Patent Application
20080319513
This application relates generally to medical devices and, more particularly, to systems, devices and methods for delivering neural stimulation.
The autonomic nervous system has been stimulated to modulate various physiologic functions, such as cardiac functions and hemodynamic performance. The myocardium is innervated with sympathetic and parasympathetic nerves. Activities in these nerves, including artificially applied electrical stimuli, modulate the heart rate and contractility (strength of the myocardial contractions). Neural stimulation that elicits a parasympathetic response (e.g. stimulating nerve traffic at a parasympathetic neural target such as a cardiac branch of the vagus nerve and/or inhibiting nerve traffic at a sympathetic neural target) is known to decrease the heart rate and the contractility, lengthen the systolic phase of a cardiac cycle, and shorten the diastolic phase of the cardiac cycle. Neural stimulation that elicits a sympathetic response (e.g. stimulating nerve traffic at a sympathetic neural target and/or inhibiting nerve traffic at a parasympathetic neural target) is known to have essentially the opposite effects. The ability of the electrical stimulation of the autonomic nerves in modulating the heart rate and contractility may be used to treat abnormal cardiac conditions, such as to improve hemodynamic performance for heart failure patients and to control myocardial remodeling and prevent arrhythmias following myocardial infarction. The autonomic nervous system regulates functions of many organs of the body. Vagus nerve stimulation, for example, affects respiration as the vagus nerve includes many lung, bronchial and tracheal afferents that feed into the respiratory centers of the brainstem.
This disclosure relates to systems, devices methods for monitoring respiration to improve the efficacy of a neural stimulation therapy and/or reduce or avoid side effects of a neural stimulation therapy. Respiration changes during sleep or rest, a state with a predominant vagal/parasympathetic activity and stabilized respiration, are used to titrate the neural stimulation therapy. Various embodiments use a measurement of respiratory stability or instability during sleep or rest as a feedback to control stimulation of an autonomic neural target (e.g. vagus nerve stimulation). Various embodiments use a measurement of variability of a respiratory parameter, such as respiratory rate, as an indicator of respiratory stability or instability. A decrease in respiratory variability is a sign of improvement, and an increase in respiratory variability is a sign of disease progression.
A system embodiment comprises at least one respiration sensor, a neural stimulation therapy delivery module, and a controller. The respiration sensor is adapted for use in monitoring respiration of the patient. The neural stimulation therapy delivery module is adapted to generate a neural stimulation signal for use in stimulating the autonomic neural target of the patient for the chronic neural stimulation therapy. The controller is adapted to receive a respiration signal from the at least one respiration sensor indicative of the patient's respiration, and adapted to control the neural stimulation therapy delivery module using a respiratory variability measurement derived using the respiration signal.
According to a method embodiment, a chronic neural stimulation therapy is delivered. The therapy includes stimulation to an autonomic neural target. Respiration is monitored during a low activity period. Respiration variability is determined using the monitored respiration. An intensity of the stimulation to the autonomic neural target is adjusted using a comparison the respiration variability to at least one predetermined threshold.
This Summary is an overview of some of the teachings of the present application and not intended to be an exclusive or exhaustive treatment of the present subject matter. Further details about the present subject matter are found in the detailed description and appended claims. Other aspects will be apparent to persons skilled in the art upon reading and understanding the following detailed description and viewing the drawings that form a part thereof, each of which are not to be taken in a limiting sense. The scope of the present invention is defined by the appended claims and their equivalents.
The following detailed description of the present subject matter refers to the accompanying drawings which show, by way of illustration, specific aspects and embodiments in which the present subject matter may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized and structural, logical, and electrical changes may be made without departing from the scope of the present subject matter. References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.
Various embodiments use a measurement of respiratory stability or instability as a feedback to control stimulation of an autonomic neural target (e.g. vagus nerve stimulation). Various embodiments use a measurement of variability of a respiratory parameter as an indicator of respiratory stability or instability. Various embodiments use respiration rate variability (RRV) or tidal volume variability (TVV) as an indicator of respiratory stability or instability. Changes in respiration (patterns or rates) reflect an underlying therapy benefit or pathological process. A decrease in respiratory variability is a sign of improvement, and an increase in respiratory variability is a sign of disease progression. For example, some embodiments use a measure of variability of a respiratory parameter (e.g. rate, tidal volume, an inspiratory/expiratory ratio, etc.) during sleep or a rest state to adjust a chronic vagus nerve therapy. The neural stimulation intensity can be adjusted to reduce the mean of the monitored respiratory parameter, or reduce the variability of the monitored respiratory parameter, or reduce both the mean and variability of the monitored respiratory parameter. Various embodiments provide a respiration monitor to improve the efficacy of vagus nerve stimulation and/or reduce or avoid undesired side effects, such as a breathing disorder. The present subject matter monitors respiration changes during sleep and/or rest, which is a state with a predominant vagal/parasympathetic activity, and with stabilized respiration.
Various stimulator embodiments include at least one respiration sensor adapted for use in monitoring respiration of the patient, a neural stimulation therapy delivery module adapted to generate a neural stimulation signal for use in stimulating the autonomic neural target of the patient for the chronic neural stimulation therapy, and a controller adapted to receive a respiration signal from the at least one respiration sensor indicative of the patient's respiration, and adapted to control the neural stimulation therapy delivery module using a respiratory variability measurement derived using the respiration signal. Various embodiments include a respiration variability analyzer adapted to determine the respiration variability measurement using the respiration signal, a titration detector adapted to deliver a control signal to control a therapy intensity using the respiration variability measurement from the respiration variability analyzer, and a safety detector adapted to compare the respiration variability measurement from the respiration variability analyzer to a threshold and deliver a control signal to control a therapy intensity based on the comparison. The respiration sensor and the controller are adapted to monitor respiration during a period of low activity, and the controller is adapted to control the neural stimulation delivery module using a respiratory variability measurement corresponding to the period of low activity. The period of low activity can be a period of sleep or rest, such as may be detected by an activity detector. A predetermined schedule can be used to anticipate periods of low activity.
Various embodiments deliver a chronic neural stimulation therapy to an autonomic target. The term chronic indicates a period of time on the order of days, weeks, months or years. Chronic therapy includes therapy with intermittent stimulation and therapy with and constant stimulation. Respiration is monitored during a low activity period, and respiration variability is determined. An intensity of the stimulation to the autonomic neural target is adjusted using a comparison of the respiration variability to at least one predetermined threshold, such as a titration threshold indicative of an efficacy of the simulation for the therapy and/or a side effect threshold indicative of an undesired side effect of the stimulation. Various embodiments include identifying a patient indicated for a particular therapy, and delivering the therapy, such as a heart failure therapy, a hypertension therapy, or a post myocardial infarction therapy. A footprint representative of the respiration variability can be generated, along with one or more indices representative of quantitative measurements of the footprint. Examples of indices include a feature, a pattern, a shape or a contour of the footprint.
Embodiments of the present subject matter include cardiac, renal neuromodulation and other therapeutic devices for patient populations, such as heart failure, post myocardial infarction, and hypertension. Respiration provides an early marker (respiration) for the efficacy of vagal nerve stimulation, or other therapies that affect the autonomic balance of a patient (such as therapies for heart failure, post myocardial infarction, and hypertension). Respiration can also be used to detect undesired side effects, such as predetermined breathing disorders.
The automatic nervous system (ANS) regulates “involuntary” organs, while the contraction of voluntary (skeletal) muscles is controlled by somatic motor nerves. Examples of involuntary organs include respiratory and digestive organs, and also include blood vessels and the heart. Often, the ANS functions in an involuntary, reflexive manner to regulate glands, to regulate muscles in the skin, eye, stomach, intestines and bladder, and to regulate cardiac muscle and the muscle around blood vessels, for example.
The ANS includes the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system is affiliated with stress and the “fight or flight response” to emergencies. Among other effects, the “fight or flight response” increases blood pressure and heart rate to increase skeletal muscle blood flow, and decreases digestion to provide the energy for “fighting or fleeing.” The parasympathetic nervous system is affiliated with relaxation and the “rest and digest response” which, among other effects, decreases blood pressure and heart rate, and increases digestion to conserve energy. The ANS maintains normal internal function and works with the somatic nervous system.
The heart rate and force is increased when the sympathetic nervous system is stimulated, and is decreased when the sympathetic nervous system is inhibited (the parasympathetic nervous system is stimulated). An afferent nerve conveys impulses toward a nerve center. An efferent nerve conveys impulses away from a nerve center.
Stimulating the sympathetic and parasympathetic nervous systems can have effects other than heart rate and blood pressure. For example, stimulating the sympathetic nervous system dilates the pupil, reduces saliva and mucus production, relaxes the bronchial muscle, reduces the successive waves of involuntary contraction (peristalsis) of the stomach and the motility of the stomach, increases the conversion of glycogen to glucose by the liver, decreases urine secretion by the kidneys, and relaxes the wall and closes the sphincter of the bladder. Stimulating the parasympathetic nervous system (inhibiting the sympathetic nervous system) constricts the pupil, increases saliva and mucus production, contracts the bronchial muscle, increases secretions and motility in the stomach and large intestine, increases digestion in the small intention, increases urine secretion, and contracts the wall and relaxes the sphincter of the bladder. The functions associated with the sympathetic and parasympathetic nervous systems are many and can be complexly integrated with each other.
Vagal modulation may be used to treat a variety of disorders, including a variety of cardiovascular disorders, including heart failure, post-MI remodeling, and hypertension. These conditions are briefly described below.
Heart failure refers to a clinical syndrome in which cardiac function causes a below normal cardiac output that can fall below a level adequate to meet the metabolic demand of peripheral tissues. Heart failure may present itself as congestive heart failure (CHF) due to the accompanying venous and pulmonary congestion. Heart failure can be due to a variety of etiologies such as ischemic heart disease.
Hypertension is a cause of heart disease and other related cardiac co-morbidities. Hypertension occurs when blood vessels constrict. As a result, the heart works harder to maintain flow at a higher blood pressure, which can contribute to heart failure. Hypertension generally relates to high blood pressure, such as a transitory or sustained elevation of systemic arterial blood pressure to a level that is likely to induce cardiovascular damage or other adverse consequences. Hypertension has been arbitrarily defined as a systolic blood pressure above 140 mm Hg or a diastolic blood pressure above 90 mm Hg. Consequences of uncontrolled hypertension include, but are not limited to, retinal vascular disease and stroke, left ventricular hypertrophy and failure, myocardial infarction, dissecting aneurysm, and renovascular disease.
Cardiac remodeling refers to a complex remodeling process of the ventricles that involves structural, biochemical, neurohormonal, and electrophysiologic factors, which can result following a myocardial infarction (MI) or other cause of decreased cardiac output. Ventricular remodeling is triggered by a physiological compensatory mechanism that acts to increase cardiac output due to so-called backward failure which increases the diastolic filling pressure of the ventricles and thereby increases the so-called preload (i.e., the degree to which the ventricles are stretched by the volume of blood in the ventricles at the end of diastole). An increase in preload causes an increase in stroke volume during systole, a phenomena known as the Frank-Starling principle. When the ventricles are stretched due to the increased preload over a period of time, however, the ventricles become dilated. The enlargement of the ventricular volume causes increased ventricular wall stress at a given systolic pressure. Along with the increased pressure-volume work done by the ventricle, this acts as a stimulus for hypertrophy of the ventricular myocardium. The disadvantage of dilatation is the extra workload imposed on normal, residual myocardium and the increase in wall tension (Laplace's Law) which represent the stimulus for hypertrophy. If hypertrophy is not adequate to match increased tension, a vicious cycle ensues which causes further and progressive dilatation. As the heart begins to dilate, afferent baroreceptor and cardiopulmonary receptor signals are sent to the vasomotor central nervous system control center, which responds with hormonal secretion and sympathetic discharge. The combination of hemodynamic, sympathetic nervous system and hormonal alterations (such as presence or absence of angiotensin converting enzyme (ACE) activity) account for the deleterious alterations in cell structure involved in ventricular remodeling. The sustained stresses causing hypertrophy induce apoptosis (i.e., programmed cell death) of cardiac muscle cells and eventual wall thinning which causes further deterioration in cardiac function. Thus, although ventricular dilation and hypertrophy may at first be compensatory and increase cardiac output, the processes ultimately result in both systolic and diastolic dysfunction. It has been shown that the extent of ventricular remodeling is positively correlated with increased mortality in post-MI and heart failure patients.
Respiration, as can be quantified or measured using a respiratory rate, tidal volume and the like, demonstrates a non-randomness with small variability among normal people especially during sleep. More than 50% of heart failure patients experience central sleep apnea or periodic breathing. Respiratory instability, such as can be measured by the ratio of minute ventilation to minute production of carbon dioxide (VE/VCO2) or the like, can be attributed to sympathetic elevation as well as cardiac dysfunction. It has been observed that heart failure and breathing disorders are associated. For example, an association was observed between improving heart failure and reducing respiration rate/variability, as well as worsening heart failure and increasing respiration rate/variability. This observation agrees with a long-lasting intuitive belief that respiration and heart are connected.
Also, as illustrated in the
The illustrated implantable neural stimulator 411 is adapted to internally-process the therapy inputs, including internally determine a respiration variability. As shown in
The illustrated implantable neural stimulator 411 includes a titration detector 424 adapted for use in detecting an indicator for an efficacy of the neural stimulation therapy, and further includes a side effect detector 425 for use in detecting an indicator of an undesired side effect of the neural stimulation therapy. According to various embodiments, the titration detector 424 can use a signal from the respiration variability analyzer 423, a signal from the respiration sensor(s), and/or a signal from other physiologic sensor(s) 422 such as heart rate sensors, blood pressure sensors, chemical sensors, electrogram sensors, and the like. Some embodiments compare monitored respiratory variability footprints or indices to predetermined respiration variability footprints or indices to determine whether the neural stimulation therapy is effective whether to adjust the intensity of the neural stimulation therapy.
According to various embodiments, the side effect detector 425 can use a signal from the respiration variability analyzer 423, a signal from the respiration sensor(s), and/or a signal from other physiologic sensor(s) 422 such as heart rate sensors, blood pressure sensors, chemical sensors, electrogram sensors, and the like. The illustrated side effect detector includes a detector of predetermined respiratory disorder(s) such as a prolonged absence of breathing, a high apnea-hypopnea index (AHI) or other index for respiratory disturbance. Some embodiments use predetermined respiration variability footprints or indices to determine predetermined side effects. Some embodiments also detect undesired side effects using other physiologic sensors such as heart rate and cardiograms.
The illustrated system 510 includes a number of patient-external devices. An external system interface 526 includes communication circuitry configured to effect communications with implantable device 511. The external system interface 526 may also be configured to effect communications with external sensors 527. The external system interface may be communicatively coupled to, or integral with, one or more of a programmer, an advanced patient management system, a portable or hand-held communicator, or other patient-external system. The external system interface 526 is coupled to a user interface 528, such as a graphical user interface or other interface that provides a display. The user interface 528 can include a user actuatable input/output device, such as a keyboard, touch screen sensor, mouse, light pen, and the like. The user interface may be used to input therapy information, such programming a schedule, and programming stimulation parameters that can effect an intensity for the neural stimulation therapy. The system 510 includes a respiration variability processor 529, illustrated as an RRV processor, coupled to the external system interface. The RRV processor may be incorporated as a component of the implantable device 511, a communicator 530, a programmer 531, or an advanced patient management (APM) system 532. The respiration variability processor determines respiratory variability (e.g. an RRV footprint and indices developed from the RRV footprint). This and other relevant information can be communicated to the external system interface 526 for display to the physician, clinician, and/or patient.
Changes of the RRV footprint may be monitored 1457. Heart failure status, change in heart failure status, disordered breathing status, and/or change is disordered breathing status may be determined and monitored 1458. Various statistical analyses may be performed 1459 on the RRV footprint and associated indices may be computed. Neural stimulation therapy may be monitored and titrated based on the RRV footprint and one or more indices 1460. Effectiveness of the therapy may be quantified using the RRV footprint and associated indices 1461.
An alert to the clinician and/or patient may be generated 1462 and communicated in various forms to the clinician and/or patient based on the RRV footprint and associated indices. The RRV footprint and associated indices may be used to predict decompensation episodes 1463. For example, gradual or sudden changes in a heart failure patient's respiration pattern can be detected from changes in the patient's RRV footprint and associated indices, which can indicate the relative likelihood of a decompensation episode. The RRV footprint and associated indices may be used to discriminate 1464 between stable and worsening heart failure status of a patient.
Pattern and/or feature recognition may be performed 1465 on the RRV footprint, such as for recognizing or identifying areas, locations, shapes/contours of interest that can be associated with particular respiration or patient conditions. Various known pattern and/or feature recognition techniques may be employed, such as by using neural networks and other statistical pattern recognition techniques. Such techniques may include principal component analysis, fisher and variance weight calculations and feature selection. Neural network methods may include a back propagation neural network and/or radial basis function neural network. Statistical pattern recognition, may include linear discriminate analysis, quadratic discriminate analysis, regularized discriminate analysis, soft independent modeling of class analogy, and/or discriminate analysis with shrunken covariance.
An RRV footprint may be mapped 1466 to different physiological states, such as determined by other sensors (e.g., posture sensor, motion sensors). Conditional distributions may be generated 1467 from the RRV footprint. For example, a respiration rate (RR) histogram may be obtained by integrating the RRV footprint along the appropriate axis of the RRV footprint. A respiration rate variability histogram may be obtained by integrating the RRV footprint along the other axis of the RRV footprint.
An RRV footprint may be combined with a heart rate variability (HRV) footprint to provide increased robustness of cardio-respiratory function assessment. A combined RRV and HRV footprint provides for the measurement and tracking of a patient's cardio-respiratory function 1468. Various indices, such as area ratios of the HRV footprint and RRV footprint, may be generated 1469 to quantify a patient's cardio-respiratory function status.
A third dimension may be added to, or superimposed on, the footprint (e.g., two dimensional histogram) 1470. Such third dimension may be tidal volume, a duration of time during which a patient is in a particular respiration pattern or a frequency of occurrence of a particular respiration pattern or rate, for example. The third dimension may be indicated by use of a color scheme 1471 or by a graphical construct or indicia extending from a two dimensional plane of the footprint into a plane orthogonal of this two-dimensional plane.
A variety of RRV footprint and index data, trend data, and other physiological data may be displayed 1472 for use by the patient, clinician, and/or physician.
The respiratory signal is a physiologic signal indicative of respiratory activities. In various embodiments, the respiratory signal includes any physiology signal that is modulated by respiration. In one embodiment, the respiratory signal is a transthoracic impedance signal sensed by an implantable impedance sensor. In another embodiment, the respiratory signal is extracted from a blood pressure signal that is sensed by an implantable pressure sensor and includes a respiratory component. In another embodiment, the respiratory signal is sensed by an external sensor that senses a signal indicative of chest movement or lung volume.
As provided above, embodiments of the present subject matter detect undesired side effects. One example of an undesired side effect is a respiratory disorder.
The physiologic sensor 1783 senses one or more physiologic signals in addition to the physiologic signal sensed by respiratory sensor 1774. In various embodiments, the physiologic sensor 1783 senses various combinations of one or more of cardiac signals, signals indicative of heart sounds, cardiac and/or transthoracic impedance signals, signals indicative of blood oxygen level, and signals indicative of nerve traffic. Sensor processing circuit 1784 processes the one or more physiologic signals sensed by physiologic sensor 1783 for use by respiration-controlled neural stimulation circuit 1776 in controlling the neural stimulation. In various embodiments, the physiologic sensor 1783 or portions of physiologic sensor 1783 are included in implantable medical device or communicatively coupled to implantable medical device via one or more leads or telemetry. In various embodiments, the sensor processing circuit 1784 or portions sensor processing circuit 1784 are included in an implantable medical device or communicatively coupled to an implantable medical device via one or more leads or telemetry.
The illustrated respiration-controlled neural stimulation circuit 1776 includes a stimulation output circuit 1777 and a controller 1778. The controller 1778 includes a respiratory signal input 1779, a respiratory disorder detector 1780, a physiologic signal input 1785, a physiologic event detector 1786, a stimulation adjustment module 1781, and a stimulation delivery controller 1782.
The respiratory disorder detector 1780 detects one or more respiratory disorders using the respiratory signal. In the illustrated embodiment, the respiratory disorder detector includes an apnea detector, a hypopnea detector, and a dyspnea detector. In various other embodiments, the respiratory disorder detector includes a combination of one or more of the apnea detector, the hypopnea detector, and the dyspnea detector. In various embodiments, the respiratory disorder detector also detects abnormal values of one or more respiratory parameters, such as a low respiratory rate when the respiratory rate is below a threshold rate, a low tidal volume when the tidal volume is below a detection threshold volume, and a low minute ventilation when the minute ventilation is below a detection threshold value.
Apnea is characterized by abnormally long non-breathing periods. The apnea detector detects apnea by comparing the non-breathing period to a detection threshold period. Apnea is detected when the non-breathing period exceeds the detection threshold period. Hypopnea is characterized by abnormally shallow breathing, i.e., low tidal volume. The hypopnea detector detects hypopnea by comparing the tidal volume to a detection threshold volume. Hypopnea is detected when the tidal volume is below the detection threshold volume. In one embodiment, the tidal volume is an average tidal volume over a predetermined time interval or a predetermined number of respiratory cycles. Dyspnea is characterized by rapid shallow breathing, i.e., high respiratory rate-to-tidal volume ratio. The dyspnea detector detects dyspnea by comparing the ratio of the respiratory rate to the tidal volume to a detection threshold ratio. Dyspnea is detected when the ratio exceeds the threshold ratio. In various embodiments, the threshold period, the detection threshold volume, and/or the threshold ratio are empirically established.
The physiologic signal input receives the one or more physiologic signals sensed by the physiologic sensor and processed by sensor processing circuit. The physiologic event detector detects one or more physiologic events from the one or more physiologic signals. In various embodiments, the physiologic event detector detects one or more of changes in cardiac signal morphology, changes in heart sound waveform morphology, changes in impedance signal morphology, and changes in blood oxygen saturation.
The stimulation adjustment module adjusts the delivery of the neural stimulation pulses in response to at least the detection of a respiratory disorder by the respiratory disorder detector. In one embodiment, the stimulation adjustment module adjusts the delivery of the neural stimulation pulses in response to the detection of a respiratory disorder by the respiratory disorder detector and the detection of a physiologic event by the physiologic event detector. The stimulation delivery controller controls the delivery of the neural stimulation pulses by executing one or more stimulation algorithms. The stimulation adjustment module includes a stimulation switch. The stimulation switch stops executing a first stimulation algorithm in response to the detection of a respiratory disorder such as apnea, hypopnea, or dyspnea. For example, the first stimulation algorithm is executed to treat a cardiac condition by vagal nerve stimulation. If apnea, hypopnea, or dyspnea is detected, the vagal nerve stimulation is to be stopped to avoid the worsening of the condition due to the vagal nerve stimulation designed for treating the cardiac condition.
According to various embodiments, the device, as illustrated and described above, is adapted to deliver neural stimulation as electrical stimulation to desired neural targets, such as through one or more stimulation electrodes positioned at predetermined location(s). Other elements for delivering neural stimulation can be used. For example, some embodiments use transducers to deliver neural stimulation using other types of energy, such as ultrasound, light, magnetic or thermal energy.
One of ordinary skill in the art will understand that, the modules and other circuitry shown and described herein can be implemented using software, hardware, and combinations of software and hardware. As such, the terms module and circuitry, for example, are intended to encompass software implementations, hardware implementations, and software and hardware implementations.
The methods illustrated in this disclosure are not intended to be exclusive of other methods within the scope of the present subject matter. Those of ordinary skill in the art will understand, upon reading and comprehending this disclosure, other methods within the scope of the present subject matter. The above-identified embodiments, and portions of the illustrated embodiments, are not necessarily mutually exclusive. These embodiments, or portions thereof, can be combined. In various embodiments, the methods are implemented using a computer data signal embodied in a carrier wave or propagated signal, that represents a sequence of instructions which, when executed by a processor cause the processor to perform the respective method. In various embodiments, the methods are implemented as a set of instructions contained on a computer-accessible medium capable of directing a processor to perform the respective method. In various embodiments, the medium is a magnetic medium, an electronic medium, or an optical medium.
The above detailed description is intended to be illustrative, and not restrictive. Other embodiments will be apparent to those of skill in the art upon reading and understanding the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.
