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WO2015013252A1 - Traitement de la maladie d'alzheimer - Google Patents

Traitement de la maladie d'alzheimer Download PDF

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WO2015013252A1
WO2015013252A1 PCT/US2014/047566 US2014047566W WO2015013252A1 WO 2015013252 A1 WO2015013252 A1 WO 2015013252A1 US 2014047566 W US2014047566 W US 2014047566W WO 2015013252 A1 WO2015013252 A1 WO 2015013252A1
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olfactory
recited
insertion end
sphenoid sinus
nerve
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Totada R. Shantha
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Wedge Therapeutics LLC
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Wedge Therapeutics LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0526—Head electrodes
    • A61N1/0546—Nasal electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36017—External stimulators, e.g. with patch electrodes with leads or electrodes penetrating the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/36025—External stimulators, e.g. with patch electrodes for treating a mental or cerebral condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/1054—Balloon catheters with special features or adapted for special applications having detachable or disposable balloons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease

Definitions

  • This invention disclosure relates to methods of treating Alzheimer's disease (AD) and other neurodegenerative diseases by electrical impulses delivered to the central nervous system (CNS) through one or more of the olfactory nerves (ORE), trigeminal nerve branches, sphenoid sinus with its 10 (five on each side) cranial nerves surrounding it, and pituitary-hypothalamic-hypoph sis complex; and sphenopalatine ganglion, such as to be received at the central nervous system.
  • the present disclosure involves a medical device and medical procedures that stimulate nerves by transmitting electrical energy to adjacent nerves From there the energy is transmitted to the central nervous system non-invasively to treat Alzheimer's and other neurodegenerative diseases.
  • This medical procedure is defined as being noninvasive when no break in the skin (or other surface of the body, such as a wound , bed) is created through use of the method, and when there is no contact with an internal body cavity beyond a body orifice (Examples: mouth, anus, external auditory meatus of the ear, nasal passages and its air sinuses).
  • invasive including minimally invasive procedures
  • procedures do involve inserting a substance or device into, through the skin, or into an internal body cavity beyond a body orifice.
  • Neural activity is controlled by electrical impulses or "action potentials" generated in and propagated by neurons.
  • a neuron In an inactive dormant state, a neuron is negatively polarized, and exhibits a resting membrane potential that is typically between -70 and -60 mV.
  • any given neuron receives from other neurons excitatory and inhibitory input signals or stimuli.
  • a neuron integrates the excitatory and inhibitory input signals it receives, and generates or fires a series of action potentials in the event that . the integration exceeds a threshold potential.
  • a neural firing threshold may be, for example, approximately -55 mV Action potentials propagated to the neuron's synapses, then conveyed to other neurons to which the neuron is connected through the synapses connected by axons and dendrites.
  • Neural activity in the brain is influenced by electrical energy supplied from a waveform generator type of device as explained in this invention.
  • Nerve stimulation is accomplished directly or indirectly by depolarizing a nerve membrane, causing the discharge of an action potential; or by hyperpolarization of a nerve membrane, preventing the discharge of an action potential.
  • Such stimulation may occur after electrical energy, or also other forms of energy, transmitted to the vicinity of a nerve [Rattay, F. The basic mechanism for the electrical stimulation of the nervous system. Neuroscience Vol. 89, No .2, pp. 335-346,1999; Heimbur, T. G, Andrew D. Jackson. On soliton propagation in biomembranes and nerves. PNAS vol. 102 (no. 28, Jul.
  • Nerve stimulation is measured directly as an increase, decrease, or modulation (inflection) of the activity of nerve fibers. It may be also secondary from the physiological effects that follow the transmission of electrical energy to the nerve fibers, its connected neurons, glia, and neuropil.
  • Neural stimulation systems encompass a pulse generator and an electrode assembly as described here in this invention.
  • the present disclosure involves such a device and medical procedures that stimulate nerves (nerve fibers and neurons) by transmitting energy to nerves and tissue (neuropil) non-invasively with no break in the skin or mucus membrane.
  • the neurons of the brain central nervous system- CNS
  • a neuron generates an electrical impulse, causing the cell to release its neurotransmitters, which in turn, bind to adjacent neurons or synapses. Then the recipient neurons (through synapses) generate their own electrical impulses and release their neurotransmitters, triggering the process in more neurons and the processes continues until the impulse becomes to weak to be conducted, or no longer produced. This is how messages to and from the CNS to various structures are propagated with their effect felt all over the body.
  • ATP adenosine triphosphate
  • the invention described herein is intended to increase the ATP levels, which will in turn enhance all the activities of the neuron, its extensions, and synapses.
  • Insulin and other therapeutic agents are incorporated in the treatment of Alzheimer's disease, along with the inventive device described here as illustrated in
  • the ATP enhances the protein, peptides, amino acid synthesis, and their output by the nucleus and endoplasmic reticulum by using the ATP energy provided by the mitochondria.
  • the combination enhances the protein-peptide-amino acid complex production of every kind, including tau proteins involved in the construction and maintenance of neurotubules, neurotrophic factors,
  • neurotransmitters enzymes, and hormones, that are also involved in memory and cognition.
  • Electrical impulses and insulin augment the production of substrates needed to assemble neurotransmitters; and protein complexes to maintain the cell wall, the integrity of the neurons, and their extensions and synapses.
  • electrical energy with insulin along with other therapeutic agents described in this invention prevents or delays further decay of the neurons afflicted by this disease, reduces the ROS damage to the remaining healthy nerve tissue, improves synaptogenesis, enhances the output of glutathione, and augments the production of acetylcholine and their functions as memory enhancer and neurotransmitter.
  • the cited patent publication, U. S. Patent Application Publication Number US 2012/0323214 Al contains information that overlaps with certain aspects of the present disclosure. But the present description includes certain additional features.
  • the '214 publication involves stimulation to produce electroporation and inontphoresis, to cause membranes of nerve or other tissue more permeable to therapeutic agents, allowing improved delivery of therapeutic agents to the central nervous system by passing the blood-brain-barrier.
  • Methods of and devices of the description may cause this same effect, but in a distinct manner transmit impulses to nerve fibers of up to fourteen nerve trunks, which cause or allow the impulse to spread to various centers of the brain and wake the brain to enhance memory, increase memory, and cure or curtail AD and other neurological diseases or one or more symptom thereof.
  • the electrical activity generated may be similar to electrical activity associated with biological release of a neurotransmitter such acetyl choline, generating electrical activity that is translated into various neurological activities including memory and recall.
  • Electrical synapsis is the term used to describe the reaction in which the membranes of the two neurons or cells touch and share proteins. This allows the action potential to pass directly from one neuronal cell membrane to the next. Our invention will enhance the mechanism of electrical synapse.
  • Action potentials occur in several types of animal cells. Such cells are called excitable cells; for example neurons, muscle cells, and endocrine cells, and some plant cells. In neurons, action potential plays a fundamental role in cell-to-cell communication. In muscle cells, for instance, an action potential is the first step in the chain of events leading to contraction. Action potentials in the neurons are known as “nerve impulses" or “spikes”, and the temporal sequence of action potentials generated by a neuron is called its “spike train”. A neuron that emits an action potential is said to "fire”.
  • Action potentials in neurons are generated by special types of voltage-gated ion channels embedded in a cell's plasma membrane (Barnett MW, Larkman PM (June 2007). "The action potential”. Pract Neurol 7 (3): 192-7). These channels shut when the membrane potential is near the resting potential of the cell, but they rapidly begin to open if the membrane potential increases to a precisely defined threshold value. When the channels open, they allow an inward flow of sodium ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane potential. This then causes more channels to open, producing a greater electric current, and so on. The process proceeds explosively until all of the available ion channels are open, resulting in a large upswing in the membrane potential.
  • One type is generated by voltage-gated sodium channels; sodium-based action potentials usually last for less than one millisecond.
  • the second type is generated by voltage-gated calcium channels; calcium-based action potentials may last for 100 milliseconds or longer.
  • slow calcium spikes provide the driving force for a long burst of rapidly emitted sodium spikes.
  • cardiac muscle cells on the other hand, an initial fast sodium spike provides a "primer" to provoke the rapid onset of a calcium spike, which then produces cardiac muscle contraction.
  • a cell membrane consists of a layer of lipid molecules with larger protein molecules embedded in it.
  • the lipid layer is highly resistant to movement of electrically charged ions, so it functions mainly as an insulator.
  • the large membrane-embedded protein molecules in contrast, provide channels through which ions can pass across the cell membrane, and some of the large molecules are capable of actively moving specific types of ions from one side of the membrane to the other. This is the basis of sodium and calcium pumps, which generate action potential to initiate cell activity and related function especially in the CNS neuronal complex as described in this invention.
  • sodium ion channels on the cell membrane open, allowing the entry of sodium ions into the cell. This event is followed by the opening of potassium ion channels that permit the exit of potassium ions from the cell.
  • the inward flow of sodium ions increases the concentration of positively charged cations in the cell and causes depolarization, where the potential of the cell is higher than the cell's resting potential.
  • the sodium channels close at the peak of the action potential, while potassium continues to leave the cell.
  • the efflux of potassium ions decreases the membrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassium current exceeds the sodium current and the voltage returns to its normal resting value, typically -70 mV.
  • the amplitude, duration, and shape of the action potential are determined largely by the properties of the excitable membrane and not the amplitude or duration of the stimulus.
  • the all-or-none property of the action potential sets it apart from graded potentials such as receptor potentials, electrotonic potentials, and synaptic potentials, which scale with the magnitude of the stimulus.
  • graded potentials such as receptor potentials, electrotonic potentials, and synaptic potentials, which scale with the magnitude of the stimulus.
  • a variety of action potential types exist in many cell types and cell compartments as determined by the types of voltage-gated channels, leak channels, channel distributions, ionic concentrations, membrane capacitance, temperature, and other factors.
  • the principal ions involved in an action potential are sodium and potassium cations; sodium ions enter the cell, and potassium ions leave, restoring equilibrium. Relatively few ions need to cross the membrane for the membrane voltage to change drastically. The ions exchanged during an action potential, therefore, make a negligible change in the interior and exterior ionic concentrations. The few ions that do cross are pumped out again by the continuous action of the sodium-potassium pump, which, with other ion transporters, maintains the normal ratio of ion concentrations across the membrane. Calcium cations and chloride anions are involved in a few types of action potentials, such as the cardiac action potential and the action potential in the single-cell alga Acetabularia, respectively.
  • action potentials are generated locally on patches of excitable membrane, the resulting currents can trigger action potentials on neighboring stretches of membrane, precipitating a domino-like propagation.
  • action potentials are generated anew along excitable stretches of membrane and propagate without decay.
  • Myelinated sections of axons are not excitable and do not produce action potentials and the signal is propagated passively as electrotonic potential.
  • Regularly spaced unmyelinated axons called the nodes of Ranvier, generate action potentials to boost the signal.
  • this type of signal propagation provides a favorable exchange of a signal velocity and axon diameter.
  • Depolarization of axon terminals in general, triggers the release of neurotransmitters into the synaptic cleft.
  • back propagating action potentials have been recorded in the dendrites of pyramidal neurons, which are ubiquitous - everywhere in the neocortex. These are thought to have a role in spike-timing-dependent plasticity.
  • the main excitable cell is the neuron, which also has the simplest mechanism for the action potential.
  • Neurons are electrically excitable cells composed, in general, of one or more dendrites, a single soma, a single axon and one or more axon terminals.
  • the dendrite is one of the two types of synapses, the other being the axon terminal boutons. Dendrites form protrusions in response to the axon terminal boutons. These protrusions or spines are designed to capture the
  • neurotransmitters released by the presynaptic neuron They have a high
  • concentration of ligand-activated channels It is, therefore, here where synapses from two neurons communicate with one another. These spines have a thin neck connecting a bulbous protrusion to the main dendrite. This ensures that changes occurring inside the spine are less likely to affect the neighboring spines.
  • the dendritic spine can, therefore, with rare exception, act as an independent unit.
  • the dendrites then connect onto the body of the neurons.
  • the neuron houses the nucleus, which acts as the regulator for the neuron.
  • voltage activated ion channels populate the surface of the soma, these channels help transmit the signals generated by the dendrites. Emerging out from the soma is the axon hillock.
  • This region is differentiated by having an incredibly high concentration of voltage-activated sodium channels. In general, it is considered a spike initiation zone for action potentials. Multiple signals generated at the spines and transmitted by the soma all converge here.
  • the present inventive device will initiate and activate the electrical signal and conductivity in these neuronal components, which are silenced in the neurons of Alzheimer's.
  • An axon is a thin tubular protrusion traveling away from the soma of a neuron.
  • the axons are insulated by a myelin sheath.
  • Myelin is composed of
  • buttons have voltage-activated calcium channels, which come into play when signaling other neurons.
  • Our invention of delivering the electrical impulses helps in activation of voltage activated ion channels.
  • the action potential generated at the axon hillock propagates as a wave along the axon.
  • the currents flowing inwards at a point on the axon during an action potential spread out along the axon, and depolarize the adjacent sections of its membrane. If sufficiently strong, this depolarization provokes a similar action potential at the neighboring membrane patches.
  • This basic mechanism was demonstrated by Alan Lloyd Hodgkin in 1937. This mechanism discovered by Hodgkin is one of the basis and foundation of our invention to treat Alzheimer's and other neurological - neurodegenerative diseases.
  • the Na and K ions play a major role in the production of electrical impulses in the neurons and nerve fibers.
  • the concentration of potassium ions inside a cell is ten times greater than the extracellular K+ concentration, and vice versa for sodium ions.
  • a special protein in the cell and nerve fiber membrane (the Na-K pump) actively transports K+ into the cell and Na+ out of the cell, using ATP as the source of energy in the resting axon membrane.
  • There is a selective permeability to K+ ions allowing the net efflux of a small number of K.+ ions and leaving the axoplasm electrically negative (polarized) while making the outside electrically positive. This accounts, for the most part, for the cell's "resting potential" which typically equals - 70 millivolts.
  • this absolute refractory period corresponds to the time required for the voltage-activated sodium channels to recover from inactivation, i.e., to return to their closed state.
  • voltage-activated potassium channels in neurons some of them inactivate fast (A-type currents) and some of them inactivate slowly or do not inactivate at all; this variability guarantees that there will be always an available source of current for repolarization, even if some of the potassium channels are inactivated because of preceding depolarization.
  • the action potential propagates from, the axon hillock towards the synaptic knobs (the axonal termini); propagation in the opposite direction— known as antidromic conduction— is very rare.
  • both halves of the axon are "fresh", i.e., unfired; then two action potentials will be generated, one traveling towards the axon hillock and the other traveling towards the synaptic knobs. This can happen with our device described here to activate the Alzheimer's disease affected neuronal complex.
  • Our invention activates the generation and propagation of action potential as described above and below without much participation of sodium, potassium, and calcium ion pumps, thus helping the neuronal action through axons and dendrites into the synapses and nerve cell itself, which translates into various functions of the brain including memory, recall, and cognition with augmentation effect on the neurotransmitters.
  • the generation of electrical impulses and propagation of these impulses is due to neurotransmitters' mediated electrical activity which must be in place in order to activate the nerve conduction, which is important for proper functioning of CNS and all the functions including motor, sensory, memory, cognition, and related functions.
  • the electrical generation takes place due to changes in the ionic concentration in the sodium and potassium at the cell membrane. If there is no generation of electrical impulses within the neurons and their processes, transmitted through the synapses, and conduction of these electrical impulses generated due to the activity of neurotransmitters such as acetylcholine which brings changes in the neuronal body, synapses, nerve fibers and terminals, the function of the CNS decreases is not carried out.
  • the life and functioning of the brain is evaluated based on the electrical activity of the brain.
  • the person In modern medicine, the person is pronounced dead if there is no electrical activity of the brain-brain stem based on electroencephalogram (EEG).
  • EEG electroencephalogram
  • This tells us how important it is to maintain the electrical activity of the brain for proper functioning of all the neuron-related activities all the time including memory and cognition as well as various CNS initiated motor, sensory, and autonomic nerve functions.
  • This electrical potential generation and its propagation is the lifeline of the brain functioning in totality.
  • the electrical activity is reduced, not generated, defective, or deficient. It is said to be both cause and effect due to synaptic and neuronal decline, associated with reduced acetylcholine neurotransmitter, which is needed to generate and transfer electrical activity of the CNS and make changes to store and retrieve the old and new memories.
  • the present inventive method activates the electrical signals, augments and amplifies the effects without the help of the neurotransmitters, and/or helps it even when the neurotransmitters are very low in concentrations in the CNS, to restore the normal function to the neurons and their synapses.
  • the invention elaborated in this application will curtail the diseases such as Alzheimer's, senile dementia and others neurodegenerative afflictions, thus restoring the memory and other functions of the CNS.
  • All cells in the body are electrically polarized; in other words, they maintain a voltage difference across the cell's plasma membrane, known as the membrane potential.
  • This electrical polarization results from a complex interplay between protein structures embedded in the membrane, called ion pumps and ion channels.
  • the types of ion channels in the membrane usually vary across different parts of the cell, giving the dendrites, axon, and cell body different electrical properties.
  • some parts of the membrane of a neuron may be excitable (capable of generating action potentials), whereas others are not.
  • the most excitable part of a neuron is usually the axon hillock (the point where the axon leaves the cell body), but the axon and the rest of neuronal cell body are also excitable.
  • Each excitable piece of neuronal membrane has two important levels of membrane potential: the resting potential, which is the value the membrane potential maintains as long as nothing perturbs the cell, and a higher value called the threshold potential.
  • the resting potential is around -70 mV and the threshold potential is around -55 mV.
  • Synaptic inputs to a neuron cause the membrane to depolarize or hyperpolarize; that is, they cause the membrane potential to rise or fall.
  • Action potential is triggered when enough depolarization accumulates to bring the membrane potential up to threshold.
  • the membrane potential When an action potential is triggered, the membrane potential abruptly shoots upward; often reaching as high as +100 mV, then equally abruptly shoots back downward, often ending below the resting level, where it remains for some period.
  • the shape of the action potential is stereotyped; that is, the rise and fall usually have approximately the same amplitude and time course for all action potentials in a given cell. In most neurons, the entire process takes place in less than a thousandth of a second. Many types of neurons emit action potentials constantly at rates of up to 10-100 per second; some types, however, are much quieter, and may go for minutes or longer without emitting any action potentials. Our invention helps the neurons to emit action potential to improve the sensory and motor function of the CNS especially related to memory, recall, and cognition.
  • the problem in the treatment of CNS diseases including Alzheimer's is that 98% of therapeutic agents are not transported to, delivered to, or reach the site of pathology in the brain.
  • the BBB is responsible for creating such a barrier to the delivery of therapeutic agents to the brain and spinal cord. This is how the brain is protected from the extraneous assault from various substances and cells that travel all over the body in the blood.
  • the BBB is located in 400 miles of capillaries within the brain and has a unique histological make up compared to the other capillaries in other regions of the body.
  • the endothelial cells of the blood vessels (BV) of the CNS differ from the peripheral capillary endothelial cells due to many structural differences such as:
  • the endothelial cells are joined by tight junctions, which block the protein molecule movement from within. In addition, they block the hydrophilic transfer of substances from the capillary to the CNS.
  • These tight endothelium junctions in the BBB are 100 times tighter than similar junctions of other systematic capillary endothelium (Butte AM, Jones HC, Abbot NJ. Electrical resistance across the blood-brain barrier in anaesthetized rats; a development study. J Physiol 1990; 429:47-62.), thus creating a daunting barrier, which blocks almost 98% of the therapeutic agents delivered to the systemic circulation reaching the neuropile and neurons of the CNS. That is why the olfactory nerve mucosal delivery (ORE) of therapeutic agents is the most important method of bypassing these tight junctions of the BBB, delivering the therapeutic agents directly to the CNS for the treatment of Alzheimer's disease and other neurodegenerative diseases.
  • ORE olfactory nerve mucosal delivery
  • the endothelial cells contain a specific receptor transport system for given
  • Astrocytes foot process covers 95% of the endothelium outer surface.
  • the cerebral vascular endothelial cell possesses a transcellular lipophilic pathway, allowing diffusion of small lipophilic compounds such as insulin, transferrin, glucose, purines, and amino acids.
  • the BBB prevents passage of ionized water-soluble compounds with a molecular weight greater than 180 Daltons.
  • Many new neuro therapeutic agents have been discovered, but because of a lack of suitable strategies for drug delivery across the BBB, these agents are fruitless and only effective if methods to break the BBB are discovered.
  • the concentration gradients also play a role in transport of therapeutic agents across the systemic BV, but make hardly any such effect across BBB blood vessels of the CNS.
  • the brain blood vessels form a daunting 400 miles of BBB capillaries within the brain.
  • the brain capillaries prevent transport of most of the therapeutic agents (98%) from inside the BV; they also prevent and / or inhibit clearance of neurotoxin compounds such as beta amyloid and their precursor in Alzheimer's; reactive oxygen species, toxic metabolites and their derivatives from the CNS entering the systemic circulation for clearance and to provide homeostatic neuropil milieu functional.
  • the brain keeps on accumulating toxins with no path or passage to exit from the brain contributing to the CNS afflictions such as beta amyloid in Alzheimer's.
  • Alzheimer's disease Even today, there is no cure for Alzheimer's disease; the cause and progression of Alzheimer's disease is not well understood and the disease progresses unabated. So is also the case with senile brain atrophy. Symptoms can include confusion, irritability, and aggression, mood swings, trouble with language, and long-term memory loss. As the sufferer declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death in about 7 years (Average lifespan after diagnosis). The disease is associated with plaques and tangles in the brain (Tiraboschi P, Hansen LA, Thai LJ, Corey-Bloom J. The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology. 2004;62(11): 1984.
  • Bexarotene (Targretin®), a vitamin A derivative, used in skin for cutaneous T cell lymphomas, off label used for lung cancer, breast cancer, and Kaposi's sarcoma show promising results in mice studies.
  • Bexarotene is a member of a subclass of compounds called retinoids. Certain retinoids are believed to selectively activate retinoid X receptors (RXRs).
  • RXRs retinoid X receptors
  • a chemical name for bexarotene is 4-[I-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2- naphthalenyl) ethenyl] benzoic acid.
  • mice studies showed that a single dose lowered the most toxic form of the amyloid beta peptide by 25 percent within six hours, an effect that lasted for up to three days in experimental mice according to Dr. Paige Cramer of Case Western Reserve University School of Medicine. Bexarotene quickly and dramatically improved brain function and social ability and restored the sense of smell in mice bred with a form of Alzheimer's disease.
  • One example of the improved behaviors involved the typical nesting instinct of the mice.
  • Alzheimer' s-diseased mice encountered tissue paper material suited for nesting, they did nothing to create a space to nest. This reaction demonstrated that they had lost the ability to associate the tissue paper with the opportunity to nest. Just 72 hours after the bexarotene treatment, however, the mice began to use the paper to make nests. Administration of the drug also improved the ability of the mice to sense and respond to odors.
  • the plaques in the CNS of Alzheimer's are compacted aggregates of amyloid that form in the brain and are the pathological hallmark of Alzheimer's disease. It appears that the bexarotene reprogrammed the brain's immune cells to phagocytose the amyloid deposits they encountered. This observation demonstrated that the drug addresses the amount of both soluble and deposited forms of amyloid beta within the brain and reverses the pathological features of the disease.
  • Bexarotene does not act directly on the ⁇ amyloid; instead, it activates retinoid receptors on brain cells that increase production of a fat-protein complex, apolipoprotein E, that helps to clear excess ⁇ amyloid in the fluid-filled space (neuropile, subarachnoid space, cerebrospinal fluid, Virchow-Robin space) between neurons.
  • apolipoprotein E retinoid receptors on brain cells that increase production of a fat-protein complex, apolipoprotein E, that helps to clear excess ⁇ amyloid in the fluid-filled space (neuropile, subarachnoid space, cerebrospinal fluid, Virchow-Robin space) between neurons.
  • Dr. Landreth and his colleagues at Case Western Reserve University at Cleveland, Ohio chose to explore the effectiveness of bexarotene for increasing ApoE expression.
  • the elevation of brain ApoE levels speeds the clearance of amyloid beta from the brain.
  • Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced in the CNS.
  • RXR retinoid X receptors
  • the invention described here can activate retinoid receptors on brain cells that increase production of a fat-protein complex, apolipoprotein E that helps to clear excess ⁇ amyloid to curtail Alzheimer's disease. Bexarotene also appears to enhance another cleanup process called phagocytosis, in which the brain immune cells engulf amyloid and move it away from the neuropile (Cramer P E, et al. (9 February 2012). "ApoE- Directed Therapeutics Rapidly Clear ⁇ - Amyloid and Reverse Deficits in AD Mouse Models".
  • Brain insulin receptors are heavily and thickly localized in the hippocampus, the entorhinal cortex (olfactory bulb connected), and the frontal cortex. They are found primarily in synapses, where insulin signaling contributes to synaptogenesis and synaptic remodeling (Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58 (5):708-719. Zhao WQ, Townsend M.
  • Insulin resistance, and myloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta. 2009;1792(5):482-496.). Insulin also modulates glucose utilization in the hippocampus and other brain regions and facilitates memory at optimal levels in normal metabolism. The importance of insulin in normal brain function is underscored by evidence that insulin
  • AD Alzheimer's disease
  • olfactory nerve delivery through olfactory mucosa resulted in rapid recovery of cognition, and many of the depressed patients became normal.
  • Insulin levels and insulin activity in the central nervous system are reduced in AD.
  • Insulin has a close relationship with the ⁇ -amyloid peptide, a toxic peptide produced by endoproteolytic cleavage of the amyloid precursor protein.
  • Insoluble ⁇ deposits in the brain's parenchyma and vasculature in Alzheimer's is an important pathology found in Alzheimer's disease.
  • Soluble ⁇ species particularly oligomers of the 42 amino acid species ( ⁇ 42) also have synaptotoxic effects (Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res. 2008;192 (1):106-113.) ⁇ We believe that bexarotene acts by removing the soluble ⁇ species, particularly oligomers of the 42 amino acid species ( ⁇ 42), which has synaptotoxic effects and improves the memory almost within hours after the administration of bexarotene.
  • Insulin will augment and amplify the effects of bexarotene and at the same time reduce the excitotoxic effects of glutamate, make easier to synthesize glutathione, which is neuroprotective, and facilitate to remove the effects of ROS. Its effects can be further augmented by insulin administered to olfactory mucosa and olfactory nerves. Insulin modulates the levels of ⁇ and protects against the detrimental effects of ⁇ oligomers on synapses. Thus, reduced levels of insulin and of insulin activity contribute to a number of pathological processes that characterize Alzheimer's disease. Restoring insulin to normal levels in the brain may therefore provide therapeutic benefit to adults with Alzheimer's disease and other degenerative brain afflictions.
  • intranasal administration of insulin provides rapid delivery of insulin to the central nervous system via bulk flow along olfactory and trigeminal subperineural epithelial space, to the SAS of the CNS, CSF and is then distributed to the rest of the brain (Shantha T.R. and Yasuo Nakajima. Histological and Histochemical Studies on the Rhesus Monkey (Macaca Mulatta) Olfactory Mucosa. Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia: Z. Zellforsch. 103, 291—319 (1970).
  • Shantha T.R. Peri-vascular (Virchow - Robin) space in the peripheral nerves and its role in spread of local anesthetics, ASRA Congress at Tampa, Regional Anesthesia 17 (March- April, 1992).
  • Shantha T.R. and Bourne G.H. The "Perineural Epithelium”: A new concept. Its role in the integrity of the peripheral nervous system. In Structure and Function of Nervous Tissues. Volume I. pp 379-458. (GH Bourne, Ed.). Academic Press, New York. 1969.
  • intranasal insulin increases insulin levels in cerebrospinal fluid (CSF) within a similar period and acutely enhances memory. Furthermore, a 3- week trial of daily administration of intranasal insulin improved delayed story recall and caregiver-rated functional status in a small sample of adults with AD and in adults with amnestic mild cognitive impairment (aMCI), a condition thought to represent prodromal AD in most cases. Insulin improves memory in normal adults and patients with Alzheimer's disease without altering blood glucose. Energy metabolism in the CNS is dependent upon glucose uptake and is regulated by insulin in key brain regions. It has long been known that glucose uptake and utilization are deficient in patients with Alzheimer's disease.
  • CSF cerebrospinal fluid
  • aMCI amnestic mild cognitive impairment
  • Alzheimer's is a neurodegenerative dementia related to aging. It is characterized by the accumulation of neurofibrillary tangles and neuritic plaques (tau — *— protein) in the brain affecting especially the degeneration of neurons in the olfactory bulb and its connected brain structures - the hippo campal formation, amygdaloid nuclei, nucleus basalis of Meynert, locus ceruleus, and the brainstem raphe nuclei, all of which project to the olfactory bulb (Figs. 14, 15). These degenerative alterations result in the loss of memory and cognitive function.
  • Alzheimer's is the most common form of dementia that demonstrates hardly any or no electrical pulse or action potential generation in the afflicted neurons due to low or the lack of neurotransmitter acetylcholine, which is associated with death and degeneration of neurons. Alzheimer's is. a complex, slow evolving disease, and there is no cure. It worsens as it progresses with advancing age, and eventually leads to death in a vegetative state.
  • Alzheimer's The incidences of Alzheimer's increase with age. In the United States, the prevalence of Alzheimer's was estimated to be 1.6% in 2000 both overall and in the 65-74 age group, with the rate increasing to 19% in the 75-84 group and to 42% in the greater than 84 age group (Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA (2003). "Alzheimer disease in the US population: prevalence estimates using the 2000 census”. Arch. Neurol. 60 (8): 11 19-22), Alzheimer's is found in about 10% of the population over the age of 65 and 47% of the population over the age of 85 affecting about 4 million people in the USA and 20 million people worldwide (Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of
  • the World Health Organization estimated that in 2005, 0.379% of people worldwide had dementia, and that the prevalence would increase to 0.441%» in 2015 and to 0.556% in 2030.
  • Another study estimated that in 2006, 0.40% of the world population (range 0.17-0.89%; absolute number 26.6 million, range 11.4-59.4 million) were afflicted by Alzheimer's, and that the prevalence rate would triple and the absolute number would quadruple by 2050 and is expected to affect 1 in 85 people worldwide by then.
  • the disease affects not only the person, but also the person's entire family, care givers and proves to be very burdensome financially and to the health care system.
  • the list of diseases treated using this inventive method described herein with or without insulin are endless but the most important ones include, among others, neurological conditions associated with memory loss, cognitive impairment and dementia, including Alzheimer's, Parkinson's-type dementia, Huntington's-type dementia, Pick's-type dementia, Lewy body disease, MS, ALS, pain, PTSD, cerebral palsy, autism and those listed and unlisted.
  • This electrical activation of the neuropil in the brain due to neurotransmitter-mediated activity is intricately involved in memory, attention, learning, cognitive processes and including various autonomic, sensory and motor function of the CNS.
  • this present invention augments, and amplifies, the effects on existing
  • methods of the invention can be therapeutic methods of delivering the electrical impulses without delivery of any therapeutic device (active agent) other than saline or non-metabolically active agent to a location of the nasal cavity.
  • embodiments of methods can involve delivery of electrical impulses that are therapeutic in themselves, without the need for metabolically active agents such as a
  • devices as described can be useful for delivery of the electrical impulses but need not be capable of delivering a therapeutic agent to a location of the nasal region such as the olfactory mucosa, the sphenoid sinus, both of these locations, or other locations of the sinus cavity, with the insertion end of the device being located in a trans-nasal location.
  • An apparatus that need not deliver a therapeutic fluid does not require and may exclude one or more ejection ports such as an opening or orifice located at a surface of the device shaft at the insertion end at the insertion end, in fluid communication with the proximal end, and through which fluid can be delivered externally of the device shaft to a region of the nasal cavity such as at the olfactory mucosa or the sphenoid sinus, with the insertion end located at the trans-nasal location.
  • Exemplary methods do not require and may exclude delivery of a therapeutic agent (e.g., any described herein for treatment of Alzheimer's Disease or another condition) to a region of a nasal cavity, e.g., olfactory mucosa or sphenoid sinus.
  • Alzheimer's is the most common form of senile and pre-senile dementia in the world. It is known clinically as the progressive loss of memory, intellectual function, and disturbances in speech (Merritt, 1979, A Textbook of Neurology, 6th edition, pp. 484-489, Lea & Febiger, Philadelphia). Alzheimer's disease starts with inappropriate behavior, gullible statements, irritability, and a tendency towards grandiosity, euphoria, and deteriorating performance at work.
  • Alzheimer's disease for example, involve degeneration of cholinergic neurons (nerves activated by acetylcholine or that release it) in the subcortical regions and of neuronal pathways that project from the basal forebrain, particularly Meynert's nucleus basalis to the cerebral cortex and hippocampus (Robert P H et al. 1999. "Cholinergic Hypothesis and Alzheimer's: The Place of Donepezil (Aricept), " Encephale 5:23-5 and 28-9).
  • Alzheimer's is characterized by the accumulation of insoluble, 10 nm filaments containing ⁇ amyloid ( ⁇ ) peptides, localized in the extracellular space of the cerebral cortex and vascular walls. There is dense accumulation of neuro fibrillary tangles of the tau ( ⁇ ) protein observed intracellular in this dementia.
  • the chief constituent of the cores is a peptide of 39 to 42 amino acids called the amyloid ⁇ protein, or ⁇ .
  • the ⁇ protein is produced by the intracellular processing of its precursor (APP), the amyloid deposits forming the core of the plaques are extracellular. Both plaques and tangles are found in the same brain regions affected by nerve cell and synaptic loss. It is a known fact that the Alzheimer's is associated with degeneration of cholinergic neurons, in the basal forebrain, which play a primary role in memory and cognitive functions; decreased cholinergic function may be a fundamental cause of cognitive decline seen in Alzheimer's patients. This invention will activate the electrical activity and will restore the memory to functional level, acting at the basal forebrain, and at the same time restore the acetylcholine function.
  • Neuro fibrillary tangles are found within the cell bodies of dying neurons as well as some dystrophic neurites in the halo surrounding neuritic plaques of the Alzheimer's afflicted brain.
  • the tangles are composed of paired-helical filaments whose biochemical analyses revealed that the main component is composed of hyper-phosphorylated form of the microtubule associated protein Tau (* ).
  • Alzheimer's disease is typified by the following neuro pathological features, which display the huge loss of neurons, and synapses in the brain regions involved in higher cognitive functions (association cortex, hippocampus, and amygdala).
  • Cholinergic neurons are particularly affected.
  • the Alzheimer's plaques in the neuropil of the brain are composed of a core of amyloid material surrounded by a halo of dystrophic neurites, reactive astrocytes, and microglial cells. Even more, diminished cholinergic function may be an underlying cause of cognitive decline seen in Alzheimer's patients.
  • No acetylcholine means no electrical pulse generation, with the loss of neuronal function, and loss of memory. This invention will remedy this deficiency.
  • Dementia testing is made by early measurement of cognitive testing.
  • Standardized testing in humans can be performed using the Reye Auditory Verbal Learning Test, the Mini-Mental State Exam (MMSE), the Schier Logical Memory Test, or the Selective Reminding Test, among others.
  • the cognitive subscale is also a major indication in the Alzheimer's Assessment Scale (ADAS-cog), and simultaneously assesses short-term memory, orientation in place and time, attention span, verbal ability and praxis.
  • ADAS-cog testing is done for diagnosis of the condition and is used to evaluate success in treatment. Testing higher scores indicates cognitive impairment. Reduced scores, following treatment with tacrine, donepezil and the longer-acting rivastigmine are noted.
  • BBB blood brain barrier
  • This invention describes transmitting the electrical nerve impulses through nerves that can include one or more of the olfactory nerves, sphenopalatine ganglion (SPG) nerve complex, trigeminal nerves, five cranial nerves in the cavernous sinus, pituitary gland to the hypothalamo - hypophysial system complex, cerebral cortex, brain stem, and cerebellum. Therefore, it improves nerve conduction, restores lost cerebral function, delays, and curtails Alzheimer's and other neurological diseases by dilating the cerebral blood vessels to deliver the therapeutic agents to the neuropil.
  • SPG sphenopalatine ganglion
  • This invention of electrical stimulation application can be adopted to deliver electrical current to create Iontophoresis and electroporation effect on the olfactory mucosa and lining of the sphenoid sinus. This enhances the permeability, uptake, and transport of therapeutic agents from the ORE and sphenoid sinus bypassing the BBB, by creating elecroporation and iontophoresis effects of olfactory mucosa and sphenoid sinus lining.
  • US 7,640,062 B2 (the entirety of which is incorporated herein by reference) describes the stimulation of the parasympathetic sphenopalatine ganglion to dilate the cerebral blood vessels to break the BBB and deliver therapeutic agents across the BBB.
  • the ⁇ 62 patent describes complex invasive surgical procedures to place a stimulator on the anatomical location of the sphenopalatine ganglion to archive the results.
  • the ⁇ 62 patent does not describe stimulation of various complex nerve structure and blood vessels of sphenoid sinus, pituitary gland or olfactory nerves that are easily accessible for widespread stimulation of the brain as described in the present inventive methods.
  • VNS vagus nerve stimulation
  • U.S. Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders by left vagus nerve stimulation, at a location on the neck by first implanting an electrode there, then connecting the electrode to an electrical stimulator.
  • US 2011/10152967 Al discloses method and devices for the non-invasive treatment of neurodegenerative diseases through delivery of energy to target nervous tissue, particularly the vagus nerve.
  • the devices used is a magnetic stimulator having coils with toroidal windings, which are in contact with an electrically conducting medium that is adapted to conform to the contour of a target body surface of a patient. These coils induce an electric current and/or an electric field within the patient, thereby stimulating nerve fibers within the patient.
  • the stimulation brings about reduction of neuroinflammation in patients suffering from conditions comprising Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, postoperative cognitive dysfunction and postoperative delirium. This is also one of the mechanisms the inventive device described here in uses to curtail Alzheimer's bringing about the reduction of neuroinflammation in the afflicted brain.
  • the present invention described here is more effective in bringing down the neuroinflammation, because the electrical impulses are transmitted directly to many centers of the brain by thousands of nerve fibers projecting to periphery.
  • This reduction in inflammation is effected by enhancing the anti-inflammatory capability of cytokines such as TGF-beta, wherein a retinoid or component of the retinoic acid signaling system provide an antiinflammatory predisposition, by enhancing anti-inflammatory activity of a neurotrophic factor such as NGF, GDNF, BDNF, or MANF, and/or by inhibiting the activity of pro-inflammatory cytokines such as TNF -alpha.
  • a more efficient approach to selecting stimulation parameters might be to select a stimulation waveform that mimics electrical activity in the region of the brain that one is attempting to stimulate, in an effort to entrain the naturally occurring electrical waveform, as suggested in U.S. Pat. No. 6,234,953, and
  • Non-invasive procedures avoid damage to tissues that can result in bleeding, infection, skin or internal organ injury, blood vessel injury, and vein or lung blood clotting and are mostly painless. Less training may be required for use of non-invasive procedures by medical professionals. The procedures may be suitable for use by the patient or family members or caregiver at home or by a medical clinic trained technician. The cost of non-invasive procedures is considerably less compared to invasive procedures.
  • this inventive device has application in the treatment of Alzheimer's disease.
  • CNS affliction where it can be applied are as follows: Autism, cerebral palsy, chronic fatigue syndrome, PTSD, senility, hypo pituitary and hyper pituitary function, intractable pain including thalamic pain, various kinds of headaches, Lewy body dementia, Parkinson's disease, multiple sclerosis, ALS, spastic paraplegia, Down's Syndrome, psychological illnesses, addiction, phantom limb syndromes, reflex sympathetic dystrophy, Vascular dementias (or multi-infarct dementia), Frontal lobe dementias (such as Pick's disease) , Subcortical dementias (such as Huntington, or progressive supranuclear palsy), Focal cortical atrophy syndromes (such as primary aphasia), Meta
  • a pharmaceutic agent or drugs administered along with neural stimulation as described herein can be selected based on the condition, e.g., disease, being treated.
  • examples include the following: the chemotherapeutics, insulin, IGF-1; levodopa (5-10% crosses BBB) combined with a dopa decarboxylase inhibitor or COMT inhibitor, dopamine agonists and MAO-B inhibitors (selegiline and rasagiline), dopamine agonists (include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride), non-steroidal anti-inflammatory drugs, acetyl cholinesterase inhibitors such as tacrine, donepezil and the longer- acting rivastigmine; antibiotics, 2,4-dinitrophenol, glutamate receptor antagonist, glutathione, NMDA-receptor blocker such as ketamine, ⁇ amyloid inhibitor,
  • This invention described herein restores and facilitates to overcome a number of obstacles posed by the CNS for the treatment of Alzheimer's;
  • activating the inactive neurons and activating the acetylcholine and their function to conduct nerve impulses that have become silent due to loss of acetylcholine neurotransmitter with abnormal accumulation of neurofibrillary tangles (amyloid ( ⁇ ) deposits) and neuritic plaques (tau -i - protein) in the neurons of the CNS is the one of the fundamental principle of this invention.
  • olfactory mucosa and sphenoid sinus lining are permeable to therapeutic agents by Iontophoresis and electroporation and transport the therapeutic agents to CNS by passing the BBB to deliver them to the site of pathology.
  • the therapeutic agents we have selected are bexarotene, insulin, acetyl-cholin-esterase inhibitors, and ketamine delivered through the olfactory mucosa.
  • the present invention disclosure involves a medical device and medical procedures that stimulate nerves by transmitting eaergy to adjacent nerves to be transmitted to the central nervous system non-invasively to treat Alzheimer's and other neurodegenerative diseases.
  • This medical procedure is defined as being noninvasive when no break in the skin (or other surface of the body, such as a wound bed) is created through use of the method, and when there is no contact with an internal body cavity beyond a body orifice (e.g., Mouth, anus, external auditory meatus of the ear, eyes, and the nose).
  • the invasive procedures including minimally invasive procedures) procedures do involve inserting a substance or device into, through the skin, or into an internal body cavity beyond a body orifice.
  • Non-invasive medical methods and devices relative to comparable invasive procedures described in this invention are as follows. 1.
  • the patient may be more psychologically complaint to use the procedure that is noninvasive and may therefore be more cooperative, ensuing in a better outcome. 2.
  • Non-invasive procedures of inserting this device avoid damage to tissue it comes in contact such as bleeding, infection, skin or internal organ injury, blood vessel injury, and vein or lung blood clotting.
  • Non-invasive procedures of inserting this device are almost painless or minimally painful.
  • the inventive device described herein may be positioned without the need for local or general anesthesia. 5. Less training may be required for use of this non-invasive device by medical professionals. 6.
  • This device may be continued to be used by the patient or family members at home with brief training. 7.
  • the cost of non-invasive device and procedures is relatively less compared to invasive procedures. 8.
  • This inventive device can be used as therapeutic, prophylactic, and diagnostic objectives in the management of
  • Alzheimer's disease Alzheimer's disease (Alzheimer's- AD) and other neurodegenerative diseases of the CNS. 9.
  • This device can be easily mass-produced using non-reacting, non-allergic or hypo allergic synthetic, semi synthetic composite material.
  • the present invention discloses methods and devices for the non-invasive delivery of electrical impulses for the treatment of neurodegenerative conditions such as Alzheimer's disease. It makes use of an energy source that transmits energy non-invasively to nervous tissue.
  • the devices can transmit energy to, or in close proximity to the CNS of the patient, in order to stimulate, block, and/or modulate electrophysiological signals in the CNS involved in Alzheimer's disease.
  • the neurodegenerative diseases that can be treated with the present invention include Alzheimer's disease, Parkinson's disease, multiple sclerosis, AIDS dementia complex, Creutzfeldt- Jakob disease , Huntington disease, Tay- Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, Vascular dementia,
  • ALS neurodegenerative diseases
  • cytokines that are small signaling proteins or peptide molecules that are secreted by glial cells of the CNS, by numerous types of immune system cells.
  • NGF Nerve growth factors
  • bFGF fibroblast growth factor
  • CNTF glial-derived neurotrophic factor
  • PEDF pigment epithelium-derived factor
  • GDNF glial-derived neurotrophic factor
  • BDNF brain-derived neurotrophic factor
  • erythropoietin's insulin, IGF- 1, platelet derived growth factor (PDGF)
  • PDGF platelet derived growth factor
  • Alzheimer's and other neurodegenerative diseases are associated with Alzheimer's and other neurodegenerative diseases.
  • the apparatus consists of an insertion body having a flexible outer surface adapted for insertion into the sphenoid sinus.
  • the insertion body is constructed of a flexible material, which contracts and conforms to the interior surface of the sphenoid sinus.
  • the insertion body is an inflatable outer membrane or balloon. This balloon attached to flexible tubing through which air or fluid can be pumped to inflate the balloon to position the balloon against the surface of the sphenoid sinus.
  • the inflatable balloon is inserted in the uninflated state into the hollow sphenoid sinus through the sphenoid foramina, which communicates with the nose.
  • the balloon is then inflated with liquid or air under slight pressure.
  • the liquid may be desirable to cool the liquid depending on the purpose for which the device is being used (e.g., to lower the activity of the hyperactive pituitary gland).
  • the device is provided with an electrical impulse transmitter on the catheter as it passes to the sphenoid sinus to stimulate the olfactory bulb and its cortical and subcortical connections in treating Alzheimer's and other neurodegenerative diseases.
  • the device is provided with electrical impulse transmitter on the catheter as it passes to the sphenoid sinus to stimulate the sphenopalatine ganglion.
  • Electrical stimulator wires are placed along the outer surface of the inflatable balloon for stimulating the pituitary gland and other nerve structures surrounding the sphenoid sinus in the cavernous sinus.
  • Temperature sensors are placed on the outer surface of the balloon to determine the temperature, which will approximate the temperature of the surface of the sphenoid sinus.
  • the interior shape of the balloon can be examined by using a fiber optic connection.
  • a fiber optic connection By visual inspection through the fiber optic connection, the
  • approximate size and shape of the sphenoid sinus can be determined and whether the balloon is filling that space or not to transmit the electrical impulses through the sidewalls and the roof of the sinus.
  • Means are provided for the quick detachment of the balloon from the rest of the apparatus.
  • the balloon is left in the sphenoid sinus cavity and its activities controlled by a controller, outside the body through radio transmission, to a receiver located in the balloon.
  • the battery-powered receiver then directs that current to be provided to electrical stimulators on the outside of the balloon or to heating elements inside the balloon to heat the fluid to a desired temperature.
  • This device will allow full mobility by the patient while being stimulated.
  • the apparatus and method of this invention is useful in the treatment of acute and chronic pain of headaches besides treating Alzheimer's and other neurological diseases. It also stimulates the structures surrounding the sphenoid sinus, and particularly the pituitary gland, which may be useful in treating various diseases that arise from the central and peripheral systems.
  • a fluid able to be heated or cooled can be pumped into the balloon to enhance the output or decrease the output of pituitary hormones including growth hormone from the pituitary gland.
  • Thermocouples applied at the tip of the catheter inside the balloon are inserted into the sphenoid sinus. They are connected to the N-doped and P-doped legs of the semiconductor material which when connected to the direct current can heat or cool the thermocouples depending on the direction of current flow.
  • This heating and cooling is called the Peltier effect and was discovered in 1831 by a Swiss Engineer.
  • the same principle is used in the heat pump. Devices embodying the Peltier effect are currently being used to cool and heat the tissue and fluids in the body. Instead of using the heating or cooling circulating pump to heat or cool the fluid inside the inflated balloon as desired to treat various conditions and to increase or decrease the pituitary function. In some applications, it is desirable simply to use the inflated balloon with its pressure and stimulating the sphenoid sinus surrounding structures with electrical conductive wires.
  • a catheter in this invention can be attached to the balloon through which drugs may be infused into the sphenoid sinus for absorption by the central nervous system directly across the sphenoid bone and its perforating blood vessels around the cavernous sinus.
  • an electrical stimulator drives electrical pulses or current into the olfactory mucosal nerves, sphenopalatine ganglion, trigeminal nerves, cranial nerves III, IV, V, VI, pituitary gland with hypothalamo hypophysial tracts and into related neuro anatomical structures including neural tracts originating from these structures.
  • the stimulator drives the current in order to control and/or modify these structures to induce changes in nerve conductivity within the neuropile and increase cerebral blood flow with more permeability for circulating therapeutic agents by modulating permeability of the BBB.
  • This invention is used in many medical applications by way of illustration and not with any limitation are as follows.
  • the list of diseases that be treated by using this electrical simulator invention with or without adjuvant therapeutic agents , as well as other pharmaceutical, biochemical, nutraceuticals, and biological agents or compounds are many. They are: Alzheimer Disease, Arachnoiditis, Autism, Brain Ischemia, CNS Infections, Cerebral Palsy, senile dementias, ALS,
  • CBGD Corticobasai Ganglionic Degeneration
  • CBGD Corticobasai Ganglionic Degeneration
  • Creutzfeldt- Jakob Syndrome Dandy- Walker Syndrome
  • Dementia Encephalitis
  • Encephalomyelitis Epilepsy
  • Essential Tremor Friedreich Ataxia
  • Huntington Disease Hydrocephalus
  • Hypoxia Brain damage Lewy Body Disease
  • Myelitis Olivopontocerebellar Atrophies
  • PTSD traumatic injury to the brain -blunt or otherwise, mental illnesses
  • Pantothenate Kinase Associated Neurodegeneration Parkinson Disease, Parkinsonian Disorders, Postpoliomyelitis Syndrome, Prion Diseases, Pseudotumor Cerebri, Shy-Drager Syndrome, Spinal Cord Diseases, Stroke, Thalamic Diseases, Tic Disorders, Truett Syndrome, Uveomeningoencephalitic Syndrome, psychological disorders, addictions, in the treatment of cerebrovascular disorders such as stroke, PTSD
  • stimulation of the olfactory mucosal nerves, sphenopalatine ganglion, trigeminal nerves, pituitary gland with hypothalamo hypophysial region, thalamus complex, brain stem and cerebellum is used. It is to be understood to alternatively or additionally to include stimulation of the complex afferent and efferent nerve connections of the sphenopalatine ganglion, olfactory bulb, pituitary gland complex, five cranial nerves, and both afferent and efferent nerve tracts including autonomic nervous system components.
  • the parameters of stimulation is described herein by way of illustration and not limitation, and that the scope of the present invention includes other possibilities, which would be obvious to someone of ordinary skill in the art who has read the present patent application.
  • the parameters of stimulation include substantially any form of the current application to designated tissue, even when the current application is configured to block or inhibit the activity of hyperactive nerves.
  • Such energy includes, but is not limited to, direct, or induced electromagnetic energy, RF transmission, ultrasonic transmission, optical power, and low power laser energy delivered through a fiber optic transmission cable.
  • hippocampus and amygdaloid nucleus, basal ganglion, cerebellum, and brain stem nuclei in the brain above and behind the nose. It is important to note the activation of these neuronal structures by electrical impulses causes restoration and
  • Circle Willis BV stimulation results in the opening of pores in the BBB vessel walls due to the dilatation effect of parasympathetic innervations, causing plasma proteins and therapeutic agents to extravasate which were unable to break the BBB thus allowing the large therapeutic molecules from within the blood vessels to the cerebral tissue to be substantially increased.
  • this invention acts as a neurological drug delivery facilitator, without altering the molecular weight.
  • the added benefit of the use of this invention is due to the vasodilatation resultants improvement in oxygen supply to the CNS tissues.
  • electrical "stimulation,” as provided by preferred embodiments of the present invention, is meant to include substantially any form of current application (galvanic) to designated tissue, even when the current configured to activate or to block or inhibit the activity of nerves. A voltage drop between two electrodes creates an electrical field. It is another object of the present invention, a method for treating
  • Alzheimer's and other neurodegenerative diseases to cause an increase in clearance of an Alzheimer's related constituent CNS of the subject.
  • This helps to remove from the neuropil of the subject to a systemic blood circulation of the subject, so as to treat the Alzheimer's or other neurodegenerative disease by electrical stimulation of one or more of the olfactory mucosal nerves, cranial nerves, sphenopalatine ganglion, trigeminal nerves, pituitary gland with hypothalamo hypophysial system, resulting and due to dilatation of BBB blood vessels.
  • Embodiments of devices can include an electrical delivery control unit adapted to drive one or more electrodes to apply a current or other electrical signal to a site, e.g., one or more nerve as described herein, capable of stimulating the CNS of the patient.
  • the electrical conduction wires and one or more (e.g., proximal and distal) electrodes are connected to the electrical output manipulator.
  • the apparatus has a catheter with balloons, which includes conductive wires adapted to connect the control unit to the one or more electrodes, wherein the control unit is adapted to drive the one or more electrodes from a position at a proximal end of the device and external to the patient.
  • an electrical signal as described herein separately or in a combined device to treat Alzheimer's or another neurological condition, to the olfactory nerves results in transmission of electrical pulses from the olfactory nerves to the olfactory bulb.
  • the pulses are delivered to subarachnoid space (SAS) to the cerebrospinal fluid (CSF) then to various centers of the brain and cerebral cortex, especially temporal and frontal lobes.
  • SAS subarachnoid space
  • CSF cerebrospinal fluid
  • the electrical stimulus reaches the CNS through the olfactory bulb, and then to the olfactory tract to prefrontal cortex, medial olfactory area, to temporal lobe ,to lateral olfactory area, hippocampus, hypothalamus ,brain stem nuclei, and to cerebellum.
  • Transmitting electrical impulses as described to treat Alzheimer's or another neurological condition separately or in a combined device to the sphenopalatine ganglion results in transmission of electrical pulses to all its connecting branches.
  • Electrical impulses from a device as described are transmitted to the CNS through the anterior, and posterior ethmoidal nerves, the communicating branch between them, the retro-orbital branch of an sphenopalatine ganglion of the subject, greater and lesser palatine nerve, sphenopalatine, communicating branch between a maxillary nerve and sphenopalatine ganglion, nasopalatine nerve, posterior nasal nerve, infraorbital nerve, otic ganglion of the subject, an afferent fiber going into the otic ganglion, Vidian nerve, greater and lesser superficial petrosal nerve, and deep petrosal nerve of the subject.
  • Transmitting the electrical impulses as described herein to treat Alzheimer's and other CNS diseases through the sphenoid sinus results in transmission of the electrical pulses to the pituitary gland. From this anatomical site, the electrical impulses are transmitted to one or more cranial nerve, e.g., I, III, IV, V, VI, to the brain stem nuclei, and other neurons in the brain stem, cerebellum; and
  • hypothalamo-hypophysial tract to the hypothalamus, the thalamus, thalamic radiation, basal ganglion, hippocampus, amygdala, Cingular gyrus, brain stem, and cerebral cortex, and cerebellum.
  • Yet another objective of described devices and methods to treat Alzheimer's is to deliver adjuvant therapeutic agents directly to olfactory mucosa and sphenoid sinus tissue in combination with electrical nerve stimulation as described, allowing the therapeutic agent to enter the brain due to iontophoresis, and electroporation electrical effects or otherwise on the olfactory mucosa and sphenoid sinus.
  • this invention will facilitate the uptake and transport of these therapeutic agents from ORE to the CNS bypassing BBB through the olfactory nerves and other cranial nerves, enumerated. It is the intent of this invention to deliver the therapeutic agents we have selected such as bexarotene, insulin, acetyl-cholin-esterase inhibitors, monoclonal antibodies and ketamine delivered through the olfactory mucosa.
  • Yet another objective of this invention to treat Alzheimer's is to deliver adjuvant therapeutic agents directly delivered to ORE and sphenoid sinus, such as bexarotene, dissolved in DMSO at 65 mg/mL or in ethanol at 10 mg/mL, which is instilled, with insulin and acetyl cholinesterase inhibitors in Alzheimer's patient's olfactory mucosa.
  • adjuvant therapeutic agents directly delivered to ORE and sphenoid sinus, such as bexarotene, dissolved in DMSO at 65 mg/mL or in ethanol at 10 mg/mL, which is instilled, with insulin and acetyl cholinesterase inhibitors in Alzheimer's patient's olfactory mucosa.
  • the stimulation of the neuropil by using this device also brings about reduction of neuroinflammation in patients suffering from conditions comprising Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, postoperative cognitive dysfunction, and postoperative delirium as such.
  • This also one of the mechanisms by which the inventive device described herein curtails Alzheimer's disease bringing about the reduction of neuroinflammation in the afflicted brain.
  • This invention delivers electrical impulses to the olfactory nerves, sphenopalatine ganglion, trigeminal nerves, pituitary gland with hypothalamo hypophysial tract, five cranial nerves in the sphenoid sinus wall (in the cavernous sinus).
  • Therapeutic agents are delivered by passing the BBB, besides the electrical stimulation of Alzheimer's disease afflicted patient's brain.
  • Therapeutic agents can be administered orally, intravenously or intranasally along with this inventive device in operation.
  • FIG. 1 is the diagrammatic presentation 100 of the olfactory mucosa covering the medial and lateral walls of the nose, sphenopalatine ganglion, and anterior ethmoidal nerve.
  • FIG. la is the diagrammatic presentation of 100a showing head position and the olfactory mucosa when the device needs to be placed in the nose.
  • FIG. 2 is the diagrammatic presentation of the lateral wall 200 of the nerve structures in the nose.
  • FIG. 3 is the diagrammatic presentation of the medial wall 300 of the nerve structures in the nose.
  • FIG. 4 presents the views of diagram 400 showing structure stimulated by electrical impulses transported to the CNS.
  • FIG. 5 is the diagrammatic presentation 500 showing structure that may be stimulated by electrical impulses to be transmitted to the CNS.
  • FIG. 6 is the diagrammatic drawing 600 showing an embodiment of the inventive device used to stimulate olfactory mucosa.
  • FIG. 7 is the drawing 700 showing an embodiment of the inventive device with an insertion end located at a location to deliver electrical stimulation, a proximal electrode at olfactory mucosa and a distal electrode at the sphenoid sinus.
  • FIGS. 8 includes diagram 800 showing an embodiment of the inventive device with an insertion end located at a location to deliver electrical stimulation, a proximal electrode at olfactory mucosa and a distal electrode at a sphenoid sinus with anchoring balloon.
  • FIG. 9 is the diagrammatic presentation 900 of an embodiment of electrical simulator inventive device as described herein, incorporating olfactory mucosal, sphenoid sinus, pituitary gland, sphenopalatine ganglion stimulators in one device.
  • FIG. 10 is the diagrammatic presentation 1O00 of an embodiment of a completely assembled electrical impulse delivering catheter as described, including balloon and inflating syringes, useful to treat Alzheimer's and other neurological diseases.
  • FIG. 11 is the diagrammatic presentation 1100 showing the longitudinal section of the olfactory bulb, which conducts electrical impulses to the cortical centers, e.g., to treat Alzheimer's and other diseases delivered through the olfactory nerves from the olfactory mucosa.
  • FIG. 12 is the diagrammatic presentation 1200 showing an embodiment of a sphenoid sinus balloon as described herein, located in the sphenoid sinus, and the surrounding structures to which electrical impulses can be transmitted.
  • FIG. 13 is the diagrammatic presentation 1300 showing the sagittal section of the sphenoid sinus with an embodiment of inventive device in the sphenoid sinus, and the surrounding cavernous sinus structures to which electrical impulses can be transmitted.
  • FIG. 14 is the diagrammatic presentation 1400 showing the spread of electrical impulses from the olfactory nerves to the olfactory bulb and to the rest of the centers in the brain involved in the Alzheimer's and other disease processes.
  • FIG. 15 is the diagrammatic presentation 1500 of the medial wall with an insertion end of an embodiment of an electrical impulse delivering device as described herein in place in electrically- stimulative contact with the olfactory mucosa, olfactory bulb, sphenopalatine ganglion, pituitary gland, other neurological structures, and BV in the cavernous sinus.
  • FIG.16 is the diagrammatic presentation of catheter device in the sinus and the nose.
  • FIG.17 is the diagrammatic presentation shows the electrical stimulator catheter device in place
  • FIG. 18 is the diagrammatic presentation shows an example of an assembled catheter in position with an insertion end located at a trans-nasal location.
  • FIG.19 is the diagrammatic presentation shows various embodiments of the electrical stimulation catheter that can be incorporated.
  • FIG.20 is the diagrammatic presentation shows another embodiment of the electrical stimulation catheter placed in a trans-nasal location.
  • FIG. 21 is the diagrammatic presentation shows another embodiment of electrical stimulation with two balloon expanding syringes and electrical cell output monitor.
  • Alzheimer's means Alzheimer's disease, Alzheimer's afflicted brain.
  • the term is used to allude to "neurodegenerative diseases” "neurological diseases” "CNS diseases” such as Parkinson's, senile brain atrophy, stroke, PTSD, Tumors, vascular disorders, and other such afflictions.
  • terapéutica refers to doses of a substance, e.g., of a protein, e.g., insulin, of an IGF-1, that result in prevention or delay of onset, or amelioration of one or more symptoms of a neurodegenerative disease such as Alzheimer's, Parkinson's, or another as described herein.
  • a substance e.g., of a protein, e.g., insulin, of an IGF-1
  • a neurodegenerative disease such as Alzheimer's, Parkinson's, or another as described herein.
  • treating or “treatment” and “example” refers to both therapeutic treatment, prophylactic or preventative measures and method of use.
  • mamal include but are not limited to, humans, mice, rats, monkeys, farm animals, sport animals, and pets.
  • nerve cell in the following description refers to an intricate, complex network of axons, dendrites, and glial branches that form the bulk of the central nervous system's grey matter with Microglial cells with BV endowed with BBB and in which nerve cell bodies are embedded.
  • BBB blood brain barrier
  • the olfactory nerves provide a route bypassing the BBB, presenting the select therapeutic agents directly to the neuropil of the brain to the site of pathology to treat CNS diseases.
  • the term "Circle of Willis,” “Cerebral BV,” or brain “BV” includes anterior cerebral arteries, anterior communicating arteries, internal carotid arteries, posterior cerebral arteries, the basilar artery and middle cerebral arteries supplying the brain and give branches to from the BBB capillaries inside the brain, brain stem, and spinal cord.
  • olfactory region includes olfactory mucosa
  • sphenopalatine ganglion and its branches branches from the trigeminal nerve, olfactory nerve fasciculi as they enter the olfactory bulb, and the communicating blood vessels of this region to the CNS . It is located in the upper third of the medial and lateral wall of the nose (figs. 1, 2, 3) and covers the entire roof of the nose (cribriform plate of the ethmoid bone).
  • olfactory mucosa refers to the olfactory area in the upper part of the nose, which contains olfactory receptor bipolar neurons, that forms about 20 bundles of olfactory nerve fasciculi (Figs. 1,2,3). Olfactory neuro-epithelium is the only area of the body in which an extension of CNS meets the external environment.
  • TNF tumor necrosis factors
  • cytokines refers to a naturally occurring cytokines present in humans or mammals, which play a key role in the inflammatory immune response and in the response to infection.
  • PE perineural epithelium
  • sub perineural epithelial space (sub PE) is used to describe the tissue space between the nerve bundles of axons (fasciculi) and below the perineural epithelium (Fig. 11).
  • antibodies and “immunoglobulins” mean the proteins produced by one class of lymphocytes (B cells) in response to specific exogenous foreign molecules (antigens, infections). They can be also be synthesized.
  • mAB monoclonal antibodies
  • immunoglobulins which recognize a single antigen that are derived from clones (identical copies) of a single line of B cell which can be a cytokine blocker, or a cytokine inhibitor, or as a cytokine antagonist.
  • Alzheimer's and related diseases and neurodegenerative disease, are interchangingly used.
  • treat means that which reduces or retards or slows the progression or severity of a disease or condition.
  • the present invention disclosure relates to devices and medical procedures that stimulate nerves by transmitting electrical energy to nerves and tissue, preferably non-invasively.
  • Described methods of treatment of Alzheimer's disease relate to stimulation of one or more cranial nerve, CN I (also referred to as the olfactory nerve), III, IV, V, and VI, (a total of 12 cranial nerves which include both sides of the sphenoid sinus and ORE).
  • neural stimulation may correspond to transcranial (through sphenoid sinus), cortical, subcortical, cerebellar, deep brain, spinal column, cranial or other peripheral nerve, and or other types of stimulation.
  • Electrical stimulation impulses described herein are capable of various effects, as described, such as reducing neuroinflammation, wherein pathways involving anti-inflammatory cytokines, the retinoic acid signaling system, and/or neurotrophic factors enhanced, and/or pathways involving pro-inflammatory cytokines are inhibited with enhancement of neurotransmitters and memory related protein and amino acid output in the neurons.
  • olfactory bulb and its relay of electrical impulses to the CNS and entorhinal cortex
  • the sphenoid sinus is located within the body of the sphenoid bone posterior to the upper point of the nasal cavity.
  • the sphenoid sinus consists of two large irregular cavities separated by a bony septum.
  • the middle of the anterior wall of the sphenoid bone forms a crest, which articulates with the perpendicular plate of the ethmoid bone, which forms part of the nasal septum (FIG.13).
  • a rounded opening called the sphenoid foramina (Fig. 13 arrows 524) about 4 mm in diameter opens into the sphenoid sinus from the posterosuperior part of the nasal cavity.
  • the hypophyseal fossa commonly known as sella turcica is located in a depression in the body of the sphenoid bone.
  • the sella turcica forms a bony caudal border for the pituitary gland.
  • Completing the formation of the saddle posteriorly is the dorsum sellae, continuous with the clivus, inferoposteriorly.
  • the pituitary gland is encased in this thin boney fossa (Figs. 3-5, 12, 13, 15) surrounded by the cavernous sinus 541 with five cranial nerves 503-507, internal carotid artery 510, and is easily accessible for electrical stimulation as described in our invention through the sphenoid sinus.
  • the sphenoid sinus is about 2 cm high, 2 cm wide and 2.1 cm antero- posteriorly.
  • the sphenoid sinus communicates with the sphenoid-ethmoidal recess behind the olfactory mucosa (Fig. 3, 4, 13) in the upper part of the nose through this ostium. It is through this ostium that a distal portion of the device as described herein, i.e., a distal portion of the insertion end of the described device, can be inserted for treatment of various neurological diseases including Alzheimer's.
  • the ostium diameter can be enlarged with a dilator without damage to any vital structures which are not in close proximity to the ostium, to facilitate the entry and placement of a distal portion of the inventive device.
  • the posterior ethmoidal blood vessels supply the sphenoid sinus.
  • the lymph is drained by retropharyngeal lymph nodes.
  • the sphenoid sinus is innervated by the posterior ethmoidal nerve and orbital branch of the sphenopalatine ganglion.
  • the pituitary gland is located inside the sella turcica in a round bony cavity that is separated from the sphenoid sinuses by a thin plate of bone; the floor of the sella turcica forms part of the roof of the sphenoid sinuses (Figs. 2-5, 12, 13, and 15).
  • a pair of intercommunicating venous channels called the cavernous sinuses connected to the brain stem and orbital part of the brain around the infundibulum.
  • Several important nerves and vascular structures pass through the cavernous sinus between the venous channels; these play an important role in conduction of electrical impulses from our inventive device from the sphenoid sinus to the brain and brain stem: They are:
  • the internal carotid artery (#510) which forms a major part of the Circle of Willis ii.
  • the ophthalmic division of the trigeminal nerve (VI -505)
  • sphenoid sinus Immediately below the sphenoid sinus embedded in the upper most part of lateral wall is the sphenopalatine ganglion with extensive connections (Figs. 2, 3). Above the sinus is the pituitary gland with infudibulum connected to the
  • hypothalamus hypothalamus, thalamus, and the rest of the brain through the thalamic radiation, which transmit electrical impulses delivered through a device and method as described.
  • the pituitary gland is connected to the hypothalamus, thalamus, central gray, reticular system, hippocampus, parahippocampal gyrus, cmgulate gyrus, and cortical centers through the thalamic projections.
  • the basal ganglion, red nucleus, and substantia nigra are in close proximity to the hypothalamus and are inter-linked.
  • the electrical impulses imparted to the pituitary gland spread to the above brain structures and play an important role in the treatment of Alzheimer's, and other nervous system diseases.
  • the pituitary gland rests immediately above the thin sphenoid bone, which will allow the electrical impulses to be transmitted to the surrounding above described brain structures.
  • the olfactory epithelium is a specialized epithelial tissue inside the nasal cavity that is involved in perception of smell located in the dorsoposterior aspect of the nasal vault. Because the olfactory neural cells are the only surface neural cells in the body, olfactory mucosa is considered in this aspect, as a "window to the brain.”
  • the human adult olfactory mucosa is a potential source of olfactory ensheathing cells and multipotent neural stem cells. They have been used in autologous transplantation therapies aimed at the treatment of degenerative or traumatic conditions of the central nervous system, spinal cord injury or Parkinson's disease (Mackay-Sim A et al (2008) Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain 131 (Pt 9):2376- 2386. Murrell W et al (2005) Multipotent stem cells from adult olfactory mucosa. Dev Dyn 233(2):496-515).
  • Olfactory epithelium Humans have about 10 cm 2 (1.6 sq inch) of olfactory epithelium. Olfactory mucosa in humans lies on the roof of the nasal cavity about 7 cm above and behind the nostrils.
  • the human olfactory mucosa consists of a pseudo-stratified columnar epithelium resting on a highly cellular lamina Propria.
  • Olfactory epithelium consists of 4 distinct cell types:
  • Olfactory cells of the epithelium are bipolar neurons, which congregate to form the olfactory nerve (cranial nerve I). They are responsible for conducting the electrical impulses to the olfactory bulb and rest of the CNS. As they emerge to the lamina basement, they form up to 20 olfactory nerve fasciculi surrounded by Perineural epithelium and sub Perineural epithelial space, which conduct the therapeutic agents to the SAS and CSF surrounding the olfactory bulb. From there, the therapeutic agents are transported to the rest of the CNS (Shantha T, . and Yasuo Nakajima. Histological and Histochemical Studies on the Rhesus Monkey (Macaca Mulatta) Olfactory Mucosa. Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia: Z. Zellforsch. 103, 291-319 (1970).
  • Supporting cells Analogous to neural glial cells are the supporting cells
  • Microvillar cells They were first described in 1982, and hypothesized as a second morphologically distinct class of chemoreceptor in the human olfactory mucosa. However, their putative role in the olfaction has not yet been definitely
  • Basal cells divided into two types. a.
  • the horizontal basal cells line the olfactory epithelium and the slightly more superficial globose basal cells thought to be the primary stem cell.
  • Brush Cells resting on the basal lamina of the olfactory epithelium are stem cells capable of division and differentiation into either supporting or olfactory cells.
  • Bowman's (olfactory) Glands deliver a protenacious secretion via ducts onto the surface of the mucosa.
  • the role of the secretions is to trap and dissolve odiferous as well as therapeutic agents to transport to the bipolar neuronal pathways, Perineural epithelium, sub Perineural epithelial space to the olfactory bulb, S AS and CSF.
  • Stimulation of the olfactory nerves in the olfactory mucosa results in transmission of electrical impulses to the olfactory neurons, olfactory nerve fasciculi, olfactory bulb, and olfactory tract to various nuclei in the CNS as shown in the figure 14.
  • Examples of devices capable of delivering therapeutic agents to treat Alzheimer's and other neurological diseases with adjuvant therapeutic agents and insulin delivered to the olfactory mucosa is described in U. S. Patent Application Publication Number: 2012/0323214 AD by Dr. Shantha, the entirety of which is incorporated herein by reference.
  • the combination of olfactory nerve stimulation and delivery of therapeutic agents through the olfactory mucosa is the most important method of treatment for Alzheimer's, senile dementia and other CNS diseases.
  • the sphenopalatine ganglion (synonym: SPG, Meckler's ganglion, ganglion pterygopalatinum, nasal ganglion, pterygopalatine ganglion,) is the largest parasympathetic ganglion in the body found in the pterygopalatine fossa associated with the branches of the maxillary nerve (Fig. 2).
  • the sphenopalatine ganglion supplies the lacrimal gland, paranasal sinuses, glands of the mucosa of the nasal cavity and pharynx, the gums, and the mucous membrane and glands of the hard palate and cerebral blood vessels, which form the Circle of Willis and its branches.
  • Sphenopalatine ganglion receives a sensory, a motor,
  • olfactory mucosal nerves sphenopalatine ganglion, trigeminal nerves, pituitary gland with hypothalamo hypophysial tract
  • cytokine cytokine
  • RNA fragments, neurotoxins and others which act as marker of neuronal pathology resulting in Alzheimer's and other neurodegenerative diseases.
  • the main object of the present invention is to deliver the electrical impulses to activate the Alzheimer's afflicted brain and reset the function of the CNS at neuronal and synaptic level (by increasing the electrical conductivity and reducing the inflammation).
  • the present invention also provides a method and apparatus for delivery of electrical impulses by stimulation of the olfactory nerves, sphenopalatine ganglion, trigeminal nerves, pituitary gland with hypothalamo hypophysial tract, five cranial nerves on each side, and their outgoing parasympathetic connection to cerebral BV. Methods and devices as described can also be optionally used to deliver therapeutic agents directly to the CNS through the olfactory mucosa by passing the BBB.
  • Stimulation as described herein of one or more of olfactory mucosal nerves, sphenopalatine ganglion, trigeminal nerves, pituitary gland with hypothalamo hypophysial tract, may lead to increased clearance of the substance from
  • cerebrospinal fluid for example amyloid, tau, cytokine, and RNA fragments, which act as a marker of neuronal death resulting in Alzheimer's and other
  • the middle and anterior cerebral arteries provide the blood supply to the cerebral hemispheres, including the frontal and parietal lobes in their entirety, the insula, the limbic system, and most of the temporal lobes, internal capsule, basal ganglia, and thalamus. These structures are involved in many of the neurological and psychiatric diseases of the brain. Hence, certain embodiments of methods and devices as described herein can involve providing improved blood supply and drug delivery to these structures. There is a presence of parasympathetic innervations in the posterior cerebral and basilar arteries from the sphenopalatine ganglion resulting in the above described therapeutic agents' delivery and effects due to BV dilatation and leakage development in the BBB.
  • a function of the present invention is to deliver the electrical impulses to activate the silent Alzheimer's afflicted brain, their neurons, and synapses.
  • described methods and apparatus also deliver therapeutic molecules bypassing the BBB. It is accomplished by this inventive device due to stimulation of the olfactory mucosal nerves, sphenopalatine ganglion, trigeminal nerves, pituitary gland with hypothalamo hypophysial tract, five cranial nerves on each side, and their outgoing parasympathetic connection to cerebral BV to make them more permeable to large molecules from within the cerebral BV.
  • the afferent fibers innervate from the cranial nerves that are stimulated by our method include several midbrain, pons and medullary structures; and their nucleus including the tractus solitarius (NTS). They receive most of the afferents and bilateral inputs of all cranial afferents.
  • the cranial nerve nuclei stimulated has widespread projections, including direct or multiple synaptic projections to the parabrachial nucleus, vermis, inferior cerebellar hemispheres, raphe nuclei, periaquaductal gray, locus coeruleus, thalamus, hypothalamus, amygdala, nucleus accumbens, anterior insula, infralimbic cortex, and lateral prefrontal and temporal cortex.
  • Brain functional imaging studies show that stimulation of these cranial nerves bring about changes in several areas of the brain, including the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, basal ganglion and medulla.
  • vagus nerve stimulation has been suggested as a mechanism for the effects of vagus nerve stimulation, but such localized stimulation of the brain may depend upon the parameters of the stimulation (current, frequency, pulse width, duty cycle, etc.). These parameters may determine which
  • VNS vagus nerve stimulation
  • the most important effects of electrical stimulation are to inhibit inflammation by inhibiting the cytokines, increase acetylcholine in the brain content and other neurotransmitters including epinephrine, facilitate the removal of the ⁇ from the neuropile, prevent further apoptosis of neurons, improve the mitochondrial, endoplasmic reticulum and nuclear function by increasing the production of proteins, and amino acids involved in memory and cognition.
  • This invention is used to deliver electrical impulses directly to the CNS through the ORE by passing the BBB by making the CNS blood vessels leaky.
  • Optional therapeutic agents that may be delivered in combination with the described electrical stimulation of nerve fibers, using an electrical stimulator- catheter system as described to treat Alzheimer's disease are numerous. Some of them are:
  • an NMDA-receptor blocker for example ketamine and others
  • IX various nerve growth factor, brain-derived neurotrophic factor, and others.
  • IGF-1 insulin like growth factors
  • XV ciliary neurotrophic factor and glial derived nexin
  • XVII an inhibitor of protein tyrosine phosphatases
  • endogenous protein for instance albumin and memory enhancing nerve growth
  • XIX anti tumor necrosis factors, (TNF), anti cytokines therapeutic agents-monoclonal antibodies, chemotherapeutic agents, and A range of known therapeutic agents, as well as other pharmaceutical, biochemical, nurticeuticals, and biological agents or compounds including stem cells which have curative or curtailing effect on Alzheimer's and other neurodegenerative CNS diseases.
  • TNF tumor necrosis factors
  • cytokines therapeutic agents-monoclonal antibodies
  • chemotherapeutic agents and A range of known therapeutic agents, as well as other pharmaceutical, biochemical, nurticeuticals, and biological agents or compounds including stem cells which have curative or curtailing effect on Alzheimer's and other neurodegenerative CNS diseases.
  • This present invention describes a method of use of electrical impulses through the above described anatomical regions transmitted and transported to the CNS to curtail Alzheimer's disease and other related diseases. These regions can also be used for administration of insulin, IGF-1 (7.65kDa) protein neurotrophic factor, vitamin A related compound bexarotene, to remove B amyloid, acetylcholine esterase inhibitors, and various adjuvant pharmaceutical, biochemical, nurticeuticals, and biological agents or compounds developed or being developed to treat
  • Ease and convenience This method is easy to use, painless, does not require strict sterile technique, intravenous catheters or other invasive devices; methods can be performed without the use of general anesthetic on a patient, and on an outpatient basis;
  • High therapeutic efficacy Due to the achievement of higher local concentration of electrical impulses in the CNS through the rich nerve plexus delivered to disease afflicted areas of the CNS; Increased efficacy of its use along with optional adjuvant therapeutic agents: Due to the ability of the administered therapeutic molecule to reach the target tissue without degradation caused by digestive enzymes, hepatic or systemic circulation (first phase metabolism); and the ability of the insulin to augment and amplify the effects of other therapeutic agents used to treat CNS disease;
  • the inventive devise can be used for long duration
  • Electrical impulses can also act as iontophoresis, and electroporation of the olfactory mucosa, sphenopalatine ganglion and sphenoid sinus lining, thus augmenting the uptake of therapeutic agents from these regions to be delivered to the CNS by passing the BBB in the treatment of Alzheimer's and other neurological diseases.
  • FIG. 1 is the diagram of the lateral and medial wall of the nasal cavity 100 reflected back at cribriform plate of the ethmoid bone 8. It shows ORE (olfactory nerves) with various nerve structures (shown in black surface with white lines) with which electrical impulses come in contact, then are conducted to the CNS to the brainstem, hippocampus, entorhinal cortex, thalamic, hypothalamic, cerebral cortical centers, cerebellum and other cortical neuropil (see FIG. 14). The olfactory tracts are connected to the entorhinal cortex (EC) located in the medial temporal lobe (area 28, and 34 of the brain). The entorhinal cortex is one of the first areas affected in Alzheimer's disease.
  • EC entorhinal cortex
  • the EC functions as a hub in a widespread network for memory and navigation-routing of impulses.
  • the EC is the main interface between the hippocampus and neocortex.
  • the EC-hippocampus system plays an important role in autobiographical/declarative/episodic memories and in particular spatial memories including memory formation, memory consolidation, and memory optimization. Electrical impulses transmitted to this area from an inventive device as described have a remarkable therapeutic effect on Alzheimer's patients and senile brain atrophy, as well as other neurodegenerative diseases.
  • OM olfactory mucosa
  • olfactory receptor and its nerve fasciculi 2 cover extensive areas of the medial 3 and lateral 4 wall of the upper part of the nasal cavity, which is separate from the respiratory part of the nose, and pass through the cribriform plate of the ethmoid bone 8 to the olfactory bulb.
  • This region also contains the sphenopalatine ganglion (Pterygopalatine) 6 with its extensive central and peripheral connecting branches (see Fig. 2 below).
  • This ORE 2, 5 is also surrounded by anterior ethmoidal nerves 7 connected to the ophthalmic branch of the trigeminal nerves.
  • the therapeutic agents and electrical impulses delivered through this invention pass on to the CNS through the olfactory nerves, trigeminal nerve branches 7 (CN V), III, IV, V (VI -2), VI th Cranial nerves 359, and sphenopalatine ganglion 6 that supply the upper third of the nasal cavity close to the olfactory mucosa, pituitary gland 362 and sphenoid sinus 361 with 10 cranial nerves in its wall located in the cavernous sinus.
  • CN V trigeminal nerve branches 7
  • III, IV, V (VI -2) VI th Cranial nerves 359
  • sphenopalatine ganglion 6 that supply the upper third of the nasal cavity close to the olfactory mucosa, pituitary gland 362 and sphenoid sinus 361 with 10 cranial nerves in its wall located in the cavernous sinus.
  • the therapeutic delivery of electrical impulses delivered through this invention is passed on to the CNS through the olfactory nerves, trigeminal nerve branches, III, IV, V, VI th Cranial nerves, and sphenopalatine ganglion that supply the upper third of nasal cavity close to the olfactory mucosa.
  • the CSF (cerebrospinal fluid) in the SAS (subarachnoid space) surrounding the olfactory bulb also conduct the electrical impulses and therapeutic agents to the brain surface from short olfactory nerves in the treatment of
  • Alzheimer's and other neurodegenerative diseases are associated with Alzheimer's and other neurodegenerative diseases.
  • FIG. la is the diagrammatic presentation 100a showing vestibule 375, respiratory nasal mucosa 376 with olfactory nerve and olfactory mucosa 377 of the lateral and medial walls of the olfactory mucosal nerve area of the nose (ORE).
  • the arrows point to the spread of electrical impulses and therapeutic agents from the ORE 377 to the CNS. Note to get the maximum delivery of therapeutic agents to the ORE, the head should be extended as shown in the diagram and electrical impulses delivered to the ORE 377 using the special delivery catheter described herein. Just passing electrical impulses through the vestibule 375 and the respiratory mucosa 376 is not effective for the treatment of Alzheimer's disease.
  • the therapeutic dose of electrical impulses and therapeutic agents' delivery catheter and Iontophoresis device are placed on the ORE 377 to treat Alzheimer's disease.
  • FIG. 2 is the diagram of the lateral wall of the nasal cavity 200 showing how various nerve structures that the therapeutic electrical current (and optional therapeutic agents) delivered by a device as described come in contact with and are transported to the CNS through nerve fasciculi of the nerve structures located in the ORE, and sphenoid sinus (525) through the sphenoid ostium 524.
  • the subarachnoid space (S AS) and the cerebrospinal fluid (CSF) surrounding the nerve fasciculi and olfactory bulb also conduct the electrical impulses to the surface of the brain.
  • the therapeutic delivery of electrical impulses passes through the olfactory bulb 35 transported by the olfactory mucosa and olfactory nerves 105 passing through the cribriform plate of the ethmoid bone 8.
  • the electrical pulse and stimulus are passed on to the CNS through the trigeminal nerve 118, external nasal nerve 116, the anterior ethmoidal nerve 117; and from the sphenopalatine ganglion 110 to the greater petrosal nerve 119, nerve of the pterygoid canal 111, pterygopalatine and pharyngeal nerve 112, lesser palatine nerve 114, greater palatine nerve 115, nasopalatine nerves 109, parasympathetics to the internal carotid artery 510 many cranial nerves immediately adjacent to the lateral wall of the sphenoid sinus 525.
  • the sphenopalatine ganglion 112 neuronal center is located in the brain behind the nose (see Fig. 13). Besides the above branches, it consists of parasympathetic neurons innervating the Circle of Willis (middle cerebral, anterior cerebral, vertebral, basilar, posterior cerebral arteries and their lumen). Activation of this ganglion causes the vasodilatation of these vessels in the Circle of Willis including the basilar and posterior cerebral arteries.
  • a second effect of such stimulation is the opening of pores in the vessel walls, breaking of the BBB causing plasma proteins and therapeutic agent's extravasations to neuropil. This effect allows better transport of molecules from within these blood vessels to surrounding nerve structures in the treatment of Alzheimer's.
  • the olfactory mucosa and olfactory nerves 105 and 10 cranial nerves adjacent to the sphenoid sinus play a major role in delivering electrical impulses and therapeutic agents in the treatment of Alzheimer's in this invention by bypassing or overcoming the BBB (diagram modified after Grays Anatomy).
  • FIG. 3 is the diagram of the medial wall of the nasal cavity 300 and nerve structures located in the olfactory anatomical region.
  • Various nerve structures on the medial wall of the nose conduct the electrical impulses to treat Alzheimer's as this invention comes in contact, and are transmitted to the CNS from the upper part of the nose from the ORE 106 and the 10 cranial nerves adjacent to the two outer walls of the sphenoid sinus 524.
  • the electrical impulses of this invention are conducted through the olfactory nerves, through the cribriform plate of the ethmoid bone 8 to the olfactory bulb 35.
  • the nerve impulses pass from the olfactory mucosa 106 and the 10 cranial nerves adjacent to the wall of the sphenoid sinus 525 to the various centers of the brain and cortex, especially the temporal and prefrontal and orbital cortex, the front part of the brain stem through the olfactory tracts 36, 38 as well as to the cerebellum (see FIG. 14).
  • Olfactory nerves are the shortest of the cranial nerves, hence it is easy for them to carry the electrical impulses to the olfactory bulb, and the impulses connect to the CNS without decay.
  • the axons and dendrites of the olfactory tract transport the therapeutic delivery of electrical impulses to the brain centers involved in Alzheimer's disease.
  • the electrical impulses also pass through the trigeminal nerve branches and sphenopalatine ganglion 110 that supply the nasal cavity through the anterior ethmoidal nerve 107, nasoplatine nerve 109, medial, posterior and superior nasal branches 108 and the sphenopalatine ganglion 110 and its branches to reach the circle of Willis to reach the brain stem cranial nerve nuclei.
  • the electrical impulses also pass from the sphenoid sinus to pituitary gland 509, a rich vascular network surrounding the gland 5 Hand pituitary stalk 512; pituitary hypothalamo-hypophysal tract 512, hypothalamic nuclei 513, and thalamic centers 514 and then to the cortical radiation of the entire brain. Note how easy it is to get into the sphenoid sinus 525 through sphenoid ostium 524 located behind the olfactory mucosa (diagram modified from Grays Anatomy).
  • FIG. 4 is the drawing of the nasal cavity diagram 400 showing the nerve structure locations involved in the transmission of electrical impulses to the brain using this invention.
  • the electrical impulses are conducted to the CNS from the olfactory mucosa 45, olfactory mucosal nerves 44, olfactory nerve fasciculi 105, olfactory bulb 35, and medial and lateral olfactory tracts 516.
  • hypothalamo-hypophysal tract 512 hypothalamic nuclei 513, and thalamic radiation 514 (insert 4A).
  • thalamic radiation 514 insert 4A.
  • cranial nerves 515 CN III, IV, V, and VI
  • FIG. 5 is the diagrammatic presentation 500 of the ORE with similar explanation of the regions as FIG. 4. It is showing the pituitary gland 509 (see insert 5A), sphenopalatine ganglion 110, olfactory mucosa with olfactory nerves, olfactory mucosal nerves 44, olfactory bulb 35 being electrically stimulated by electrical output manipulator control box 517.
  • the power source is contained within this pulse generator box, and generates a battery powered current delivered through the conducting wires 518 which will send electrical impulses to the CNS for the treatment of Alzheimer's and other neurodegenerative diseases.
  • electrical impulses are transmitted to the CNS from the trigeminal nerve branches including anterior ethmoidal nerve 107 sphenopalatine ganglion and its branches 110, parasympathetic supply from the sphenopalatine ganglion to Circle of Willis 510, pituitary gland 509, rich portal blood system of the pituitary gland 511, hypothalamo-hypophysal tract 512, hypothalamic nuclei 513, and thalamic radiation 514 (insert 4 A).
  • cranial nerves 515 CN III, IV, V, and VI
  • FIG. 6 is the diagrammatic presentation 600 of this inventive device 220 designed to stimulate the ORE and deliver therapeutic agents. It has electrical output manipulator 517 attached to the olfactory stimulator part 520 passing the conductive wires through the main body of the device 518. It has balloon 519, capable of being inflated while the device is positioned in the ORE with the insertion end at a trans-nasal location. This balloon will prevent the trauma to the delicate nasal mucosa as the device is advanced to the ORE through the external nasal opening. The balloon is connected to the inflating syringe 522. The balloon is inflated with air or sterile liquid or gel and the size of the balloon can be adjusted according to the size of the patient's nose.
  • the device connected to the therapeutic agents delivery syringe 521 which delivers them through the electrical current delivery part of the device 520 pores if needed in the treatment of Alzheimer's and other diseases.
  • This catheter acts as iontophoresis and electroporation with simple modification to facilitate the delivery of therapeutic agents to the CNS by passing the BBB.
  • the tip of the inventive device is provided with radio opaque marker 540 to identify the position of the catheter in the sphenoid sinus and/or on the olfactory mucosa after insertion and during insertion with radiographic examination.
  • the device embodiment of figure 6 does not include a opening or injection orifice at the insertion end of the device that would allow for a fluid such as a fluid containing a therapeutic agent, to be dispensed from the device at the insertion end, such as to tissue of the olfactory mucosa, sphenoid sinus, or both.
  • a fluid such as a fluid containing a therapeutic agent
  • FIG. 7 is the drawing of the medial wall of the nose 700, showing various structures of the described device (e.g., catheter) 220, that may be stimulated by the nasal stimulator device to transmit electrical pulses to the CNS.
  • the insertion end of the device is placed at a trans-nasal location.
  • the tip of the electrical impulses delivery device is positioned in the sphenoid sinus through the ostium of the sphenoid sinus 524. This positioning between the sphenoid sinus and the nasal balloon 519 will keep the proximal stimulating part of the device 520 located firmly in the desired location i.e.
  • the electrical impulses also pass (spillover effect) from this device to sphenopalatine ganglion 110 and to the anterior ethmoidal nerve 107.
  • Optional injection port 522 is used to pass guide wire 523 to facilitate placement of this device with ease.
  • Syringe with three way stop cock 521 can be used to deliver therapeutic agents to the olfactory mucosa through the catheter.
  • the device insertion is facilitated by the use of flexible fiber optic nasal scope and guide wire 523.
  • the desired current is delivered through the electrical output manipulator 517.
  • the power source is contained within this pulse generator box and generates a battery powered current delivered through conducting wires 518, which send electrical impulses to the CNS for the treatment of
  • the electrical current passes to the CNS through the pituitary gland 509.
  • FIG. 8 is the view of diagram 800 showing catheter 220 with two balloons holding the electrical impulses delivering part of the device 520 in position between the sphenoid sinus with a balloon 525 and nasal balloon 519 without movement at the olfactory region, i.e., in the insertion end is in a trans-nasal location.
  • the syringe 526 inflates the balloon in the sphenoid sinus 525 and the balloon in the nose 519 is inflated by the inflator 522 to hold the electrical impulses delivery on the olfactory mucosa (ORE) to the CNS in position especially in patients who are difficult to control.
  • ORE olfactory mucosa
  • the device is connected to optional therapeutic agents delivery syringe 521, which is capable of delivering therapeutic agent to the interior of the nasal cavity through one or more external openings or apertures present along the shaft at the electrical current delivery part of the device 520 in the treatment of Alzheimer's and other diseases.
  • the diagram also shows the proximity of portions of device 520 to the anterior ethmoidal nerve 107, olfactory mucosa 44, olfactory bulb 35, pituitary gland 509, and the sphenopalatine ganglion 110. The electrical impulses' spillover stimulates these structures. The rest of the explanation is the same as FIGS. 5 and 6.
  • the olfactory mucosa is being electrically stimulated by electrical output manipulator control box 517.
  • the power source is contained within this pulse generator box and generates a battery powered current delivered through the conducting wires 518 which will send electrical impulses to the CNS for the treatment of Alzheimer's and other neurodegenerative diseases.
  • FIG. 9 is the diagrammatic presentation 900 of the electrical impulse delivery device (catheter) 220.
  • This diagram shows three separate electrical impulses delivery methods to the nerve structure as described here.
  • This device incorporates olfactory nerve stimulator 520, and sphenoid sinus stimulator 527 which can be placed in a patient to stimulate the five cranial nerves and the internal carotid artery (part of the Circle of Willis) in the wall of the cavernous plexus located on the lateral wall of the sphenoid sinus.
  • Sphenoid sinus stimulator 527 also sends electrical impulses to the pituitary gland to distribute the electric signals to the thalamic radiation and wake up the brain in those suffering from the Alzheimer's and other CNS diseases.
  • Sphenoid sinus stimulator 527 can also be provided with a sphenopalatine ganglion stimulator in the form of an extension electrode that extends or that can be extended at the distal part of the catheter to be placed adjacent to and deliver electrical impulses to stimulate this ganglion in the treatment of Alzheimer's and other neurological diseases.
  • a sphenopalatine ganglion stimulator in the form of an extension electrode that extends or that can be extended at the distal part of the catheter to be placed adjacent to and deliver electrical impulses to stimulate this ganglion in the treatment of Alzheimer's and other neurological diseases.
  • three separate electrical impulses delivery terminals can be activated through the electrical output manipulator 517 and connecting wires 518, at the same time, one at a time or two at a time as needed and depending on the tolerability and need of the patients.
  • the balloons 519 and 520 can be expanded by using air or liquid by a tube in the interior connected through inflation stopcocks 521, 522 and 526 connected by a tube to the inflation syringe located outside the nose.
  • the tip of the inventive device may be provided with radio opaque marker 540 to identify the position of the catheter in the sphenoid sinus and/or on olfactory mucosa after insertion and during insertion with radiographic examination.
  • Injection port 522 is used to pass the guide wire 523 to facilitate placement of this device with ease.
  • FIG. 10 is the diagrammatic presentation 1000 of and embodiment of catheter device 220, which incorporates many features in the device. It has many of the features already described in FIGS. 7, 8, and 9. It shows the complete assembly of this inventive device to treat Alzheimer's disease. It has two balloons 519 and 527.
  • the balloon 527 part has the insertion body or insertion end that may be is inserted in the human nose through the sphenoid foramina and then into the hollow sphenoid sinus optionally with the aid of a fiber optic nasal scope.
  • the insertion body consists of two parts. One part is an inflatable outer membrane or balloon 527, which is adapted in size and flexibility to fit inside the sphenoid sinus cavity as illustrated in FIGS. 12, 3, and 15.
  • the interior of this balloon 527 is connected to an inflation tube or inflation lumen, which in turn is connected through an inflation stopcock and a tube to the inflation syringe 521, 522, and 526.
  • the inflation syringe 522 is used to pump air or fluid through the inflation tube to the interior of the balloon 527 so the balloon inflates to at least partially fill the sphenoid sinus cavity during the use of the apparatus.
  • This embodiment includes additional syringe 529 (which is optional) with stopcock to deliver additional therapeutic agents.
  • An infusion tube may also be connected to the interior of the balloon 527 and used to pump fluid at ambient, elevated, or low temperatures through the infusion tube and to the interior of the balloon during the operation of the apparatus.
  • a device for heating or cooling the fluid to be pumped into the interior of the balloon 527 may also be included in the apparatus 530.
  • the balloon 527 is provided with multiple electrical leads on the expandable exterior of the balloon as shown.
  • the leads may be attached to or part of an expandable structure that is for example in the form of a polymeric mesh or fabric or a wire mesh that is placed at a surface of balloon 527, and that is capable of expanding as the surface of balloon 527 is expanded, e.g., within a sphenoid sinus.
  • These leads are connected by electrical connectors 517 to an electrical output manipulator 517. This electrical output device 517 is connected to a source of electricity.
  • Electrical stimulus is provided through the electrical leads to stimulate the pituitary gland, pituitary hypophysal track and surrounding five cranial nerve structures and the internal carotid artery encased in autonomic nerves. It is accomplished by stimulating the interior surface of the sphenoid sinus cavity and its walls through the balloon surrounded by electrical conductor wires, including electrodes, which will in turn transmit electrical impulses to the above mentioned tissue structures for treatment of Alzheimer's and other diseases of the nervous system including pain. It also has electrodes 531 which come in contact with the sphenopalatine ganglion and transmit electrical impulses to it for treatment of Alzheimer's.
  • An optional catheter and liquid dispensing port or aperture can be located at on the surface or the center of the balloon (527) with a suitable tube to allow a administer drugs or other therapeutic agent or other fluid to be directly dispensed to the sphenoid sinus cavity, besides delivering the electrical impulses.
  • the therapeutic agents are infused so that they are absorbed by the central nervous system directly across the sphenoid sinus walls into the perforating vessels, which empty into the cavernous sinus plexus and circulate in the BV of the CNS. This method allows us to use a small dosage of drugs instead of using large dosages systematically.
  • the antibiotics and anticoagulants may be impregnated onto the surface of the balloon of the sphenoid sinus cavity to prevent clotting and infection.
  • the tip of the inventive device is provided with radio opaque marker 540 to identify the position of the catheter in the sphenoid sinus after insertion and during use with radiographic examination.
  • Injection port 522 is utilized to pass the guide wire 523 to facilitate placement of this device with ease.
  • All of the tubes and connectors to the balloon 527 can be assembled together in a connector assembly.
  • the inner portion of this connector assembly constitutes part of the insertion body. This assembly needs to be small in diameter and flexible for easy insertion through the nose and into the sphenoid sinus cavity ostium.
  • An optional temperature sensor wire can be connected to a temperature sensor and indicator.
  • the temperature sensor wire is connected to sensors (not shown) in the balloon 527 to determine the temperature of the balloon surface and the structures in the immediate vicinity of it.
  • This fluid within the balloon may be heated around 42°-44° C. or higher or cooled if so desired to stimulate or decrease the output of pituitary hormones, including growth hormone from the pituitary gland.
  • Other means for instance, a device embodying the Peltier 530 effect, can be used to heat or cool the outer surface of the balloon. Heating will enhance the conduction of electrical impulse and facilitate the stimulation of pituitary gland and other surrounding nerve structure.
  • FIG. 11 is the diagrammatic presentation 1100 of the longitudinal section of the olfactory bulb 1100 and the olfactory mucosa showing the route of electrical impulses transmission (and of transport of the insulin and other therapeutic agents) by the direct stimulation (application) of the olfactory mucosa in the treatment of Alzheimer's and other neurological diseases including autism.
  • Electrical impulses and optional therapeutic agents pass through the olfactory nerves from the olfactory mucosa 45 transported through the subperineural epithelial space and olfactory axons to the olfactory bulb 35.
  • the electrical impulses are also transmitted to the CNS to subarachnoid space (SAS) 36 after passing through the olfactory nerve fasciculi surrounded by perineural epithelium with CSF surrounding them.
  • SAS subarachnoid space
  • the SAS surrounding the olfactory bulb with its CSF is directly connected to the sub perineural epithelial space surrounding the olfactory nerve fasciculi 25 and other cranial nerves on the lateral wall of the sphenoid sinus which transmits the electrical impulses [Shantha et al: Z. Zellforsch. 103, 291—319 (1970). J National Cancer Inst 35(1):153-165 (1965). Expt Cell Res 40:292-300 (1965). Science 154:1464- 1467 (1966). Nature 199, 4893:577-579 (1963). Nature, 209:1260 (1966).
  • the electrical impulses pass from receptor cells 44 and are transported through the axons, olfactory nerve fasciculi, retrograde through the cribriform plate of the ethmoid bone 43 to stimulate the olfactory bulb 35. From the olfactory receptor cell axons 45, the electrical impulses travel through the olfactory glomeruli 40 to periglomerular cells 39, mitral cells 41, and granule cells 42, to olfactory tract 37, and reach the CNS 38 then to the entorihinal cortex.
  • the electrical impulses then exert their effect on the entorhinal cortical neurons, synapses between the neurons; oligodendroglia, astroglia and microglia in the neuropil involved in the disease process of Alzheimer's and other neurodegenerative diseases.
  • This diagram shows that the inventive device 220 may be placed on the olfactory mucosa to stimulate the olfactory nerves to allow the stimulation to be transmitted to the central nervous system.
  • the entorhinal part of the olfactory system is very much involved in the genesis of Alzheimer's and other
  • neurodegenerative diseases and the electrical impulses from this inventive device reach this area through the olfactory bulb with ease.
  • the above described nerve structures can be electrically stimulated by electrical output manipulator control 517.
  • the power source is contained within this pulse generator box, and generates a battery powered current delivered through the conducting wires which will send electrical impulses to the CNS for the treatment of Alzheimer's and other neurodegenerative diseases.
  • FIG. 12 is the view of diagram 1200 showing the anatomy of the sphenoid sinus 525 and its relation to the surrounding structures in the cavernous sinus 541, and possible route of electrical impulses passing to the CNS.
  • the inventive device is passed through the sphenoid ostium 524 into the sphenoid sinus 525 and the balloon 527 is inflated.
  • the balloon has fine electrical conducting wires (including electrodes) surrounding that are capable stimulating the pituitary gland, five cranial nerves, autonomic nerves and internal carotid artery.
  • the electrical impulses are transmitted to cranial nerves III, IV, V, VI and nerves 503, 504, 505, 506, 507 in the cavernous sinus that carry the electrical impulses to the brain stem and basal ganglion.
  • the parasympathetic (autonomic) nerves supplying the internal carotid arteries 510 (and the Circle of Willis) within the wall of the cavernous sinus are stimulated by this inventive device, which makes them dilate within the BBB of the brain. This effect facilitates the transport of therapeutic agents within the BBB capillary plexus of the CNS and helps to remove the accumulated toxic substances within the neuropile.
  • the tip of the inventive device is provided with radio opaque marker 540 to identify the position of the catheter in the sphenoid sinus after insertion and during use with radiographic examination.
  • the pituitary gland in the sella turcica also are exposed to electrical impulses transmitted to the pituitary gland 509, which also transmits impulses to arterio venous plexus 511, pituitary stalk 512, and hypothalamic nuclei 513 and to thalamic radiation 514 to the rest of the brain.
  • the stimulation of the pituitary gland will have a profound effect on transmitting the electrical impulses and release of many trophic hormones from this master endocrine gland and hypothalamic nuclei.
  • the pituitary gland is heated or cooled with the Peltier device within the balloon 530 to the desired temperature for the treatment of CNS disease.
  • FIG. 13 is the diagrammatic presentation 1300 of the coronal section of the sphenoid sinus with inflated balloon 527 inside the sinus and its anatomical relationship to five cranial nerves within the cavernous sinus 541 on both sides, pituitary gland in the sella turcica, hypothalamus, thalamic radiation, and internal carotid artery.
  • the inventive device is positioned in one of the sphenoid sinus 525 passed through sphenoid sinus ostium 524, and the balloon 527 is inflated.
  • the electrical impulses from the balloon are transmitted to cranial nerve III 503, CN VI 504, CN Vi and V 2 - 505, 507, and CN VI 506 and internal carotid artery 510, pituitary gland 509 with its portal system 511, pituitary stalk 512, with its connection to hypothalamus 513, and thalamus 514 (Insert 13 A- 511, 512, 513, 514).
  • the insert 13 A shows the detail of the structure, which gets stimulation from the electrical impulses from the sphenoid sinus.
  • This inventive device delivers electrical stimulating impulses to these structures in the treatment of Alzheimer's and other neurological disease.
  • saline can optionally be infused from the catheter from pores at the end of the device, e.g., at or adjacent to balloon 527, and into the interior space of the sphenoid sinus; the saline can improve the strength of the electrical current, allowing improved transmission to the pituitary gland and its connection to cranial nerves and CNS. It is important to note that when the hypertonic saline fills the sphenoid sinus; the process must wait for 30-60 minutes so that the saline saturates the mucosal and boney wall of the sphenoid sinus absorbing the salt solutions.
  • the walls of the sphenoid sinus become more conductive to electrical pulses conducted to the surrounding structures including the cranial nerves in the cavernous sinus 541 pituitary gland 509.
  • the tip of the inventive device can be provided with radio opaque marker to identify the position of the catheter in the sphenoid sinus or on the olfactory mucosa after insertion and during use with radiographic
  • the sphenopalatine ganglion 508 is located immediately close to the sphenoid sinus ostium which can also be directly stimulated with additional electrical circuitry as shown in the diagram.
  • FIG. 14 is the diagrammatic presentation 1400 and the catheter device 220 whose tip is placed at the olfactory mucosa 45 lining of the nose close to the cribriform plate of the ethmoid bone and the olfactory bulb 35 within the cranium situated immediately above cribriform plate of the ethmoid bone.
  • the diagram shows the transmission of electrical impulses and route taken by the therapeutic agents deposited at the olfactory region of the nose (ORE) in this invention to treat Alzheimer's and other neurological ailments.
  • the electrical signals (therapeutic agents as well) from the olfactory mucosa 45 are transmitted to the olfactory bulb 35 to subarachnoid space (S AS) to the cerebrospinal fluid (CSF) then to various centers of the CNS.
  • the electrical impulses spread to the olfactory tract 46, to prefrontal cortex 47, medial olfactory area 48, to temporal lobes 50 (Entorhinal cortex), to lateral olfactory area 51 and its associated adjacent nuclei 49, hippocampus 52, hypothalamus 53, brain stem nuclei 54, to cerebellum 55.
  • the arrows show the extensive area where the electrical impulses and adjuvant therapeutic agents spread from the ORE to the CNS. From the subarachnoid space, the therapeutic agents can be transported to the eyes 56 through the optic nerve subarachnoid space, and the electrical impulses can also be transmitted to the eyes' optic nerve and cranial nerve III, IV, V, and VI nerves.
  • FIG. 15 is the diagrammatic presentation of the medial wall 1500 of the sagittal section of the nose with this inventive device in place.
  • the electrical impulse transmitter comes in contact with the olfactory mucosa 44, olfactory bulb 35, sphenopalatine ganglion 110, anterior ethmoidal nerve 107, pituitary gland 509 with its connection to the hypothalamus and thalamus, and its surrounding structures in the cavernous sinus with five cranial nerves 515 on each side and internal carotid artery 510.
  • the electrical impulses from the balloon are transmitted to cranial nerve on the adjacent wall of the sphenoid sinus and internal carotid artery 510, pituitary gland 509 with its portal system 511, pituitary stalk 512, with its connection to hypothalamus 513, and thalamus 514 (Insert 13A-511, 512, 513, 514).
  • the insert 15B shows the detail of the structure, which gets stimulation from the electrical impulses from the sphenoid sinus. This inventive device delivers electrical stimulating impulses to these structures in the treatment of Alzheimer's and other neurological disease.
  • saline is infused from the catheter within the balloon 527 device and makes the electrical current more conductive and easier to be transmitted to the pituitary gland, and its connection to cranial nerves and CNS.
  • the tip of the inventive device is provided with radio opaque marker 540 to identify the position of the catheter in the sphenoid sinus and /or on the olfactory mucosa after insertion and during insertion with radiographic examination. It has balloon 519, inflated while inserting and positioning the device in the ORE.
  • a device for heating or cooling the fluid to be pumped into the interior of the balloon 527 may also be included in the apparatus 530.
  • Figure 16 shows the catheter (device) in sinus and the nose with the insertion end located in a trans-nasal location. Explanations of the dimension of the number given are as follows:
  • the catheter that enters the sphenoid sinus should be shorter, and may be a inch long (e.g., from 0.75 to 1.25 inch).
  • the ostium or the opening for the sphenoid sinus and diameter is not found in the literature. I do believe it is bout 2 to 4millimeter in diameter. It may be enlarged with a boogie or angocath dilator like catheter. It is mostly made of thin sphenoid bone. Even if it cracks, while dilating, had no consequence. So the diameter of the catheter distal end with the balloon should be no more than 3 to 5 mm, e.g., from 2 to 6 millimeters.
  • This part of the catheter represents the distance of the roof of the nose which forms the olfactory mucosa and olfactory nerve. It is about 2.5 (e.g., 2.2 to 2.7) inches long and the catheter lodged at this part can be bit bigger in diameter than the part that enters the sphenoid sinus.
  • This part represents the anterior descending part of the nose. It is about 1 ⁇ 2 -3 ⁇ 4 inches' long. No special features are needed.
  • the size of the nose varies. This portion of the device may be from about 2-3 inches long. Note there is a balloon at the junction of the # 4 and #5. It holds the catheter in place without moving downwards. It abuts against the middle concha of the nose.
  • Preferred devices may include a nasal fiber optic scope to position the insertion end of the catheter device.
  • Figure 17 shows the electrical stimulator catheter device in place with the insertion end located at a trans-nasal location, connected to expanding balloon and or injections port.
  • the device includes only a single injection port at the proximal (external) end, and no fluid delivery port at a location to deliver therapeutic fluid to olfactory mucosa.
  • Figure 18 shows an example of an assembled catheter in position with an insertion end located at a trans-nasal location. It has three syringes. One each to expand the balloon and third one (which is optional) to instill therapeutic agents into sphenoid sinus or olfactory mucosa surface. It can be used to inject antibiotics to prevent any sphenoid sinus infection also or other anti Alzheimer's disease therapeutic agents.
  • Figure 1 shows various embodiments of the electrical stimulation catheter that can be incorporated.
  • the electrodes of the distal end are located on the expandable surface (e.g., balloon) and may be placed on an expandable mesh, such as an expandable wire, polymeric, or other type of natural or synthetic fabric or expandable sheet.
  • Figure 20 shows another embodiment of the electrical stimulation catheter placed in a trans-nasal location.
  • Figure 21 shows another embodiment of electrical stimulation with two balloon expanding syringes and electrical cell output monitor.
  • the device does not include any port at the insertion end that will allow for delivery of a fluid, e.g., a therapeutic fluid, to the nasal cavity such as to the olfactory mucosa or sphenoid sinus; methods of using this device also do require delivery of therapeutic fluid to the nasal cavity.
  • a fluid e.g., a therapeutic fluid
  • the device (catheter) system described herein can be miniaturized and designed with a small diameter for insertion in the nose of children and teens to treat autism, cerebral palsy, Down syndrome and such related central nervous system diseases other than Alzheimer's disease.
  • the electrode stimulator system that is capable of conducting electricity with the least resistance and that the electrodes be made up of suitable conductive physiologically acceptable material, for example, silver, iridium, platinum, iridium alloy, titanium, nickel- chrome alloy or other suitable combination of conducting metal alloys.
  • suitable conductive physiologically acceptable material for example, silver, iridium, platinum, iridium alloy, titanium, nickel- chrome alloy or other suitable combination of conducting metal alloys.
  • Each electrode can be insulated with a physiologically acceptable material such as polyethylene, polyurethane, or a co-polymer, which is a non-conductive, non- allergic, non-reacting synthetic or semi synthetic material.
  • Each one of the electrodes can exhibit a smooth surface, except for the distal end of each such electrode.
  • the ends can be optionally constructed to have a large surface area #110 to encounter the largest surface area of the olfactory mucosal nerves, sphenopalatine ganglion (SPG), trigeminal nerves, sphenoid sinus, and pituitary gland with hypothalamo hypophysial area.
  • the amount of electrical current used for stimulation of the neurological structures described herein is conducted through these electrodes is controlled by a control pane in electrical output manipulator 517 as shown in other figure 11 in order to keep the procedure within the desired parameters.
  • embodiments of described methods can also result in improving the oxygen supply to neurons and surrounding nerve structures due to
  • an optional therapeutic agent such as a pharmaceutical agent or other biologically active agent may be delivered to a patient in combination with electrical impulses stimulation as described.
  • a pharmaceutical agent or other biologically active agent may be delivered to a patient in combination with electrical impulses stimulation as described.
  • One or more of the following therapeutic active agents may be given systemically or if available through the olfactory mucosa.
  • therapeutic agents that may be delivered to a patient for treating Alzheimer's and other CNS degenerative diseases delivered directly to ORE include:
  • NMDA-receptor blockers and antagonists including ketamine, memantine
  • mAB monoclonal antibodies
  • Etanercept VII a cholinesterase inhibitor which is already in use in the treatment of Alzheimer' s such as tacrine, donepezil (Aricept®) Rivastigmine (Exelon®), Galantamine, and similar therapeutic agents
  • inhibitors include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride
  • dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride
  • an antioxidant vitamins for example vitamin A, B 12 B complex, D3 and others XII. hormone such as progesterone; an inhibitor of protein tyrosine phosphatases; an endogenous protein
  • Neurotrophic factors for example Nerve growth factors (NGF), fibroblast growth factor (bFGF), glial-derived neurotrophic factor (CNTF), pigment epithelium- derived factor (PEDF), glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), erythropoietin's, insulin, IGF-1, platelet derived growth factor (PDGF) and as such
  • NGF Nerve growth factors
  • bFGF fibroblast growth factor
  • CNTF glial-derived neurotrophic factor
  • PEDF pigment epithelium- derived factor
  • GDNF glial-derived neurotrophic factor
  • BDNF brain-derived neurotrophic factor
  • PDGF platelet derived growth factor
  • XIV Gene and stem cell therapy; and therapeutic agents therapy through the ORE after electrical impulses stimulation, or after electroporation or Iontophoresis.
  • a thorough examination of the nasal cavity by an ENT specialist is in order.
  • the patient should not be taking any blood thinning medications, free of nasal tumors, and without the history of epilepsy. It is also important for the attending physician to examine both sides of the nose with a fiber optic nasal scope and inspect the nasal passage, turbinates, roof of the nose, and ostium of the sphenoid sinus as well as the olfactory region (ORE). These scopes are flexible, easy to use and to clean. If the patient is sensitive for instrumentation, local anesthetic spray and KY jelly or similar lubricant will facilitate the examination and insertion of this device.
  • the patient may also be connected to an EEG or EKG and record before, during, and after the insertion and turning on the electrical impulses delivery system of invention. If the EEG shows the epileptic type of brain waves, the amperes of electrical impulses delivered is reduced, so that no epileptic episode will occur during use of this inventive device. It may be important to have a brain scan and anterior-lateral view of X rays of the nose with sphenoid sinus and nasal sinuses. Have emergency first aid supplies available in case they are needed.
  • the stimulation parameters may be adjusted to stimulate at amplitude of about 5-10% below the patient's neuronal activation threshold to about 15-20% over the patient's neuronal activation threshold.
  • the amplitude of the electrical stimulation typically is about 200 micro amps (uA) to about 400-500 milliamps (mA).
  • Other suitable combinations of stimulation amplitude and frequency are provided on a per patient dependent basis.
  • the electrical stimulation can be provided by pulse trains of an intermittent duration or
  • a cotton wad soaked in local anesthetics and vaso -constrictors is packed with angled nasal forceps. Antiseptic solutions are sprayed inside the nasal cavity.
  • a fiber optic naso scope is introduced through the external naris, all the way up to the sphenoethmoidal recesses located at the posterior upper angle of the nose. Then the body of the device is guided gently into the sphenoid sinus through the sphenoid foramina. If the opening (ostium) of the sphenoid sinus is narrow, it can be enlarged by dilators or inflatable balloons. The balloon is inflated with a liquid and the stimulation started. It may be necessary in some cases to insert the apparatus into both right and left sphenoid sinuses to achieve the desired therapeutic effect. Make sure the patients and caregivers participate during the treatment so that they may carry out the treatment at home.
  • This invention is based on electrical impulses delivery to the afflicted area, as the memory recall is related to electrical activity.
  • the device also give positive results during the stimulation processes by increasing the memory, recall of the past and remembrance of the events as they are happening due to the enhancing of the memory protein generation and activation of the ones that are already inside the neurons and providing electrical impulses needed to transmit the messages.
  • the electrical impulses are delivered continuously or intermittently depending upon the comfort of the patient and diagnosis of the condition. It may need to switched off as needed and the improvement in the signs and symptoms.
  • the device can be left in place for hours and days or more at a time.
  • the device can be removed to clean, treat with antiseptics, sterilize, reuse or replace.
  • the patient can be put on antibiotics if the infection of the nose and sinus are suspected.
  • the catheter and the balloon can be impregnated with antibiotics, antiseptics such as silver nitrate, antifungal agents to prevent the growth of the microbes on the device.
  • Therapeutic agents are administered orally, intravenously or intra nasally to olfactory mucosa depending on their formulation to the patient once it is determined the electrical impulse have caused dilatation CNS BV and broken the BBB to a certain extent.
  • the drugs administered are specific to the disease. They are selected from described list herein for Alzheimer's disease.
  • any one or more of the following therapeutic agents may optionally be administered to the site of the olfactory mucosa to treat Alzheimer's disease through the delivery syringe attached to the catheter as shown in the diagrams Figs. 6-10 as an example.
  • a device and method may be used that do not involve delivery of therapeutic agent.
  • a) Take 300 mg of bexarotene; dissolve it in a solvent alcohol, or dimethyl sulfoxide (DMSO), with suitable carriers, which include physiological saline or phosphate buffered saline (PBS).
  • DMSO dimethyl sulfoxide
  • PBS phosphate buffered saline
  • This solution can contain thickening and solubilizing agents, for example glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • the final formulation contains 30 mg of bexarotene per ml of solution.
  • b) Then take 100 IU of rapid acting insulin and dilute it in 5ml of normal saline, in which each ml contains 20 units of insulin.
  • olfactory mucosal stimulation is discontinued and resumed after the delivery of therapeutic agents to the olfactory mucosa. Electrical stimulation is continuing which will facilitate the uptake of these therapeutic agents. This procedure is repeated twice a day for the first week and then three times a week and then once a week depending on the response. The concentration of therapeutic agents is increased or decreased depending upon of the reaction and response of the patient.
  • hypoglycemia and how to treat if the complication develops. It is important to note that if it is deposited on the olfactory mucosa, chances of developing hypoglycemia will be avoided. It can occur if the insulin is de osited in the respiratory part of nasal mucosa instead of olfactory mucosa; which will be absorbed systemically which may contribute to the hypoglycemic effect. Since bexarotene is a vitamin A derivative, co administration with vitamin A may add to the drug's toxicity. The dose we use is so small; we do not believe that one need to be concerned with such toxic effects including hypoglycemia.
  • Ketamine is a GABA receptors antagonist. It acts by blocking the N-methyl- D-aspartic acid (NMD A) receptor, which receives signals from glutamate.
  • NMD A N-methyl- D-aspartic acid
  • ketamine is most suitable in the treatment of Alzheimer's. Besides protecting the neurons from the NMD A receptor.
  • Ketamine is also a dissociative anesthetic (no such effect due to the very small doses we use here), an excellent sedative, it is an anti arrhythmic, and reduces the pain perception due to its local anesthetic like effects.
  • ketamine for wound dressing changing in burn patients since 1969 and postpartum after delivery to ally the anxiety under regional anesthesia.
  • the micro doses of ketamine we use in the olfactory mucosal instillation in this invention have no hallucinogenic or other ill effects.
  • the present inventor has used these therapeutic agents in hundreds of cases such as dissociative anesthesia, neuropathic pain, depression, hiccup (Shantha, T. R.
  • Ketamine for the Treatment of Hiccups During and Following Anesthesia A Preliminary Report in Anesthesia And Analgesia. Current Researches VOL. 52, No.5, September-October, 1973), ALS with Insulin -like growth factor-I (IGF-1), insulin, and experiment show that it inhibits the rabies virus multiplication (U. S. Patent Application Publication
  • the invention described herein can incorporate ketamine delivered to olfactory mucosa with bexarotene and insulin.
  • the intranasal use of ketamine delivery to the olfactory mucosa reduced or relieved the depression associated with many neurodegenerative diseases. In the early cases, it completely ameliorated the depressive condition especially in dementia. These patients felt a sense of well being. Because of the small dose used to treat the above described
  • the adjuvant therapeutic agent such as acetyl cholihesterase inhibitors are added to increase the CNS levels of acetylcholine to enhance the memory and cognition in Alzheimer's disease patients.
  • the electrical stimulation of the brain described in this invention through the peripheral nervous system projections, and pituitary gland; which in turn stimulates the malfunctioning nerve tissue (neuropil) of the CNS holds significant promise for the treatment of Alzheimer's, and other neurodegenerative diseases.
  • Such stimulation is reversible, non-destructive, easy to use, non invasive, and least expensive.
  • Nerve stimulation is accomplished directly or indirectly by depolarizing a nerve membrane, causing the discharge of an action potential; or by
  • a nerve membrane hyperpolarization of a nerve membrane, preventing the discharge of an action potential.
  • Such stimulation occur after electrical energy, transmitted to the vicinity of a nerve or directly in contact with the nerve itself as it happens in olfactory region stimulation to be transmitted to the afflicted brain of Alzheimer's disease.
  • the nerve stimulation is also anti-neuroinflammatory.
  • Neuroim arnmation is the primary denominator in all these conditions including Alzheimer's disease.
  • Example 1 A method for treating Alzheimer's diseases, with this said device and method applying to a subject a specific low frequency pulsed electrical impulses (signals, pulses) through this inventive device located at adjacent nerves whose stimulation is transmitted to the central nervous system to excite the central nervous system through the olfactory nerves, sphenopalatine ganglion, sphenoid sinus, cranial nerves III, IV, V, and VI, pituitary gland, hypothalamic - hypophysis tract, thalamic radiation, brainstem, cerebellum, parasympathetic nerves of the human body.
  • This method and device is comprising of: an insertion body having a balloon with a flexible outer surface adapted to contact and conform to the interior surface of the sphenoid sinus, the balloon having an interior;
  • thermocouple connected to and residing within the interior of the balloon for locally heating and cooling fluid present within the balloon and for locally heating and cooling the interior surface of the sphenoid sinus immediately adjacent to the outer surface of the balloon; d. a (optional) temperature sensor being connected to the interior of the balloon and to a temperature indicator external to the balloon for monitoring the temperature of the outer surface of the balloon;
  • connection means for connecting the electrical stimulators electrodes to a power source and control device outside of the sphenoid sinus for stimulating the sphenoid sinus and proximate structures with controlled electric current output;
  • an open catheter at the end of the balloon to deliver saline to increase the electrical conductivity and for delivering adjuvant therapeutic agents.
  • a method for delivering the electrical impulses according to example 1, for stimulating the brain of a Alzheimer's disease patients through olfactory nerves via olfactory mucosa comprising of: a. Electrodes, applied to the olfactory nerves through olfactory mucosal area which conducts the electrical pulses to the neural tracts connecting these structures to the CNS through the olfactory bulb, and
  • a control unit located outside the nasal cavity adapted to drive the one or more electrodes to apply a electrical current to the site capable of stimulating olfactory nerves, which will transmit the electrical impulses to the regions of the brain through their connection in the CNS conducted to the CNS affected by the Alzheimer's
  • the olfactory region (ORE) part of the inventive device is provided with therapeutic agents' delivery pores to deliver adjuvant therapeutic agents specific to Alzheimer's and neurodegenerative diseases to the olfactory epithelium to be transported to the CNS bypassing the blood brain barrier through the olfactory bulb.
  • the stimulator device for the olfactory mucosa is provided with Iontophoresis
  • Electrodes to enhance the uptake of therapeutic agents by the receptor cells to be transported to the CNS by passing the BBB.
  • a method for applying the electrical impulses according to example 1, for stimulating the brain of Alzheimer's patients using electrical impulses through sphenopalatine ganglion nerves comprising of: a. Electrodes, applied to the sphenopalatine ganglion area on the medial wall of the nasal cavity located immediately below the sphenoid sinus and to the neural tracts connecting these structures to the CNS through sphenopalatine ganglion, and b. a control unit, located outside the nasal cavity adapted to drive the one or more electrodes to apply a electrical current to the site capable of stimulating
  • sphenopalatine ganglion nerves which will transmit the electrical impulses to the regions of the brain through their extensive connection in the CNS and to the blood vessels (BV) affected by the Alzheimer's.
  • Ex. 4 The method according to example 1 , in which a tube is connected to the balloon for infusing fluid into the interior of the balloon which heats or cools the balloon.
  • the apparatus is further comprising of a device external to the balloon and connected to the balloon for heating and cooling fluid prior to infusion into the interior of the balloon while the balloon is in the sphenoid sinus.
  • Ex. 5 The method according to example 1 , in which the means for inflating the balloon is at least one tube connected to an inflator syringe.
  • the method according to example 1 is comprised to configure the electrical impulses to cause an increase in the electrical activity in these diseases afflicted neurons and synapses of the brain and brain stem.
  • Example 7 According to the method of treating Alzheimer's and other neurodegenerative diseases using this device involves applying the electrical stimulation continuously or intermittently to olfactory nerves, sphenopalatine ganglion, trigeminal nerves, five cranial nerves, pituitary gland with hypothalamo hypophysial region, entorihinal and other cortical cognition centers.
  • This present inventive method of treating Alzheimer's disease involves applying the electrical impulses through the transmitting device connected to the generator housing stimulator outside the nose by connecting electricity conduction wires.
  • This present inventive method of treating Alzheimer's disease involves applying the electrical impulses through fine electrical wires made of suitable conductive physiologically acceptable material such as silver, iridium, platinum, iridium alloy, titanium, nickel-chrome alloy and other suitable combination of conducting metal alloys.
  • Each electrode is insulated with a physiologically acceptable material such as polyethylene, polyurethane, or a co-polymer, which is non-conductive, non-allergic, non-reacting synthetic or semi synthetic materiel.
  • the apparatus according to example 1 is comprised of flexible insulated electrodes adapted for insertion through a nostril of the patient to the desired anatomical and histological areas.
  • the apparatus according to example 1 is comprised of three wires, connected to the control unit separately so that they may be individually turned on and off to stimulate olfactory nerve, sphenopalatine ganglion, or structures around the sphenoid sinus individually or combination, as needed from the electrical output manipulator, from the external position to get the maximum therapeutic effect.
  • each one of the wires connected to these individual anatomical sites has an Ampere (mAP) adjuster and a time setter to deliver the desired amperage of stimulating electricity at a set time, located outside the nose from the electrical output manipulator.
  • mAP Ampere
  • the apparatus according to example 1 is configured such that the electrical control delivery unit is introduced to both sides of the nose.
  • the apparatus according to example 1 is configured such that the catheter with electrical wired embodiment is provided with the temperature and location sensor located at the tip of the stimulator device.
  • the apparatus according to example 1 is configured such that one or more electrodes are adapted for use for hours, weeks, and months at a time, based on the patient's compliance and the stage of the disease afflicting the patient.
  • the apparatus according to example 1 is configured such that the electrical amplitude and milliamps delivered are adapted to set the amplitude of the current, to induce the increase therapeutic effect and induce permeability in the BBB blood vessels.
  • the apparatus according to example 1 is configured such that the shape of the electrical impulse waveform is selected and delivered from the catalog, consisting of an exponential decay, a ramp up and down, square wave, a monophasic shape, a biphasic shape, a sinusoid, a saw tooth, and with a direct current (DC) component.
  • the control unit is set to deliver the selected waveform of the current, so as induce the desired therapeutic effect on the brain in the treatment of
  • Alzheimer's, and other neurodegenerative diseases are associated with Alzheimer's, and other neurodegenerative diseases.
  • the apparatus according to example 1 is configured such that the electrical amplitude and milliamps delivered are adapted to set the amplitude of the current, to induce the desired therapeutic effects. At the same time, it enhances the
  • Iontophoresis permeability for the uptake and transport of therapeutic agents from the olfactory mucosa, and sphenoid sinus sites, bypassing the BBB, by creating elecroporation and iontophoresis effects of olfactory mucosa and sphenoid sinus lining, which allows large molecules of therapeutic agents' transportation to the CNS, the site of pathology bypassing blood-brain barrier.

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Abstract

L'invention concerne un dispositif de distribution d'impulsions électriques inoffensives et efficaces pour stimuler le SNC par transmission d'impulsions électriques dans les nerfs olfactifs, le ganglion sphéno-palatin et ses ramifications; les 3ème, 4ème, 5ème, 6ème nerfs crâniens; l'hypophyse, la voie hypothalamo-hypophysaire, le thalamus, la radiation thalamique, le tronc cérébral et le cervelet en vue du traitement de la maladie d'Alzheimer.
PCT/US2014/047566 2013-07-22 2014-07-22 Traitement de la maladie d'alzheimer Ceased WO2015013252A1 (fr)

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