Patent ID: 12214202

5 DETAILED DESCRIPTION OF SOME EXEMPLARY EMBODIMENTS

In the following, some exemplary embodiments of the present invention are described in more detail, with reference to a CBI device that may be interfaced with neurostimulation electrodes such as spinal cord stimulation electrodes and/or DBS electrodes, e.g. via an intermediate neurostimulation device. However, the present invention may also be used with any other neurostimulation interface that is capable of stimulating afferent sensory axons of the central or peripheral nervous system targeting directly or indirectly a sensory cortex area of an individual.

While specific feature combinations are described in the following paragraphs with respect to the exemplary embodiments of the present invention, it is to be understood that not all features of the discussed embodiments have to be present for realizing the invention, which is defined by the subject matter of the claims. The disclosed embodiments may be modified by combining certain features of one embodiment with one or more technically and functionally compatible features of other embodiments. Specifically, the skilled person will understand that features, components and/or functional elements of one embodiment may be combined with technically compatible features, components and/or functional elements of any other embodiment of the present invention which is defined by the appended claims.

Moreover, the various modules of the devices and systems disclosed herein may for instance be implemented in hardware, software or a combination thereof. For instance, the various modules of the devices and systems disclosed herein may be implemented via application specific hardware components such as application specific integrated circuits, ASICs, and/or field programmable gate arrays, FPGAs, and/or similar components and/or application specific software modules being executed on multi-purpose data and signal processing equipment such as CPUs, DSPs and/or systems on a chip (SOCs) or similar components or any combination thereof.

For instance, the various modules of the CBI devices discussed herein above may be implemented on a multi-purpose data and signal processing device configured for executing application specific software modules and for communicating with various sensor devices and/or neurostimulation devices or systems via conventional wireless communication interfaces such as a NFC, a WIFI and/or a Bluetooth interface.

Alternatively, the various modules of the CBI devices discussed in the present application may also be part of an integrated neurostimulation apparatus, further comprising specialized electronic circuitry (e.g. neurostimulation signal generators, amplifiers etc.) for generating and applying the determined neurostimulation signals to a neurostimulation interface of the individual (e.g. a multi-contact electrode, a spinal cord stimulation electrode, peripheral sensory nerve stimulation electrode etc.).

As discussed above the present invention may be realized in situations where the perceptual channels of a general-purpose CBI are not calibrated via subject-experimenter interactions. Instead, the CBI stimulation parameters may be self-calibrated by tapping into the neural activity of the tissue in vicinity of the stimulation interface. For instance, the level of induced bioelectric activation may be measured by interleaving several special calibration test pulses in between the normal stream of communication stimuli.

In some examples, the special test waveforms are defined by modulating various aspect of the waveform in bursting mode. The modulated parameters of the waveform may include but are not limited to: a spatial activation pattern of the electrode contacts, an amplitude, an inter-pulse frequency, an inter-burst frequency, a pulse width, a wave-form shape (e.g. mono-phasic, biphasic with symmetric or with long active discharge period, multiphasic, etc.), a density of pulses within a burst or a burst duration. In an exemplary stimulation paradigm, a few symmetric pulses (e.g. in a range of 4-9 pulses) are delivered within short bursts (e.g. lasting 40 ms-60 ms) to convey information related to intensity of sensation. The intensity may then be varied at a second measurement loci point in time by changing density of pulses per burst while keeping pulse numbers constant i.e. shortening duration but increase intra-burst frequency and vice-versa.

For instance, neural recordings/sensing of bioelectric responses may take place by ramping stimulation signal bursts in repetition, aggregate frequency power pre- and post-pulse for each step of the ramp across repeated bursts then create differential response profile to pulses with varied intensity for the same purpose, so that the CBI device may estimate the neural excitation behavior of the stimulated afferent sensory nerve fibers by fitting a response function to the amplitude of the ECAP or theta frequency band of the ECAPs taking into account the response at every intensity increment. As stated above the excitation behavior may also be estimated not only by varying the amplitude of the burst in a ramp by also by changing other parameters of the stimulation such as frequency, pulse width, as well as the inter burst intervals, for example.

The estimated excitation behavior allows then to determine optimal stimulation parameters which are adequate to generate desired level of activity in the target tissue thereby stabilizing the intensity, locus and/or quality of artificial sensory perceptions in the targeted sensory cortex area. This may be achieved by determining the highest value parameter coefficients which crucially contribute to determination of sensation intensity.

FIG.1illustrates a person/individual100that is equipped with a CBI device as described in section 3 above. In the illustrated embodiment, the CBI is implemented via direct neurostimulation of afferent sensory nerve fibers in the spinal cord106via one or more multi-contact electrodes104driven by an IPG102that may be operatively connected to or integrated with a CBI device as disclosed herein.

For establishing a perceptual communication channel to the brain of the individual100the CBI device may be calibrated such that neurostimulation signals generated by the CBI device and applied via the IGP102and the multi-contact electrode104elicit one or more action potentials108in one or more afferent sensory nerve fibers of the spinal cord106targeting (e.g. via multi-synaptic afferent sensory pathways) one or more sensory cortex areas110of the individual where the one or more action potentials108generate artificial sensory perceptions that may be used to communicate with the individual100. As discussed in detail in US 2020/0269049, fully incorporated herein by reference, artificial sensory perceptions that are elicited in a sensory cortex area (e.g. a sensory cortex area processing touch sensations on the left or right hand) may be associated with any kind of abstract information that is intelligible (i.e. consciously or subconsciously) by the individual.

FIG.2shows an exemplary CBI device according to an embodiment of the present invention. In this embodiment, the CBI device comprises an integrated neurostimulation and sensing module230(e.g. comprising a neuronal signal generator and an output amplifier as well as a sensing amplifier and an analog to digital converted) that is connected to a plurality of output signal leads270and a plurality of separate or identical sensing signal leads280that may be interfaced with a neurostimulation interface of the individual (e.g. a multi-contact spinal cord stimulation electrode such as the electrode104shown inFIG.1). The CBI device may further comprise a communication antenna260operably connected to a communication interface module210, configured for wireless communication (e.g. via NFC, Bluetooth, or a similar wireless communication technology).

The communication interface module210may be configured, for example, to receive one or more sensor signals from one or more sensors (not shown; e.g. acceleration signals obtained form an accelerometer etc.) and/or control information from a control device such as a remote control or a smart phone. The communication interface module210is operably connected to a data/signal processing module220configured to generate one or more neurostimulation signals and/or signal parameters (e.g. waveform, pulse shape, amplitude, frequency, burst count, burst duration etc.) for generating the one or more neurostimulation signals. For instance the processing module220may access a data storage module240configured to store a plurality of relations, specific for the individual, associating a plurality of neurostimulation signals (or parameters used for generating a plurality of neurostimulation signals) with a plurality of corresponding pieces of information to be communicated to the individual.

The generated neurostimulation signals and/or the signal parameters are input into the integrated neurostimulation and sensing module230that may be configured to process (e.g. modulate, switch, amplify, covert, rectify, multiplex, phase shift, etc.) the one or more neurostimulation signals generated by the processing module220or to generate the one or more neurostimulation signals based on the signal parameters provided by the processing module220.

The generated and processed neurostimulation signals are then output by the neurostimulation and sensing module230and may be applied to one or more electric contacts of a neurostimulation electrode (e.g. a DBS electrode or spinal cord stimulation electrode as shown inFIG.1) via output leads270. The CBI device ofFIG.2may also comprise a rechargeable power source250that, for instance may be wirelessly charged via a wireless charging interface265.

As discussed above, the data/signal processing module220may be further configured to, e.g. in conjunction with the data storage module240and the neurostimulation and sensing module230, to execute an on-line autocalibration method as discussed in section 3 above. For example, it may generate one or more neurostimulation test signals (for examples seeFIGS.5-9below) configured to elicit a bioelectric response in one or more afferent sensory nerve fibers such as an evoked (compound) action potential in one or more afferent sensory nerve fibers of the spinal cord106shown inFIG.1.

The neurostimulation test signal(s) (e.g. a combined intensity and burst-duration ramp; seeFIG.8) may then be applied via output stimulation leads270to a neurostimulation interface such as the most caudal contact112of the multi-contact electrode104shown inFIG.1. The neurostimulation and sensing module230may then sense, via the neurostimulation interface (e.g. via the most rostral contact114), a bioelectric response108of the stimulated afferent sensory nerve fiber of the spinal cord106.

Based on the sensed bioelectric response, the excitation behavior of the stimulated afferent sensory nerve fibers with respect to the neurostimulation interface may then be estimated by the neurostimulation and sensing module230and/or the processing module220. As discussed above (e.g. see section 3), based on the sensed bioelectric responses, a set of recalibrated neurostimulation signal parameters may then be determined and stored in the data storage module240for later use, e.g. for operating the CBI device to transmit information via the afferent sensory nerve fibers of the spinal cord106to a sensory cortex area110of the individual100.

FIG.3aillustrates exemplary reference bioelectric responses310,320,330(e.g. extracellularly sensed ECAPs) of a sub-population of afferent sensory nerve fibers (e.g. of the spinal cord106; seeFIG.1) sensed and recorded upon initial calibration of a neurostimulation interface (e.g. the multi-contact spinal cord stimulation electrode104shown inFIG.1) driven by a CBI device (seeFIG.2) according to an embodiment of the present invention. The illustrated bioelectric responses are sensed after neurostimulation using different sets of stimulation parameters such as different values for stimulus strength and duration. The bioelectric response310corresponds to a set of stimulation parameters that result in a sub-threshold stimulation of the targeted afferent sensory nerve fibers (see data points indicated with a “−” symbol inFIG.3bandFIG.3c). Consequently, no action potentials are elicited, and no artificial sensation may be elicited in the sensory cortex area(s), in which the targeted nerve fibers ultimately terminate. During initial calibration such a stimulation signal would thus not trigger individual to provide positive subjective feedback. The waveform of the bioelectric response310could then be stored in a memory module of the CBI device as a reference example of a sub-threshold bioelectric response that should be avoided when carrying out the autocalibration method as described above.

The bioelectric response320corresponds to a combination of stimulation parameters resulting in a supra-threshold stimulation of the targeted nerve fiber (see data points indicated with an “x” symbol inFIG.3bandFIG.3c) and eliciting a desired artificial sensory perception in a sensory cortex area of the individual, such as a mild tingling touch sensation on the left index finger that is clearly perceivable by the individual but is not unpleasant or painful. The waveform of the bioelectric response320could then be stored in a memory module of the CBI device as a reference example of a desired supra-threshold bioelectric response when carrying out the autocalibration method as described above.

Here it is important to note that that the terms “sub-threshold” &“supra-threshold” are tied to axonal activation (i.e. action potential generation in the targeted nerve fiber(s)) but are not necessarily tied to conscious perception. In other words, in some embodiments, a CBI device as disclosed herein may provide behavioral benefits (such as balance support or gait improvement cues) by generating supra-threshold spinal cord activation for which, however, the artificial sensations remain sub-conscious, e.g. after training and sematic calibration of the CBI device.

In such a configuration, the sematic calibration of the CBI device would be done conventionally with consciously reported sensations and objective behavioral tests and then one could gradually diminish the intensities (or different signal parameters) until the subject no longer reports any conscious perception but a behavioral benefit still persists. In other words, due to training (similar as when learning Braille script or Morse code) it is possible that the subject may not report the same conscious percepts anymore but may still intelligibly process the communicated information.

The bioelectric response330corresponds to a combination of stimulation parameters resulting in a supra-threshold stimulation of the targeted nerve fiber (see data points indicated with an “o” symbol inFIG.3bandFIG.3c) and eliciting a stronger (e.g. different or undesired) artificial sensory perception (e.g. too strong, wrong type of sensation, wrong locus of sensation, etc.) in a sensory cortex area of the individual, such as an unpleasant touch sensation on the abdomen of the individual. The waveform of the bioelectric response330could then be stored in a memory module of the CBI device as a reference example of a desired supra-threshold bioelectric response having an alternate sematic meaning or as an undesired supra-threshold bioelectric response when carrying out the autocalibration method as described above.

Naturally, several different bioelectric responses such as the response320may result in similar or essentially identical artificial sensations that may all be used for communicating the same block of information to the individual. The more response waveforms that are labeled with “desired/undesired” are stored in memory the better the on-line autocalibration method discussed above performs.

In order to serve as references for later use in an autocalibration method as discussed above, the stimulation parameters are thus associated, during initial calibration of the CBI device, to a threshold for eliciting an active, non-linear bioelectric response of the respective nerve fiber (e.g. an bioelectric response such as an ECAP having a specific intensity and signal shape). The excitation threshold of a nerve fiber may depend, inter alia, on the electric transfer function of the neurostimulation equipment, on the distance and relative orientation between stimulation contact and nerve fiber, the electric properties of the tissue surrounding the stimulation site, and the bioelectric properties (e.g. Na-ion and K-ion channel density) of the targeted nerve fiber etc.

By recording, upon initial calibration of the CBI device, the wave-form of bioelectric responses of the nerve fibers and by relating them activation threshold and a plurality of desired artificial sensations the CBI device may later be auto-calibrated in an on-line manner by observing the bioelectric responses of the nerve fiber alone without the need to record cortical activity patterns and/or without the individual participating in a laboratory-based calibration procedure.

FIG.3bshows a diagram illustrating a plurality of systematic measurements of bioelectric responses of a sub-population of afferent sensory nerve fibers depending on two different neurostimulation parameters recorded/sensed during initial calibration of a CBI device according to an embodiment of the present invention. By such a collection of measurements across a two or higher-dimensional stimulation parameter space the excitation behavior of the stimulated afferent sensory nerve fibers with respect to the neurostimulation interface driven by the CBI device may accurately be characterized.

For instance, data points are sampled from the parameter space and bioelectric response (e.g. ECAPs) are recorded. Some parameter combination elicit no responses (data points indicated with “−”), some elicit responses that the individual has reported as sensation intensity level 1 (data points indicated with “x”) and some as sensation intensity level 2 or higher (data points indicated with “o”). It is simpler to retune the function if subjective perceptions of subjects are clearly mapped to the bio response signatures (e.g. during an initial calibration sessions) but this is not critically relevant. More important is that the dotted-line340(or a hyperplane for higher dimensional parameter spaces) delineates the dividing line between response and no response and this line is altered upon e.g. moving the implant or moving the spine in a certain way thereby changing the excitation behavior of the targeted afferent sensory nerve fiber.

Further, such functions may be calculated (e.g. to differentiate x & o intensity levels), so that shells of dividing lines may be pictured. In a certain sense they are also isolines—in the sense that alle parameters that trigger a response along that isoline trigger similar intensity responses. In the following a numerical example is given to illustrate the underlying concepts:

Example 1: Initial Calibration Session

0.5 mA; 500 ms burst duration: No Subjective Response/No ECAP2.5 mA; 500 ms burst duration: No Subjective Response/Weak ECAP

For example, such bioelectric responses may be associated during a sematic training session with a too weak stimulation that should be avoided. Accordingly, prior to re-calibration using the autocalibration method described above, this combination of stimulation parameters will not be used by the CBI device.2.5 mA; 1000 ms burst duration: Response-Intensity weak perceived/Middle ECAP

For example, such a bioelectric response may be associated during a sematic training session with a piece/block of information to be communicated via the CBI device (e.g. the letter “A”).3.5 mA; 500 ms burst duration: Response—Intensity middle perceived/Strong ECAP

For example, such a bioelectric response may be associated during a sematic training session with a further piece/block of information to be communicated via the CBI device (e.g. the letter “B”).3.5 mA; 1000 ms burst duration: Response-Intensity very strong perceived/Very Strong ECAP.

For example, such a bioelectric response may be associated during a sematic training session with an unpleasant artificial sensation to be avoided. Accordingly, prior to re-calibration using the autocalibration method described above, this combination of stimulation parameters will not be used by the CBI device.

FIG.3cshows a diagram illustrating a change in the excitation behavior of the afferent sensory nerve fibers on which the initial calibration procedure resulting inFIG.3awas performed. For instance, in this example, the position of the test signal stimulation contact moved with respect to the targeted afferent sensory nerve fiber. In the shown example, the dotted delimiting line304shifted towards the origin of the diagram as compare to the reference calibration procedure ofFIG.3b. In such a configuration, not changing stimulation parameters may well lead to an overstimulation of the targeted afferent sensory nerve fiber thereby degrading the quality of the corresponding perceptual communication channel.

However, the present invention allows, based on the reference bioelectric responses recorded forFIG.3b, to recalibrate stimulation parameters (e.g. intensity and/or pulse duration, etc.) and thereby maintain the quality of the corresponding perceptual communication channel.

FIG.4shows an exemplary sequence of operation of a CBI device executing an on-line auto-calibration method according to an embodiment of the present invention in an interleaved manner with actual information transmissions to the brain of an individual. In this automated routine channel checks are interleaved with blocks of information transmission. Specifically, channel check periods420are interleaved with data transmission periods420. Each channel check period420involves application of neurostimulation test signals and recording of a bioelectric response of the stimulated afferent sensory nerve fiber as discussed above. For instance, the examplary test signal—sensing sequences illustrated inFIGS.5-9may be used during such a channel check period420.

Based on the sensed bioelectric response of the stimulated afferent sensory nerve fiber(s) a current activation function of the nerve fiber may be determined and compared to a reference activation function (seeFIG.4). If deviations from the reference activation function(s) are detected stimulation parameters may be recalibrated43o. For instance, a set of recalibrated stimulation parameters (intensity, duration, pulse width, etc.) may be determined and then be used for a subsequent data transmission410. In this manner, the intensity, quality, and/or locus of the corresponding artificial sensory perceptions may be stabilized. For instance, the present excitation behavior (seeFIG.3cabove) may be estimated by utilizing bioelectric response measurements using at least two types of stimulation parameters such as the illustrated intensity and pulse duration.

The activation curve may however include other modalities or other dimensions (e.g. multi-dimensional activation curves). Importantly, a full re-sampling of the activation curve is not absolutely necessary since in many configurations a sparse sampling approach indicating a rheobase and chronaxie values would be enough to estimate the activation function without having to move through parameter space in brute force. As a result, the properties such as the channel bandwidth of the corresponding perceptual communication channel may be maintained even in normally behaving subjects during a broad range of daily activities.

FIG.5illustrates a test signal/recording configuration where the CBI device delivers (e.g. via a neurostimulation module; seeFIG.2) or commands an implanted stimulator to deliver whole bursts of test stimuli then waits for detection and recording of the induced bioelectric responses (e.g. action potentials, ECAPs, etc.) after the last pulse stimuli is applied. In this first example, stimulation parameters during burst stimulation510remain constant and bioelectric response (e.g. ECAP) measurement520takes place after the last pulse iteration within the burst.

FIG.6shows a test signal/recording sequence where the intensity of the neurostimulation test signal610is ramped and bioelectric response (e.g. ECAP) measurement620takes place after each pulse iteration within the burst.

FIG.7shows a test signal/recording sequence where the intensity of the neurostimulation test signal710is kept constant and the pulse duration is ramped. As inFIG.6bioelectric response (e.g. ECAP) measurement720takes place after each pulse iteration710within the burst.

FIG.8shows a combined intensity and pulse duration ramp, that for instance may be used to efficiently estimate a two-dimensional activation function (e.g. seeFIGS.3band3c). As inFIG.6andFIG.7bioelectric response (e.g. ECAP) measurement820takes place after each pulse iteration810within the burst sequence.

FIG.9illustrates how averaging across multiple channel check sequences may improve data quality and thus make the estimation of the current activation function more precise and noise tolerant.