsy, an individual having Rasmussen's epilepsy, an individual having Lafora's body disease, an individual having Lennox-Gestaut, an individual having Landau-Kleffner syndrome, an individual having West Syndrome, an individual having primary generalized epilepsies, an individual having partial epilepsy, or an individual having post-traumatic epilepsy, wherein the microvoltammogram uses the sensor of  claim 1 .  
     
     
         36 . The method of  claim 35 , wherein said microvoltammogram of a subject is compared with more than one reference microvoltammogram.  
     
     
         37 . The method of  claim 35 , wherein said microvoltammogram of a subject is compared with the reference microvoltammogram of a healthy individual, an individual having mesial temporal lobe epilepsy, and an individual having neocortical temporal lobe epilepsy.  
     
     
         38 . A diagnostic method for temporal lobe epilepsy comprising: generating a temporally resolved microvoltammogram of temporal lobe test tissue; determining from said microvoltammogram the presence and concentration of at least two biomolecules comprising: pharmaceutical compounds, pharmaceutical compounds specific for neurodegenerative or neuropsychiatric diseases, disorders, and conditions, neurotransmitters, neuromodulators, hormones, surfactants, soaps, detergents, pramipexole, topiramate, clozapine, dopamine, serotonin, norepinephrine, acetylcholine, adenosine, estrogen, vitamins, vitamin A, vitamin E, brain lipids, phosphotidylethanolamine, tallow, sodium lauryl sulfate, N-acetyl-aspartate, choline, lactate, uric acid, stabilizing proteins, amyloid proteins, ascorbic acid, γ-aminobutyric acid, glutamate, neurotensin, somatostatin, dynorphin, homovanillic acid, nucleic acids, tryptophan, tyrosine, nitrous oxide, nitric oxide, or combinations thereof; and comparing said test tissue biomolecule concentrations to specific threshold values of each of the biomolecules to determine the presence of statistically significant concentration differences, wherein said threshold values are derived from the microvoltammogram(s) of tissue selected from the group consisting of healthy temporal lobe tissue, mesial temporal lobe epileptic tissue, and neocortex temporal lobe epileptic tissue, wherein the microvolatammogram uses the sensor of  claim 1 .  
     
     
         39 . The method of  claim 38 , wherein said step of comparing said biomolecule distinguishes whether the test tissue is healthy tissue, mesial temporal lobe epileptic tissue, or neocortex temporal lobe epileptic tissue.  
     
     
         40 . A method for determining the concentration of a therapeutic material in a brain tumor comprising: contacting said tumor with the sensor of  claim 1;  applying a potential to said sensor; generating a temporally resolved sensor microvoltammogram; and determining from said microvoltammogram the concentration of said material.  
     
     
         41 . The method of  claim 40 , wherein said determining comprises calculating the concentration of said material using the Cottrell equation.  
     
     
         42 . A method of guiding neurosurgery comprising: distinguishing gray matter, white matter, tumor tissue, necrotic tissue, ischemic tissue, and edematous tissue, wherein said distinguishing comprises: 
 a) generating a temporally resolved microvoltammogram of a test tissue using the sensor of  claim 1 , an EEG sensor, or combinations thereof;    b) determining from said microvoltammogram the presence and concentration of at least two biomolecules comprising pharmaceutical compounds, neurotransmitters, neuromodulators, hormones, surfactants, soaps, detergents, dopamine, serotonin, norepinephrine, acetylcholine, adenosine, estrogen, vitamins, vitamin A, vitamin E, brain lipids, phosphotidylethanolamine, tallow, sodium lauryl sulfate, N-acetyl-aspartate, choline, lactate, uric acid, stabilizing proteins, amyloid proteins, ascorbic acid, γ-aminobutyric acid, glutamate, neurotensin, somatostatin, dynorphin, homovanillic acid, nucleic acids, tryptophan, tyrosine, nitrous oxide, nitric oxide, or combinations thereof; and    c) comparing said test biomolecule concentrations to specific threshold values of each of the biomolecules to determine the presence of statistically significant concentration differences, wherein said threshold values are derived from the sensor microvoltammogram(s) of reference tissue of gray matter, white matter, tumor tissue, necrotic tissue, ischemic tissue, edematous tissue, or combinations thereof, wherein the microvolatammogram uses the sensor of  claim 1 .    
     
     
         43 . The method of  claim 42 , wherein said reference microvoltammogram is from a human or non-human mammal having mesial temporal lobe epilepsy, neocortical temporal lobe epilepsy, parietal lobe epilepsy, frontal lobe epilepsy, Rasmussen's epilepsy, Lafora's body disease, Lennox-Gestaut, Landau-Kleffner syndrome, west Syndrome, primary generalized epilepsy, partial epilepsy, or post-traumatic epilepsy.  
     
     
         44 . The method of  claim 42 , wherein said intraoperative neuroanatomic localization comprises delineating marginal boundaries in brain substrates.  
     
     
         45 . The method of  claim 42  wherein said contacting step is minimally invasive and occurs through a burr hole, small craniotomy, or an incision.  
     
     
         46 . A method for continuous or intermittent monitoring and administration of pharmacological and nonpharmacological treatments for a neurological disorder in a mammal, comprising: 
 a) contacting neural cells with the sensor of  claim 1;     b) applying a potential to the sensor;    c) generating a temporally and/or spatially resolved sensor microvoltammogram;    d) interpreting the microvoltammogram with a microprocessor or computer, wherein said microprocessor or computer determines the presence and concentration of a biomolecule comprising: pharmaceutical compounds, pharmaceutical compounds specific for neurodegenerative or neuropsychiatric diseases, disorders, and conditions, neurotransmitters, neuromodulators, hormones, surfactants, soaps, detergents, pramipexole, topiramate, clozapine, dopamine, serotonin, norepinephrine, acetylcholine, adenosine, estrogen, vitamins, vitamin A, vitamin E, brain lipids, phosphotidylethanolamine, tallow, sodium lauryl sulfate, N-acetyl-aspartate, choline, lactate, uric acid, stabilizing proteins, amyloid proteins, ascorbic acid, γ-aminobutyric acid, glutamate, neurotensin, somatostatin, dynorphin, homovanillic acid, nucleic acids, tryptophan, tyrosine, nitrous oxide, nitric oxide, or combinations thereof, and compares said biomolecule concentration to a threshold value of said respective biomolecule, and wherein said microprocessor or computer generates an output which administers the pharmacological or nonpharmacological treatment in an amount sufficient to treat said neurological disorder.