WO2022226606A1 - Implantable semi-invasive eti-nd device to elicit repetitive waves of spreading depression - Google Patents
Implantable semi-invasive eti-nd device to elicit repetitive waves of spreading depression Download PDFInfo
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- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/316—Modalities, i.e. specific diagnostic methods
- A61B5/369—Electroencephalography [EEG]
- A61B5/37—Intracranial electroencephalography [IC-EEG], e.g. electrocorticography [ECoG]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
- A61B5/686—Permanently implanted devices, e.g. pacemakers, other stimulators, biochips
-
- 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
- A61N1/36064—Epilepsy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
- A61B5/021—Measuring pressure in heart or blood vessels
-
- 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
- A61N1/0529—Electrodes for brain stimulation
- A61N1/0531—Brain cortex 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
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/205—Applying electric currents by contact electrodes continuous direct currents for promoting a biological process
-
- 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
- A61N1/36128—Control systems
- A61N1/36135—Control systems using physiological parameters
- A61N1/36139—Control systems using physiological parameters with automatic adjustment
Definitions
- the inventions disclosed herein involve devices implanted at the top or under the exposed dura mater 408, after extensive craniotomy procedures, to detect and stop electrographic seizures and treat epilepsy.
- the system triggers waves of Leao Spreading Depression (SD) 301, leading to a silencing of abnormal electrical brain activity.
- SD Leao Spreading Depression
- the phenomenon of excitability inhibition propagates as a wave in the gray matter by means of contiguity, regardless of functional divisions or arterial territories.
- ICP and iTemperature measures multimodal detection
- the electrode-to-tissue interface neurodepressor (ETI-ND) device invention is tailor made for drug-resistant seizures (“personalized medicine”) in epileptic patients facing a year-long wait to repair extensive cranial defects (FIG. 1). BACKGROUND OF THE INVENTION
- the skull 401 is hard and inflexible, while the brain is soft with the consistency of gelatin.
- the brain is encased by three meningeal layers of protective covering inside the skull.
- the outermost layer, the dura mater 408, contributes to compartmentalization of the brain and maintenance of intracranial pressure (ICP).
- ICP intracranial pressure
- Cerebrospinal fluid (CSF) 405 fills the ventricles 406 of the brain and the space between the pia mater and the arachnoid, innermost layers.
- CSF Cerebrospinal fluid
- the primary function of the meninges and of the cerebrospinal fluid is to protect the nervous system (CNS).
- the dura mater 408 is partitioned into several septa, which support the brain. The outer portion of the dura over the brain serves as a covering, or periosteum, of the inner surfaces of the skull bones. The strong dural layer has been described by B.
- the pressure in the cranial vault is normally ⁇ 20 mm Hg (Lassen, 1959).
- the clinical implication of the change in volume of the component is an increase in ICP, leading to a decrease in cerebral blood perfusion and/or to herniation of the brain.
- DCT decompressive craniectomy
- Cranioplasty (cranial repair) 101, 102 should be performed as soon as the brain is lax to mitigate many of the late complications (FIG. 1) (Rozental’s group) - DOI: 10.21203/rs.3.pex-1384/v1 .
- ICP monitoring is key in neurocritical care, including TBI, hemorrhage, stroke, and intracranial hypertension.
- Information which can be derived from ICP and its waveforms includes cerebral perfusion pressure, regulation of cerebral blood flow and volume (FIG. 2). These parameters support customized medicine and critical prognosis (Czosnyka and Pickard, 2004).
- the configuration of the ICP pulse wave, generated by arterial pulse represent a sum of three major components: #1 ) the P1 wave, also known as the percussion wave, correlates with the arterial pulse transmitted through the choroid plexus into the CSF 405, and via a column of fluid into the EVD transducer; #2) the P2 wave, also known as the tidal wave, represents cerebral compliance, it can be thought of as a "reflection" of the arterial pulse wave bouncing off the springy brain parenchyma; and, #3) the P3 wave, also known as the dicrotic wave, correlates with the closure of the aortic valve, which makes the trough prior to P3 the equivalent of the dicrotic notch (FIG.
- the P1 wave also known as the percussion wave
- the P2 wave also known as the tidal wave
- the P3 wave also known as the dicrotic wave
- Epilepsy is a debilitating toll and a clinical conundrum, especially because 30% with the condition are not controlled by existing pharmacological treatments;
- Neuronal synchrony activity can be brought about by several mechanisms, including enhancement of excitatory synaptic transmission, abnormal excitatory connections, decreased activity of inhibitory synaptic transmission, increased synchrony of inhibitory neuronal networks. Chemical synapses are undoubtedly necessary in the generation of most, if not all, types of seizures.
- Reduction in life expectancy can be up to 2 years for people with a diagnosis of idiopathic/cryptogenic epilepsy, and the reduction can be up to 10 years in people with symptomatic epilepsy.
- Seizures are classified into two major groups: i) Generalized seizures, affecting both sides of the brain (absence seizures and tonic-clonic seizures [‘grand mal seizures’]); and, ii) Focal seizures, located in just one area of the brain (also called ‘partial seizures’).
- i) Generalized seizures, affecting both sides of the brain absence seizures and tonic-clonic seizures [‘grand mal seizures’]
- Focal seizures located in just one area of the brain (also called ‘partial seizures’).
- Epileptic patients who continue to have abnormal discharges are at greater risk of a number of complications, ranging from brain injuries to SUDEP, one of the most common cause of death from seizures (F. Lado and S.L. Moshe, Epilepsia, 2009).
- iTemperature brain temperature preceded by an increase in cortical blood flow, edema, increase in ICP in association with changes in heart rate and arterial pressure, and increase in GJ-coupling among neural cells. Detection of early events can reduce epilepsy risks.
- CSF 405 temperature measured directly in the frontal horn of the lateral ventricle 406 ( «5 cm below the brain surface), is on average 0.3-0.9°C above body temperature (Hirashima et al., 1998; Rossi et al., 2001). Reports on human brain temperatures confirmed a thermal gradient from the hotter core to the cooler periphery (Whitby, 1971 ; Mellergard and Nordstrom, 1990; Hirashima et al., 1998).
- Hypoxic-ischemic encephalopathy is the brain injury caused by O2 deprivation, also known as perinatal asphyxia. The newborn's body can compensate for brief periods of depleted O2, but if the asphyxia lasts, brain tissue is compromised - “Gap junctions: Impact of seizures following perinatal HI insults on the extent of delayed neurotoxicity”, Epilepsy Foundation (US), Special Grants Program (2002) to Moshe S and Rozental, R.; Blockade of GJs in vivo provides neuroprotection following perinatal global ischemia. Stroke 36(10), 2005 (Rozental’s group).
- Gap junctions specializations of cell surfaces, mediate electrical synchrony and metabolic cooperation between apposed cells by providing conduits for the exchange of ions and small molecules ( ⁇ 1.5 kDa) by diffusion directly from one cell to another.
- These macrochannels appear as a plaque-like contact among cells, widespread in both the immature and adult brain - work by our group: “Molecular physiology of gap junction channels formed by connexin43”. In Ion Channels to Cell-Cell Conversations (R. Torre and J.C. Saez, eds.) Plenum Press, 1997; “Cell-cell communication via gap junctions”.
- GJs are built up by docking of two hemi-channels, each hemi-channel is composed of six protein subunits, called connexins (Cxs) (DeRobertis and DeRobertis, 1980). At least 20 Cx subtypes have been identified and at least 9 are expressed in the brain (Cx26, Cx30, Cx32, Cx33, Cx36, Cx37, Cx40, Cx43, Cx45 and Cx47). For most of them, orthologs in the human genome have been found - follows studies by our group: “Temporal expression of neuronal connexins during hippocampal ontogeny”. Brain Res. Reviews 32(1 ), 2000; “Nervous system diseases involving gap junctions”. Brain Res. Reviews, 2000.
- Cx36 is the specific Cx subtype expressed in CNS neurons (Rozental et al. , 2000), while Cx43 accounts for approximately 95% of all functional GJs expressed in cortical astrocytes - studies by our group: “Cell to cell signaling: An overview emphasizing gap junctions”. Cellular and Molecular Neuroscience (Ed: J. Byrne & J. Roberts), 2003; “Functional Properties of Channels Formed by the Neuronal GJ Protein Connexin36”. J. Neuroscience 19 (22): 1999.
- Cx36 expression in the CNS appears to be restricted to neurons.
- Cx43 expression has been established in astrocytes and a variety of studies support a role for interastrocytic GJs in cell death (Lin et al., 1998; Rami et al., 2001 ). Numerous roles have been postulated for GJ in the brain, including propagation of waves of spreading depression (SD) 301 and seizures. Intercellular communication mediated by GJs mediates direct exchange of ions and signaling molecules between cells thereby synchronizing electrical activity between neurons and metabolic activity within astrocytes, neurons and from one cell type to another. - studies by our group: Gap junctions: The “kiss of death” and the “kiss of life”. Brain Res.
- a HI penumbra is characterized by the potential for functional recovery, without damage, provided that local blood flow can be reestablished - as described in a number of studies, including ours - “Prevention of cerebral vasospasm by local delivery of cromakalim in subarachnoid hemorrhage”. J Neurosurq. 110(5), 2009; “Blockade of GJs in vivo provides neuroprotection following perinatal global ischemia”. Stroke 36(10), 2005; “Reentrant Spiral Waves of Spreading Depression” PNAS 109(7): 2585-2589, 2012 (FIG. 3 A)
- GJ-mediated intercellular coupling increases within the penumbra, and between cells within the penumbra and adjacent healthy cells, to support exchange of vital metabolites through intercellular communication, and multiple electrical and biological signals are triggered by periinfarct tissue, triggering physiological waves of SD 301, which, in turn, antagonize electrographic seizures in areas adjacent to the penumbra.
- ictal period refers to states such as a seizure.
- interictal refers to the period between seizures.
- SD 301 is a slow diffusion-mediated self-sustained wave of generalized depolarization of gray matter that does not respect synaptic connectivity and severely disrupts neuronal function.
- SD results in a temporary collapse of transmembrane ionic gradients and membrane potential and is characterized by a negative field potential IQ- 20 mV in amplitude and 1-2 min in duration, propagating at a velocity of a few millimeters/min.
- the advancing wave front is accompanied by a K + efflux into the interstitial space, followed by a long lasting electrical silence, (FIG. 3A) - PNAS 109(7), 2012 (Rozental’s group).
- SD waves may be elicited repetitively in a time frame in which the nervous tissue is still refractory to action potentials generation and propagation (absolute refractory period) - PNAS 109(7):2585-2589, 2012 (Rozental’s group).
- SD phenomenon
- tetanic or direct current (DC) stimulati KCI
- hypo/hyper-osmotic medium e.g., a droplet of H2O [50 pL]
- mechanical e.g., vibration, balloon-stretching
- photonics e.g., pulse lasers
- thermal-based catheter microtubing e.g., metabolic inhibitors, ouabain, glutamate receptor agonists (e.g.
- Intracranial monitoring of waves of SDs 301 can be performed with platinum electrodes in unfiltered DC-coupled recordings (Hartings JA et al., 2017 - “Direct current ECoG for clinical neuromonitoring of spreading depolarizations”, J. Cereb Blood Flow Metab 2017, Vol. 37(5) 1857-1870).
- the SDs are characterized by negative DC shifts throughout recordings.
- EEG waveforms may be characterized based on their location, amplitude, frequency, morphology, continuity (rhythmic, intermittent or continuous), synchrony, symmetry, and reactivity.
- the most frequently used method to classify EEG waveforms is by the frequency, so that EEG waves are named based on their frequency range: delta (0.5 to 4Hz); theta (4 to 7Hz); alpha (8 to 12Hz); sigma (12 to 16Hz) and beta (13 to 30Hz).
- delta 0.5 to 4Hz
- theta (4 to 7Hz
- alpha 8 to 12Hz
- sigma (12 to 16Hz) sigma
- beta 13 to 30Hz
- there are other waveforms such as infra slow oscillations (ISO) ( ⁇ 0.5Hz) and high-frequency oscillations (HFOs) (> 30Hz).
- ISO infra slow oscillations
- HFOs high-frequency oscillations
- BCI are systems that allow communication, through wired or wireless networks, between the brain and a variety of machines.
- the BCI system works in three main steps: collecting brain signals, interpreting them and outputting commands to a connected machine according to the signal received.
- BCI is separated in three categories depending on the method used to collect brain signals: i) non-invasive; ii) semi-invasive; and, iii) invasive.
- the EEG signal is taken by placing electrodes on the scalp, so on the most external part ( non- invasive) , the ECoG signal can be taken from electrodes placed in the dura 408 or in the arachnoid ( semi-invasive ) or the intraparenchymal signal is taken directly implanting electrodes in the cortex ( invasive ) (FIG. 2, FIG. 4, FIG. 7).
- EEG provides the recording of electrical activity of the brain from the surface of the scalp. It takes thousands of snapshots of electrical activity across different sensors in a single sec.
- the spatial resolution of EEG is determined by the number of electrodes used. Typically at least 32 electrodes are used, up to 256. In general, spatial resolution for EEG is low (e.g., compared to ECoG and fMRI) because the signal needs to travel through different layers up to the skull 401.
- ECoG uses electrodes placed on the exposed surface of the brain to measure electrical activity from the cerebral cortex.
- the electrodes may be placed on top of the dura mater (epidural) or under the dura mater (subdural) 408.
- the strip or grid electrodes covers a large area of the cortex (from 4 to 256 electrodes).
- the positive characteristics of ECoG are: i) high spatial resolution and signal fidelity; ii) resistance to noise; iii) lower clinical risk and robustness over long recording period; and, iv) higher amplitude.
- Deep brain stimulation is a neuromodulation procedure designed to help in the management of refractory seizures.
- DBS involves implanting electrodes into specific areas of the brain, and then stimulating these areas with small regular electrical pulses modulated by electrical stimulation devices (ESDs).
- ESDs electrical stimulation devices
- ESDs electrical stimulation devices
- NeuroPace only a few developers, including NeuroPace, claim to perform and detect seizures prior to their onset.
- NeuroPace efficacy is limited to 67% during the first year of the therapeutic procedure. The estimated cost of the system is about $37,000 ($35,000-$40,000), out of reach to a large fraction of individuals.
- Implantable devices have been developed aiming to provide both detection/prediction of ictal activity and electrostimulation for attenuating or stopping an epileptic seizure, like NeuroPace (US Pat. No. 6,810.285).
- the EEG recording electrodes at a depth of up to about 1 to 2 cm into the brain lobes - at most 1/3 to 1/4 of the average distance between the scalp and the ventricle 406, are connected to the implant device implanted on the outer surface of the cranium - used for the detection of ictal activity as well as the delivery of DC electrostimulation.
- Direct current (DC) is the flow of electric charge in only one direction. It is the steady state of a constant-voltage circuit. Most well-known applications, however, use a time-varying voltage source.
- Alternating current (AC) is the flow of electric charge that periodically reverses direction. If the source varies periodically, particularly sinusoidally, the circuit is known as an alternating current circuit.
- Fluctuating DC does not exist, but, at the instant of connection of a DC voltage to a load, a transient current flow through the conductors (wires, PCB traces, etc.) charging up their capacitances.
- This transient current is AC, and is actually a propagating EM wave that generates fluctuating EM fields (magnetic and electric) as it travels along. Afterwards, the current is DC and there is no more propagating EM wave.
- the EM fields are static instead of fluctuating.
- AC current travels at the speed of light in the medium, which is about 300,000 kilometers/sec for a bare wire in air, and about 210,000.000 km/s for a wire with a thick layer of PVC insulation.
- Continuous DC currents are associated with a continuous flow of electrons from the negative to the positive terminal - travelling at a velocity of about 4 kilometers (about 3 miles)/hr.
- the literature shows that both DC and AC stimulation support effective neurostimulation outcomes (e.g., Fusca, Ruhnau, Demarchi, Weisz, & Neuling, 2015). However, because of unique aspects of AC stimulation properties, it may command the wider range of clinical applications going forward (Antal & Paulus 2013; Herrmann et al., 2013).
- DC is commonly found in many extra-low voltage applications and some low- voltage applications, especially where these are powered by batteries or solar power systems (since both can produce only DC). Most electronic circuits require a DC power supply.
- the DC current unlike AC, does not change the magnitude and polarity with time. It is characterized by a constant magnitude and direction and as the direction and magnitude not changes so the frequency of the current is zero. In contrast, the AC current displays Time Period and Frequency.
- DC stimulation tends to modulate neuronal activity in a polarity-dependent way, either increasing local neural excitation (anodal stimulation) or decreasing it (cathodal stimulation), depending on which of two electrodes is placed over a target area. That is, DC stimulation mainly affects the firing rate of neurons in the target area. Stimulation may be continuous or intermittent (pulsed). EEG findings support the notion that DC stimulation’s site-specific effects also can provoke sustained and widespread changes in other parts of the brain via the brain’s multicircuit networks (Zaghi et al., 2009; Tanaka & Watanabe 2009; Jaberzadeh & Zoghi, 2013).
- tDCS is applied to modulate excitability of dysfunctional neurons. Accordingly, weak electrical pulses (in the range of 0.1 - 2 mA [0.002 amps), applied through electrodes placed on top of the scalp, with conduction to the scalp facilitated by conductive gels, modulate the static DC fields altering the firing rates of neurons.
- tDCS has shown to improve cognitive functions (such as memory, attention, or language processing) as well as motor functions (such as strength or dexterity) in patients with neurological conditions (Boggio et al., 2006; Reis et al., 2009; Orban de Xivry et al., 2011 ; BOtefisch et al., 2004; Fregni et al.
- Frequently used parameters include an electrode size of 25-35 cm 2 , a current of 1-2 mA for up to 20-40 min, for 1 up to 20 sessions; shown to be safe and effective (Brunoni et al., 2012).
- EEG electrode-to-tissue interface
- Non-pulsatile or near-DC stimulation and DC stimulation are expected to be less effective than to pulsatile or to AC stimulations when applied through an implanted ETI because of charge densities and the inability to maintain charge balancing during delivery (Merril et al. (2005).
- TH Therapeutic hypothermia
- Electrodes strips are usually manufactured from soft, flexible, thin transparent Silastic sheets that have small metal contacts and wires embedded within them. Both stainless steel and platinum contacts are available. Commercial providers offer an array of choices in varying dimensions. A common configuration spaces the 5 mm electrode centers 1 cm apart. Various sizes of grids are available, such as 4 c 5 cm and 6 x 8 and 8 c 8 cm. Both strips and grids have electrode leads.
- VPS Ventriculoperitoneal shunt catheters
- MXenes a kind of two-dimensional unit that displays an ‘accordian-like shape’.
- MXenes have emerged as a unique class of layered-structured material with key features, as good conductivity (comparable to metals), enhanced ionic conductivity, hydrophilic property (derived from their hydroxyl or oxygen-terminated surfaces), and mechanical flexibility (Xin M et al., Front Chem 21 April 2020).
- ETI-ND The ETI-ND device is a light-weight “3-in-1 sensor system” (EEG/ iTemperature/ICP), an important seizure monitoring tripod, combined with 1 effector electrode system to trigger SD waves 301, is mechanically flexible and stretchable to meet patient needs (FIGS. 5-6).
- the different modal units contained within a single physical enclosure, namely the ‘housing’ (FIGS.
- 5-6) may comprise a plurality of spatially separate units each performing a subset of capabilities mentioned above.
- the combined multiple functions (EEG, thermal and pressure sensors and SD electrodes) and capabilities of the subsystems described above may be performed by electronic hardware, computer software (or firmware), or a combination thereof.
- It includes a remote terminal that wireless collects information from the device’s ‘central processing unit’ (CPU) 507 and transfers it to a patient data management system, where neurologists may evaluate seizure activity and provide a tailored feedback through the ‘’Communication System” (FIG. 6A), updating the CPU 507 by fine-tuning the seizure ‘Detection Subsystem” (FIGS. 5-6).
- CPU central processing unit
- an active feedback loop triggers waves of SD more efficiently, capable of leading to a silencing of brain excitability.
- These early detection systems are able to effectively abort seizures, tailoring antiseizure treatment.
- ICP intracranial pressure
- iTemperature is closely associated with partial and generalized seizures.
- changes in ICP can be a useful surrogate marker of seizures on the intensive care unit in association with changes in heart rate and arterial pressure (Yang et al. Epilepsy Res., 2002).
- focal seizures produce an increase in local cerebral metabolism and blood flow, leading to changes in brain temperature within a few sec of seizure onset. (FIG. 2, FIG.6A,B,C; FIG. 7).
- An ETI device, 3-in-1 sensor system, capable of monitoring ICP and iTemperature measures (FIG. 6): an implantable device according to the invention is tailored made for detecting and abolishing epileptic, high frequency EEG discharges, and EEG seizures in real-time on a 24-7 basis.
- the ETI device system includes a low-power CPU, as well as customized electronic circuit modules in a detection subsystem (FIG. 6A).
- the detection subsystem which in the context of the present application is a form of detection of abnormal EEG discharge patterns, ictal and electrographic seizures, and monitor SD slow waves, triggered by the ETI system to abolish the abnormal electrical activity.
- An ETI system for detecting and abolishing seizures of a living being semi-invasive (epidural or subdural) 404 wherein the system comprises: EEG sensors for detecting brain fast and slow electrical activity, ‘accordian-like pressure sensors’ (e.g., multi-layer sensors or single layer pressure sensors), and a set of thermosensors; an analyzer that receives the intracerebral blood arterial pressure information and derives at least one parameter that correlates with ICP (e.g., a time delay between systolic maximum and the dicrotic notch) to provide ICP data from the blood pressure information; and an output device (e.g., a monitor, cell phone) for displaying the ICP and iTemperature data.
- EEG sensors for detecting brain fast and slow electrical activity
- ‘accordian-like pressure sensors’ e.g., multi-layer sensors or single layer pressure sensors
- thermosensors e.g., thermosensors
- an analyzer that receives the intracerebral blood arterial pressure information and der
- An aspect of one of the embodiments disclosed herein includes the realization that maximizing treatment outcomes can be achieved by providing epileptic patient with an implantable ETI system that is configured to trigger and to detect neurodepressive waves of SD 301 , followed by an electrical silence (i.e., refractory period), during which ictal discharge can not propagate (FIG. 3B).
- an electrical silence i.e., refractory period
- 5 thermal sensors are placed along an intraparenchymal conduit extending downwardly from the ‘housing’ (level of the ETI-ND system implantation - level 0) to the vicinity of the cerebrospinal fluid (CSF) 405, 407 (ventricles 406) (FIG. 4, FIG. 8).
- Sensors are therefore positioned at 1 cm, 2 cm, 3 cm, 4 cm (to assess parenchymal temperatures), wherein the 5 th sensor directly senses the temperature of the CSF 405 (i.e. , temperature of the liquor) ( baseline temperature), providing a signal representative of the thermal gradient from the hotter core to the cooler periphery to the temperature device circuitry by way of the conduit 604 (FIG. 8).
- the 5 th sensor directly senses the temperature of the CSF 405 (i.e. , temperature of the liquor) ( baseline temperature), providing a signal representative of the thermal gradient from the hotter core to the cooler periphery to the temperature device circuitry by way of the conduit 604 (FIG. 8).
- the ETI-ND system can be implanted within the bone defect 408, placed either over the exposed dura mater, or subdural, facing the brain parenchyma.
- an existing large-sized cranial defect arising from many etiologies, can easily accommodate the ETI-ND.
- the implantable ETI- ND system can be repositioned and fixed on the inner face of the cranial prostheses (periosteum/pericranium placement).
- the attachment of the ETI-ND system to the prostheses is independent of the physical and mechanical properties of material used for its construction (e.g., PMMA bone-like cement, titanium mesh, PEEK polymer, ceramics).
- FIG. 1 illustrates cranial reconstruction on patients who could not afford medical support.
- Cranial defect printout 101 (B) customized PMMA prosthesis 102; (C) assembled models to test precision prior to fixation 102.
- D Postoperative CT. Notice the coaptation of the prosthesis to the bone defect.
- E view of the cranial defect after craniectomy.
- F 30 days postoperative follow-up patient J.S.S. shows a great cranial symmetry.
- Bone defect features surface area (cm 2 ): 148.70; prosthetic volume (cm 3 ): 53.30. DOI: 10.21203/rs.3.pex-1384/v1 (Rozental’s group, 2021 ).
- FIG. 2 illustrates ICP and brain temperature monitoring in TBI patients
- a mechanical NI-sensor & transducer set 201 consists of a support bar for detection of local bone tissue or prosthesis deformations adapted with strain sensors. The equipment filters, amplifies, and digitalizes the signal from the pressure sensor (Sensor PICNI2000), and sends the data to a computer. Detection of these deformations, modeled by finite elements calculations, reveals: i) the Percussion P1 wave (cerebral arterial pulsation); while, ii) the tidal P2 wave (brain ‘compliance’).
- Bone defect features surface area (cm 2 ): 145.50; prosthetic volume (cm 3 ): 51.17.
- B Abnormal noncompliant ICP waveform before cranioplasty (sensor positioned adjacent to the bone defect). Under abnormal conditions (e.g., decompressive craniectomy), brain compliance starts decreasing resulting in reversal of P1 :P2 ratio (i.e., P2>P1 ) which is a sensitive predictor of poor brain compliance.
- ICP cerebral perfusion pressure
- cerebrovascular pressure reactivity index and microdialysis markers during 72 hrs (sampling rate/hr)
- CMA Microdialysis AB LICOX probe, perfusion flow rate of 0.3 ml/min, dialysis probe length 10-mm.
- FIG. 3 is interplay between slow waves (SD) 301 and fast waves (seizure discharge).
- the negative direct current shift ( ⁇ 0.05 Hz) 301 is an important identifier of cortical depolarization, followed by a long-lasting period of electrical silence (‘refractory period) of the nervous system.
- SD 301 the hallmark of SD 301 is a DC shift in the milli-Hertz range ( ⁇ 0.05 Hz) that reflects the mass breakdown of electrochemical membrane gradients and reaches up to 20mV in amplitude.
- the depolarization block of synaptic activity, along with subsequent factors, further cause suppression of cortical activity, known as SD, in the functional range of 0.5-70 Hz.
- FIG. 5 is a schematic illustration of the ETI-ND device system.
- the hardware 505, 506 can be viewed in two layers.
- (Superior layer) 505 (1 ) electrode interface. (2) detection subsystem; (3) SD interface; (4) stimulation subsystem; (5) CPU/microcontroller; (6) memory subsystem; (7) communication system; ( ) energy 508.
- (Inferior layer) 506 electrodes to trigger SD waves 501, Thermal sensors 502, Pressure sensor 503 and EEG sensors 504.
- the ETI-ND system is mechanically flexible and stretchable to meet patient needs.
- FIG. 6 is a block diagram illustrating the main functional subsystems of the ETI-ND implantable system according to the invention, as shown in FIG. 5;
- (B) is a schematic illustration of an extensive cranial defect (14 cm larger diameter), after a DCT procedure (lateral view), showing the placement of an implantable ETI-ND device system (shown in A) according to an embodiment.
- the diagram depicts the electronic components (sensors and electrodes) within the lower layer 506 (i.e. , the case and the components of the hardware within the upper layer 505 of the system, as shown in FIG. 5, were removed for clarity) placed on top of the dura.
- the outermost small rectangle delineates the area containing stimulation electrodes to trigger SDs 501; the small gray rectangle (adjacent to the large circle) delineates the area containing thermal sensors 502; thermal recordings illustrated underneath; the large black circle (middle) delineates the area containing the pressure receptor(s) 503 - above recordings of normal ICP waves (P1 , P2, P3); the larger rectangle area delimits the area containing AC-EEG sensors 504 (epilepsy and electrographic discharges monitoring); EEG tracing samples (right hand side); scale: vertical bar: 1 mV; horizontal bar: 1 sec) and DC-EEG sensors (SD monitoring - negative shifts recordings [bottom recordings, in black]; scale: vertical bar 10 mV);
- FIG. 7 illustrates EEG video-monitoring in the management of patients with refractory epilepsy.
- A Schematic display of EEG electrode positions anterofrontal (AF), frontal (F), frontocentral (FC), central (C), centroparietal (CP), parietal (P), parietooccipital (PO), and temporal (T);
- B Optimal EEG window size for neural seizure detection;
- C Recording of a typical seizure event (duration 1 min).
- FIG. 8 illustrates optional intraparenchymal catheters 407 that can be attached to the ETI-ND device.
- iTemperature sensors 603 are positioned at 1 cm, 2 cm, 3 cm, 4 cm 604 along the parenchyma. These thermal sensors (l st -4 th unit 603) provide a signal representative of the gradient from the hotter core to the cooler periphery.
- Membrane excitability is a general term used to encompass the processes of activation of ion channels and energy-dependent pumps critical for the generation of an action potential, underlying seizures and epilepsy, and that subsequently restore the local environment such that neurons can generate and maintain impulse conduction.
- the functional recovery of a neuron after an activation process terminates, takes up to 100 msec (Baker et al. , 1987).
- the refractory period results from inactivation of transient Na + channels (Hodgkin and Huxley, 1952).
- the refractory period may be prolonged in neurons by waves of SD, due to maintained neuronal depolarization and slowing Na + channel kinetics of reactivation.
- a single episode of a triggered SD wave 301 can induce a prolonged period of electrical cortical silence (> 5 min) (‘refractory period’).
- sequential application of brief stimuli to trigger SD waves e.g., one pulse at each 2-4 min
- prolong the refractory period to ongoing seizures improving seizure control in AED-resistant epilepsy.
- An implantable device for detecting and abolishing epileptic seizures (ictal high frequency and interictal EEG oscillations) in real-time on a 24-7 basis while monitoring EEG 504, iTemperature 502, and ICP 503 measures.
- the ETI-ND device includes a low-power CPU, as well as customized electronic circuit modules in a detection subsystem (hardware - upper layer) 505 (FIGS. 4-5A).
- the detection subsystem which in the context of the present application is a form of detection of EEG electrographic discharge patterns and/or slow waves, among them waves of SD.
- an event such as an epileptic seizure or electrographic pattern
- an event may be detected, not statistical or stochastic in nature, as indicative of the event and promptly elicit an SD wave 501 (interplay sensor interface/detection subsystem/SD interface/stimulation of SD electrode to elicit a SD wave 301,505, 506 (FIG. 5B,C).
- SD wave 501 interplay sensor interface/detection subsystem/SD interface/stimulation of SD electrode to elicit a SD wave 301,505, 506 (FIG. 5B,C).
- the invention and particularly the EEG detection subsystem thereof, is specifically adapted to perform much of the signal processing and prompt analysis requisite for accurate and effective event detection and perform a positive feedback loop to trigger waves of SD 301.
- the CPU (507) remains in a resting ‘sleep’ state characterized by relative inactivity and is periodically awakened by interrupts from the detection subsystem to perform tasks related to ICP wave and iTemperature measures, or to detect triggered SD waves, enabled by a different module (DC) of the same device system.
- DC module
- the ETI-ND’s EEG circuitry is sensitive to subtle changes in ICP and iTemperature measures of individual epileptic patients, improving the criteria of detection/validation window of threshold to trigger SD waves 301. Three patterns of responses/processes are considered (FIG.
- ‘SHORTEST LOOPING PATH’ the electrode interface/detection subsystem/stimulation subsystem/SD interface/elicited SDs - this allows for faster actions to occur by promptly activating the SD interface (e.g., during monitoring of an EEG event that is associated with ictal activity, showing fast spike-and- wave, polyspike-and-wave and slow wake superimposed with fast activity patterns); ii) ‘FULL SELF-LOOP’ - electrode interface/detection subsystem/CPU/Memory subsystem/CPU/stimulation subsystem/SD interface/elicited SDs - offers a more sophisticated/personalized approach to the variety of hemodynamic data (EEG, ICP and iTemperature); and, iii) ‘LONGEST LOOPING PATH’ - ETI-ND/communication system/PC/cloud network.
- a system includes a CPU 507, a detection subsystem located therein that includes a waveform analyzer. Identification of consistent distinguishing features between preictal and interictal epochs (cycles within a given dataset) in the EEG is an essential step towards performing seizure validation and eliciting ND responses (i.e. , SDs) 301 to counteract abnormal electrical activity.
- the ETI-ND system separates preictal and interictal states based on the analysis of the high frequency activity and amplitude (i.e., temporal summation of the synchronous activity) of EEG waves, quantifying the similarities between their underlying states and a reference state.
- a discriminant analysis is then used in the features space to classify epochs. Performance is assessed based on sensitivity and false positive rates and validation is performed.
- the waveform analyzer includes waveform feature analysis capabilities (such as wave characteristics) as well as window-based analysis capabilities (such as line length and area under the curve), and both aspects are combined to provide enhanced electrographic event detection.
- a CPU FIG. 5, FIG. 6A is used to consolidate the results from multiple EEG sensors and coordinate responsive action when necessary.
- pressure and thermal sensors may give an accurate measurement of intracranial ICP and iTemperature and therefore help tailor threshold for EEG seizure detection and thereby effectively elicit personalized SD responses and prevent “kindle”.
- the ETI-ND system also includes a remote monitor that wirelessly collects information from the device and transfers it to a patient data management system, where physicians may view and follow-up seizure activity, reprogram the internal memory of the device (learning procedure) and adjust therapy progress, enabling neurologists to personalize and optimize therapy over time (personalized treatment) (LONGEST LOOP PATH) (FIG. 6A).
- a remote monitor that wirelessly collects information from the device and transfers it to a patient data management system, where physicians may view and follow-up seizure activity, reprogram the internal memory of the device (learning procedure) and adjust therapy progress, enabling neurologists to personalize and optimize therapy over time (personalized treatment) (LONGEST LOOP PATH) (FIG. 6A).
- ETI-ND system can be powered 508 by either a small battery unit, inductive coupling, or by body heat (Fujitsu Laboratories Ltd).
- Optional invasive catheters (6-10 cm long parenchymal probe) 407, 604 (FIG. 8): iTemperature 601,603 or iTemperature & ICP sensors 602,603.
- the sensor can be attached to a probe-like extension that can extend from the vicinity of the ETI-ND (subdural or epidural), through the dura, and down to the level of the CSF 405 ( «5 cm).
- the probe can include a pressure sensor (model 2) 602 or a thermal sensor (model 1) 601 attached thereto and positioned to communicate directly with the CSF 405 (FIG. 4).
- the subdural sensor of the invention can thus directly sense the pressure or the temperature of the CSF.
- the additional subdural thermal sensors can provide a direct reading of the thermal gradient across the brain parenchyma (FIG. 4).
- a ‘housing’ 404 can contain the other elements of the ICP monitoring system, such as the battery and the electronics (FIG. 6A), and any other required components (FIG. 5).
- the ETI-ND system can also be placed on the inner face of the prosthesis (FIG. 1, FIG. 4), during cranial repair 101, 102, facilitating implanting an intraparenchymal (FIG. 4) monitoring system 407 under adverse seizure conditions.
Abstract
Description
Claims
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BR112023020149A BR112023020149A2 (en) | 2021-04-26 | 2021-04-26 | SEMI-INVASIVE IMPLANTABLE DN-IET DEVICE TO CAUSE REPETITIVE WAVES OF SPREADING DEPRESSION |
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US8761868B2 (en) * | 2004-12-17 | 2014-06-24 | Medtronic, Inc. | Method for monitoring or treating nervous system disorders |
US8948836B2 (en) * | 2003-12-26 | 2015-02-03 | Medtronic Minimed, Inc. | Implantable apparatus for sensing multiple parameters |
US20150305625A1 (en) * | 2008-03-12 | 2015-10-29 | The Trustees Of The University Of Pennsylvania | Flexible and Scalable Sensor Arrays for Recording and Modulating Physiological Activity |
US20180325386A1 (en) * | 2017-05-09 | 2018-11-15 | Yale University | Multiplexed implantable sensor probe |
US20200170542A1 (en) * | 2017-07-17 | 2020-06-04 | Ice Neurosystems, Inc. | Systems and methods for positioning an intracranial device using brain activity |
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- 2021-04-26 WO PCT/BR2021/050174 patent/WO2022226606A1/en active Application Filing
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US8948836B2 (en) * | 2003-12-26 | 2015-02-03 | Medtronic Minimed, Inc. | Implantable apparatus for sensing multiple parameters |
US8761868B2 (en) * | 2004-12-17 | 2014-06-24 | Medtronic, Inc. | Method for monitoring or treating nervous system disorders |
US20150305625A1 (en) * | 2008-03-12 | 2015-10-29 | The Trustees Of The University Of Pennsylvania | Flexible and Scalable Sensor Arrays for Recording and Modulating Physiological Activity |
US20180325386A1 (en) * | 2017-05-09 | 2018-11-15 | Yale University | Multiplexed implantable sensor probe |
US20200170542A1 (en) * | 2017-07-17 | 2020-06-04 | Ice Neurosystems, Inc. | Systems and methods for positioning an intracranial device using brain activity |
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