WO2017091863A1

WO2017091863A1 - Stimulus pattern, method and system to evoke spike train patterns in tactile sensory neurons

Info

Publication number: WO2017091863A1
Application number: PCT/AU2016/051187
Authority: WO
Inventors: Ingvars BIRZNIEKS; Richard VICKERY
Original assignee: Newsouth Innovations Pty Limited
Priority date: 2015-12-04
Filing date: 2016-12-02
Publication date: 2017-06-08

Abstract

Provided is a stimulus sequence to evoke a controlled spike train pattern in neurons of the tactile sensory system. Also provided are systems for generating and delivering stimulus sequences. The stimulus sequence uses a plurality of stimulus pulses having substantially identical amplitude, and a pulse shape wherein the rising edge of the stimuli pulse is less than 3 milliseconds in duration, the plurality of stimulus pulses being arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds. Each burst comprises two or more stimulus pulses having a maximum time interval of 15 milliseconds between successive stimulus pulses within the pulse burst. The pattern of pulse bursts and time intervals is configured to, when applied to evoke a spike train pattern, convey a perception of physical sensation of which vibration is a part, the physical sensation having controlled properties of vibration frequency and intensity. Where the vibration intensity is conveyed by a burst duration and a number of stimulus pulses within the burst duration of each burst and the vibration frequency is conveyed by time interval between bursts. The perception of intensity is influenced by burst duration and number of stimulus pulses within a burst, and perception of vibration frequency is influenced by time intervals between successive pulse bursts.

Description

STIMULUS PATTERN, METHOD AND SYSTEM TO EVOKE SPIKE TRAIN PATTERNS IN TACTILE

SENSORY NEURONS

Technical Field

The present invention is applicable to the field of neuroscience (in particular vibrotactile stimulation of sensory nerve fibres), prosthetic, haptic and other devices implementing tactile feedback.

Background to the Invention

The nervous system encodes sensory information arising in the environment using short (< 1 ms) electrical impulses (called spikes or action potentials). The spikes are generated in nerve fibres in response to sensory stimulation for transmission to the brain.

Sensory information is transmitted to the brain via sensory (or afferent) nerve fibres. This is a form of digital code where each electrical impulse has identical characteristics, and information is encoded by means of trains of spikes as either the number of spikes generated per unit of time (rate code) and/or by more complex patterns dependent on the relative timing of individual spikes (temporal code). An analogy for the patterns of spikes in a temporal code is that of "Morse code for the brain", the patterns of spikes bear some similarities to Morse code but consists only of "dots" at the time of each spike occurrence. Using the same analogy "dashes" may bear similarity to bursts of spikes (multiple spikes generated in short succession). The neural code is much more complex and versatile as the exact timing between individual "dots" may also encode information.

These spike trains are the only means for the brain to receive information from sensory organs. So, if one would be able to create such spike trains in sensory nerve fibres, in theory, any kind of information could be encoded and sent to the brain to artificially create any kind of conscious experience. While activation of just a few sensory nerve fibres may evoke sensation with distinguishable properties, normally information is signalled by the activity of many thousands of nerve fibres (a population of afferents). In a population of afferents, information is encoded by spike trains in a single nerve fibre as well as in the pattern of spike trains compared across multiple nerve fibres. An analogy is from computing where one bit of information per output channel becomes one byte when information is encoded across 8 such output channels combined.

Decoding the information in spike trains depends on the type of sensory nerve fibre conveying the information. A spike train in a nerve fibre connected with pain receptors will cause pain, but in a nerve fibre connected with mechanically sensitive skin receptors specialised to detect skin vibrations, this same spike train will be interpreted as vibration. The same applies to the many types of nerve fibres: nerve fibres associated with pressure receptors evoke pressure, fibres associated with cold receptors evoke cold, and so on.

A known method to create spike trains with time-controlled parameters in sensory nerve fibres related to the sense of touch is to use electrical stimulation. A problem with electrical stimulation is that to convey information, this electrical stimulation must be applied to a single or limited number of nerve fibres of the same type (determined by their connected receptor) otherwise the information will be a jumble of different types determined by the mix of sensory nerve fibres activated. For example, in the region where the electrical stimulation is applied there may be nerve fibres associated with pain receptors as well as nerve fibres associated with vibration, thus applying the electrical stimulation may evoke both a perception of vibration and pain as nerve fibres associated with both types of receptors are activated by the electrical stimulation.

Therefore selective activation of one or a few nerve fibres by electrical stimulation normally requires implantable electrodes and surgical intervention to allow close physical proximity to single nerve fibres. However, the predictability of the stimulus targets for surgically implanted electrodes is limited. The selectivity of electrical stimulation is limited by chance to what nerve fibres are in close proximity. For example, the median nerve receiving information from a hand has about 40 000 different nerve fibres. There is little benefit if a spike train intended for nerve fibres carrying information from vibration receptors is concurrently generated in pain fibres and in fibres carrying information about pressure or stretch applied to the skin.

There is a need for methods and systems to enable selective and controlled stimulation of specific types of nerve fibres.

Summary of the Invention

According to one aspect there is provided a stimulus sequence to evoke a controlled spike train pattern in neurons of the tactile sensory system, the stimulus sequence comprising:

a plurality of stimulus pulses having substantially identical amplitude, and a pulse shape wherein the rising edge of the stimuli pulse is less than 3 milliseconds in duration,

the plurality of stimulus pulses being arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds,

each burst comprising two or more stimulus pulses having a maximum time interval of 15 milliseconds between successive stimulus pulses within the pulse burst, and

the pattern of pulse bursts and time intervals being configured to, when applied to evoke a spike train pattern, convey a perception of physical sensation of which vibration is a part, the physical sensation having controlled properties of vibration frequency and intensity,

the vibration intensity being conveyed by a burst duration and a number of stimulus pulses within the burst duration of each burst and

the vibration frequency being conveyed by time interval between bursts,

whereby perception of intensity is influenced by burst duration and number of stimulus pulses within a burst, and

perception of vibration frequency is influenced by time intervals between successive pulse bursts.

In an embodiment stimulus pulses are mechanical pulses of substantially identical shape and length. In an embodiment stimulus pulses have mechanical pulse amplitude of up to 5 microns to thereby selectively stimulate fast adapting type II (FAN) nerve fibres.

In an alternative embodiment of a stimulus sequence pulse amplitude is controlled to selectively stimulate one or more types of nerve fibres. In one embodiment the stimulus pulses are mechanical pulses having mechanical pulse amplitude within range 1-10 microns to stimulate FAN nerve fibres; and having mechanical pulse amplitude of above 10 microns and below 50 microns to stimulate FAN and FAI fibres. In another embodiment the stimulus pulses are mechanical pulses having mechanical pulse amplitude of about 5 microns to selectively stimulate FAN nerve fibres. Preferably stimuli pulse duration is between 1 and 3 milliseconds.

The property of intensity can reflect a combination of perceptually and physically definable parameters including any one or more of amplitude, wave shape, texture, strength, sharpness and complexity.

According to another aspect there is provided a method of selectively stimulating type II fast adapting tactile afferents (FAN) across all frequencies, the method comprising:

providing a mechanical pulse generator configured to deliver short mechanical pulses of around 5 micron amplitude, around 1 to 3 millisecond duration, and substantially identical pulse shape;

applying the mechanical pulse generator to a region proximate to FAN nerve fibres; and driving the mechanical pulse generator to deliver a sequence of mechanical pulses, whereby each pulse evokes an electrical impulse (spike) in the FAN nerve fibre.

In an embodiment the mechanical pulse generator is driven in accordance with a stimulus sequence pattern comprising a plurality of stimulus pulses arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds,

each burst comprising two or more stimulus pulses having a maximum time interval of 15 milliseconds between successive stimulus pulses within the pulse burst,

the pattern of pulse bursts and time intervals being configured to convey a perception of physical sensation of which vibration is a part, the physical sensation having controlled properties of vibration frequency and intensity,

the vibration frequency being conveyed by time interval between bursts,

According to another aspect there is provided a method of selectively stimulating one type of nerve fibres for a subject across all frequencies, the method comprising:

providing a pulse generator configured to deliver short pulses of around 1 to 3 millisecond duration, substantially identical pulse shape, and adjustable amplitude;

tuning the pulse generator amplitude to determine an amplitude for stimulating one type of nerve fibres by:

a) setting the adjustable amplitude of the pulse generator at an initial pulse amplitude; b) applying to a stimulation site of the subject using the pulse generator a stimulus sequence of pulses;

c) receiving feedback from the subject indicating sensation perception evoked by the applied pulse sequence, and d) if the applied pulse sequence evoked no sensation incrementally increasing the pulse amplitude and repeating steps b, c and d until a sensation is perceived to provide the tuned amplitude; or

e) if the applied pulse sequence evokes sensation incrementally decreasing the pulse amplitude and repeating steps b, c and e until no sensation is perceived, then incrementing the pulse amplitude once to provide the tuned amplitude,

the tuned amplitude and slightly above being a pulse amplitude where the subject's most sensitive sensory nerve fibres at the stimulation site are activated;

and

subsequently driving the pulse generator at the tuned amplitude or slightly higher to deliver a sequence of pulses, in accordance with a stimulus sequence pattern comprising a plurality of stimulus pulses arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds,

the pattern of pulse bursts and time intervals being configured to convey a perception of sensation of which vibration is a part, the sensation having controlled properties of vibration frequency and intensity,

the vibration frequency being conveyed by time interval between bursts,

According to another aspect there is provided a neuronal stimulation system comprising:

a stimulus sequence controller configured to generate a stimulus sequence for one or more vibrations each having defined vibration frequency and intensity, the generated stimulus sequence comprising a plurality of stimulus pulses the plurality of stimulus pulses being arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds, each burst comprising two or more stimulus pulses having a maximum time interval of 15 milliseconds between successive stimulus pulses within the pulse burst, and the pattern of pulse bursts and time intervals being configured to convey a perception of sensation of which vibration is a part, the sensation having controlled properties of vibration frequency and intensity, the vibration intensity being conveyed by a burst duration and a number of stimulus pulses within the burst duration of each burst and the vibration frequency being conveyed by time interval between bursts, whereby perception of intensity is influenced by burst duration and number of stimulus pulses within a burst, and perception of vibration frequency is influenced by time intervals between successive pulse bursts; and

a stimulus device configured to receive the generated stimulus sequence from the controller and deliver stimulus pulses to a subject in accordance with the stimulus sequence. In an embodiment of the neuronal stimulation system described above the stimulus device is a mechanical stimulus device configured to deliver substantially identical pulses of duration between 1 to 3 milliseconds and amplitude between 1 to 5 microns.

Brief description of the drawings

Figure 1 is a block diagram of an example of a computer controlled mechanical stimulator for applying a stimulus pattern to a subject;

Figure 2 illustrates applied stimuli and measured spike train responses in tactile afferents;

Figure 3 illustrates fast adapting (FA) tactile afferents entrained by vibrotactile stimuli;

Figure 4 illustrates examples of spike train patterns in accordance with an aspect of the present invention;

Figure 5 is a graph showing detection thresholds as function of frequency for pulsatile and sinusoidal stimuli;

Figure 6 is a graph showing mean perceived intensity of electrical burst stimuli and 95% confidence level; and

Figure 7 is a graph of mean perceived frequency data compared with models.

Definitions

As used herein, the following terms are considered to have the following meanings:

Intensity - Intensity of tactile stimulus is understood as a complex interplay between various perceptually and physically definable contributing factors including but not limited to amplitude, strength, texture, sharpness, complexity etc.

Perception - Perception of vibration refers to conscious perception or subconscious neural processes within the nervous system associated with information processing pertaining to vibration or complex stimuli for which physical vibration is a part of.

Sensation - Sensation is a feeling of the body caused by physical interaction and perceived either cognitively, being consciously perceived and understood, or imperceptibly being perceived by subconscious neural processing.

Detailed Description

Aspects of the present invention include stimulus patterns, systems and methods to enable controlled evocation of spike train patterns in nerve fibres to convey both vibration frequency and intensity. Further aspects enable non-invasive selective stimulation of tactile sensory nerve fibres.

A first aspect of the present invention relates to defining characteristics of stimulus patterns for evoking of spike trains to influence specific perceptions of vibrations. A second aspect of the present invention relates to selective activation of types of afferents based on afferent sensitivity. These two aspects can be utilised individually or in combination. Embodiments of the invention are particularly directed to stimulation of tactile afferents. It is known in different areas of neuroscience that spike train timing plays an important role in the encoding of complex stimulus properties and conveying this information to the brain. However, for a vibrotactile stimulus, which is temporal in nature, the role of spike train rate code and the temporal codes at different levels of processing is not clear and an area of ongoing research. To research spike trains the inventors have developed a method and system to non-invasively evoke spike trains in a controlled manner.

Overview of stimulation method

Research of the inventors has shown that precisely controlled temporal patterns of spike trains can be evoked in rapidly adapting afferents using a computer-controlled mechanical stimulator. An illustrative example is shown in Figure 1. The inventors determined that a short (1 - 3 ms) mechanical pulse will evoke a single spike in a population of tactile afferents. As illustrated in figure 1, the system 100 comprises a controller 110 and a mechanical stimulator 120. The mechanical stimulator 120 of this example is a mechanical stimulator where stimulus is provided via a moveable pin, for example the pin impacting on a fingertip 130 of a subject/person. The stimulator 120 is configured such that each pin protraction is a reproducible and uniform stimulus with fixed speed and amplitude, not influenced by the rate of recurrence. The inventors research evidence indicates that the same population of afferents will be excited by each pin protraction regardless of stimulation frequency. Furthermore, because of the very brief movement (for example, 2 ms), each pin protraction generates only a single time-controlled spike in each responding peripheral afferent. Therefore, the timing of each spike can be precisely controlled, and so control generation of a pattern of spike trains in the responding afferent, the pattern of spike trains to evoke was arbitrarily chosen in testing performed by the inventors. This was confirmed by the inventors using microneurographic recording from the afferents. Some examples of these results are shown in Figure 2, which illustrates applied stimuli 210 and measured spike train responses 220. The spike train responses were measured as shown at the bottom of Figure 2 using a tungsten

microneurography electrode 240 inserted in a fascicle 250 of a human Median nerve 230.

Using a uniform stimulation pulse amplitude and shape to evoke single predictable spikes has an advantage of avoiding confounding effects of a concurrent change in the number of activated afferents or of recruiting additional types of afferents. These are problems which inevitably occur using classical methods (using sinusoidal stimuli) when changing the amplitude or frequency of sinusoidal skin indentation. For example, as illustrated in Figure 3 fast adapting (FA) tactile afferents are readily entrained by vibrotactile stimuli and respond with 1 spike per sine wave cycle (1:1 ratio; panel A). However, when vibration amplitude increases, at some point two or more spikes per cycle can be generated (1:2 ratio; panel B) in more sensitive afferents in the region closest to the stimulation site. This is accompanied by an increase in the area over which afferents remote from the probe contacting skin will start responding. Thus, when some afferents switch their firing rate from 1: 1 to 1:2 there will also be new afferents recruited, which will begin firing at ratio 1: 1 and so on. In addition, with increases in intensity the other types of afferents which are less sensitive to vibratory stimuli at the given frequency begin responding as well. Thus, artificial mimicry and reproduction of such multifactorial complex afferent population activity is technically very challenging and is limited by the current lack of understanding of the underlying neural sensory processing mechanisms. The inventors have developed methods using pulsatile mechanical stimuli providing an alternative methodological path for evoking time-controlled spike train patterns and investigating corresponding perceptual correlates. This type of neural code for communication via sensory input channels provides fundamental advantages in regard to technical implementation and ability to acquire clear definition of perceptual or sensorimotor interpretation rules.

The technology to generate the desired spike train in sensory nerve fibres innervating skin receptors is based on delivering pulsatile mechanical stimuli to the skin. At the heart of this non-invasive method is the application of stereotypical mechanical pulses with a very short protraction time (for example 2 ms) which is comparable with the duration of one spike and its following refractory period. This pulse should be brief enough so that there is no time for a receptor to generate a second spike. This ensures that each mechanical pulse generates only a single time-controlled spike in each responding nerve fibre.

With this technology the inventors were able to non-selectively activate nerve fibres connected with two different types of mechanoreceptors: Meissner and Pacinian corpuscles innervated by so called FAI and FAN nerve fibres respectively. In this context non-selective activation of nerve fibres refer to being unable to differentiate activation of or (selectively activate) the FAI and FAN fibres. Both types of receptor encode properties of stimuli by means of sensing vibrations (vibrations as such may reflect more complex properties of stimuli like texture of the surface, friction, slippage, movement, making contact with an object, hitting an obstacle etc.). It is a huge step ahead in comparison to nonselective electrical stimulation, as the information encoded by these two types of vibroreceptors (vibration sensitive mechanoreceptors) bears considerable functional similarity, unlike the case if there were concurrent activation of pain, temperature, pressure or stretch receptors.

Due to the high density of receptors in the skin, mechanical pulses will affect multiple receptors. In systems previously developed by the inventors it was unavoidable that mechanical pulses would affect multiple receptors and both types of receptors would usually be co-activated.

Selective Activation of Types of Vibroreceptors

Embodiments of the present invention enable selective activation of only one type of vibroreceptor - namely FAN nerve fibres associated with Pacinian corpuscle receptors. This aspect of the invention is based on existing prior physiological knowledge that Pacinian receptors are more sensitive to high speed and acceleration corresponding to high frequency continuous sinusoidal stimuli traditionally used to test receptor properties. It is known that high frequencies of sinusoidal mechanical stimuli best activate Pacinian receptors, whereas Meissner corpuscle receptors and associated FAI nerve fibres are best activated at lower frequencies.

The inventors developed mechanical pulsatile stimuli having characteristics of high speed and acceleration to which FAN nerve fibres are more sensitive than FAI nerve fibres, and by reducing the amplitude of the pulses, configured pulses to which only FAN nerve fibres would respond. Normally, even with high speed and acceleration both types of nerve fibres would be activated, but, if the amplitude of the mechanical pulses becomes low enough (around 5 μιη) only the FAN nerve fibres will respond. Thus, for the first time the inventors have developed technology to activate FAN afferents selectively, noninvasively and can create spike trains of any arbitrary pattern. However, this technology gains significant practical benefit if it can be demonstrated that the information encoded in such spike trains can be perceived and interpreted.

Thus this technology underpins a further development whereby spike trains evoked in and transmitted by FAN nerve fibres are interpreted by the brain as low frequency (<60Hz) vibration previously believed to be signalled only by FAI nerve fibres. Since sinusoidal mechanical stimuli can activate Pacinian receptors selectively only at high frequencies it was not known whether FAI Is would be able to create a conscious perception of low frequency (<60Hz) vibration. Prior to the development of the present invention it was not possible to find out, because there was no reliable technology available for selective activation of FAN nerve fibres with low frequency vibrations. Further, embodiments of the invention enable selective activation of more than one type of nerve fibre based on controlling the amplitude of the stimuli. For example, at amplitudes of around 1 μιη to around 9μιη, preferably around 5 μιη, only FAN nerve fibres are activated by the pulsatile stimuli. However, if the amplitude of the pulsatile signal is increased above 9 μιτη, for example to a range of around 10 to 20 μιτι, FAI fibres will also start to be activated by the stimuli. In this instance both FAN and FAI fibre populations will be activated. By further increasing the amplitude of the pulsatile stimuli eventually afferents normally signalling pressure applied to the skin (SAI) will become activated in addition to the two types of vibroreceptors. At even higher amplitudes spike trains will be induced in SAI I afferents normally signalling skin stretch.

The inventors are first in the world to show that they can create arbitrary spike trains in only one or several types of tactile sensory nerve fibres non-invasively.

While this embodiment exemplifies selective activation of FAN afferents as the most sensitive afferent type, the same principle may be applied if the most sensitive afferent type in a given skin region or in given individual (due to pathology, for example) is not the FAIL The exact indentation amplitude ranges to activate the most sensitive type of afferents only or multiple types of afferents may also vary depending on: the afferent types innervating a given type of skin; skin mechanical properties; and shape and size of the stimulation probe.

Spike Train Patterns

Previous research by the inventors has shown that complex periodic vibrotactile stimuli evoke corresponding spike patterns in tactile afferents. These spike train patterns are characterised by bursts of two or more spikes separated by gaps. The inventors have made a previous discovery about how spike trains encode the frequency of skin vibration.

Previous research by the inventors determined that frequency perception is based on the time period between bursts (longest inter-spike interval). If there are multiple spikes following in short succession (called a burst) and then there is a gap between bursts, the reciprocal of the time interval between the last spike in one burst to the first spike in the next burst corresponds to the perceived frequency. Examples are shown in Figure 4. Figure 4 shows a schematic representation of spike train patterns. Each of the vertical lines represents one spike evoked by a mechanical pulse. The corresponding stimuli in panels A and B have the same perceived frequency equal to the reciprocal of t_L. Stimuli in #2, 3 and 4 of panel A are perceived to have the same frequency but different intensity than the corresponding stimuli #2, 3 and 4 in panel B. The burst duration within certain limits has no effect on perceived frequency. Before the inventors' study it was believed that only the average number of spikes per unit of time regardless of spike train temporal arrangement (pattern) encoded vibration frequency.

The inventors have now demonstrated that the number of spikes contained within a burst and burst duration does not influence frequency perception. The inventors test results show that the number of spikes within a burst and burst duration influences intensity perception without contributing to the perceived frequency. There is prior knowledge that the number of spikes in a population of afferents contributes to the encoding of stimulus intensity (including vibration amplitude).

However, as detailed above, due to the complex population effects inevitably accompanying changes in amplitude of sinusoidal vibration, it has never been proven or shown whether and how the number of spikes within single FAI or FAN afferents influence stimulus intensity or vibratory amplitude perception. Most importantly, the number of spikes generated in FAI and FAN afferents was always associated with frequency perception and there have been no solutions for how to manipulate vibration amplitude/intensity perception independently from frequency by stimulating these types of afferents. Intensity perception increase previously has been achieved by increasing the number of stimulated afferents - either by increasing the amplitude of mechanical stimuli or increasing the strength of stimulation current. In contrast, the inventors have discovered how to manipulate the perception of frequency and intensity independently by stimulating the same afferents, and by changing spike train patterns: the gap between bursts will encode frequency of vibration and the duration and number of spikes within the burst will influence the perceived amplitude of stimuli. In particular the perception of vibration frequency and intensity can be influenced without changing the amplitude of the stimulation signal.

Thus an aspect of the invention provides a method of controlling frequency and intensity independently using a simple fixed level stimulus device that emits different spike patterns. This can enable a simple stimulation device which may be part of a prosthetic system or other devices implementing tactile feedback.

Examples of test outcomes using electrical pulsatile stimuli are shown in Figures 6 and 7. In these tests pulsatile stimuli were delivered as brief electrical pulses. The graph of Figure 6 shows mean perceived intensity of electrical burst stimuli. This graph shows that as the number of pulses in a burst are increased, the apparent intensity of the sensation (magnitude score) increases. This testing also showed that changes to intensity do not necessarily cause changes in frequency perception. The changes to intensity are achieved without changing any properties of afferent population recruitment (only the spiking pattern in responding afferents is changed). Figure 7 is a graph of mean perceived frequency data compared with models. This graph shows the mean 710 of perceived frequency values of each subject for each complex electrical stimuli. This graph includes the frequency expected 720 from the periodicity of the burst stimuli (21 Hz), the expected temporal frequency 730 derived from the longest inter-spike interval (Lll) (33Hz) and the frequency expected 740 from the rate code, the number of impulses a second (imp/s). The data from P04 has also been plotted 750 as that subject perceived the frequency of the electrical burst stimuli differently. This figure shows that although the number of spikes in a burst increases from 2 to 5, the frequency perception does not increase as a simple prediction from impulse/seconds would suggest. The stimulus patterns were the same as used in the example of Figure 6, but with the test subjects asked to report on perceived frequency rather than intensity. While the embodiments of the present invention are directed to systems and methods to create such spike train patterns noninvasively, the knowledge of this neural code is universal and is applicable to a wide range of applications. For example, the spike train patterns could be used to achieve a similar result (combining frequency and intensity information in a single channel) with technology achieving sufficiently selective electrical stimulation of single nerve fibres. This has a particular benefit of varying intensity information without actually changing the intensity of a stimulus, as real intensity changes can lead to activation of pain nerve fibres, especially with electrical stimulation. Spike train patterns in accordance with the present invention may be applicable for some applications using electrical stimulation, where it is advantageous to enable variation of perceived intensity without increasing the amplitude of the electrical stimulation in some cases entailing undesired effects, for example, loss of specificity (activation of more neurons with various properties within the same or different modalities) or increasing risk of damage to tissue due high density of current). Other factors related to the nature of the subject (for example a child) or environment (minimising electromagnetic radiation from stimulus equipment) may also play a role.

For spikes to be considered as contained within a burst, the time interval between successive spikes should be less than 15ms. At the time of writing this application the exact maximum possible duration of a burst or the maximum possible number of spikes in a burst while not affecting frequency perception is not fully known. However, the inventors have successfully tested stimuli with up to 5 spikes separated by 4ms, or only two spikes up to 17.5ms apart with a gap between bursts as short as 26ms. These parameters are not constant and may change in different combinations.

The inventors have shown that the stimulus pattern for artificially evoking a perception of vibration in tactile afferents disclosed is not identical to naturally occurring spike train responses to an actual vibration signal. For example, a sinusoidal stimulus at larger amplitudes in some afferents will evoke one spike per cycle and in others, regular bursts of spikes. These bursts repeat at the period of the stimulus. The precise timing of spikes within the burst period cannot be predicted or controlled using traditional sinusoidal stimulus because it is continuous in its makeup. Thus with naturalistic stimuli different afferents will fire different numbers of spikes at slightly different phase shifts within the vibratory cycle. It is believed by the inventors that information encoding principles within population discharge are yet unknown and too complex for artificial mimicry and reproduction within population of tactile afferents using electrical stimulation or other methods of controlling afferent spiking activity.

The stimulus patterns of the present invention can be regarded as substitution of a naturalistic spatio-temporal complex population response with artificially created time-controlled uniform synchronous afferent firing input with predictable interpretation. This solution takes advantage of natural information processing circuits within the nervous system. Uniform synchronous firing at the periphery reduces complexity of naturalistic population firing making it assessable for artificial reproduction and implementation in various communication systems between the nervous system and technical control devices. In other words the stimulus patterns evoke spike trains to artificially represent a physical sensation of which vibration is a part. For example, physical sensations of a knock, tap, buzz, scrape, etc. all include some aspect of vibration and intensity. The spike train pattern technique of the inventors allows an artificial representation of vibration frequency and intensity parameters of the sensation via the stimulus pattern, to, when the corresponding spike train is evoked, convey in this neurological response (spike train) a perception of the physical sensation. It should be appreciated that the stimulus patterns and evoked spike trains will be different from a naturally occurring neurological response to a real physical sensation stimulation - i.e. an actual tap, brush or touch.

Using the stimulus patterns of the present invention, frequency perception is not dependent on the period of the stimulus pattern, only on the time gap between bursts. Further, the timing between pulses within a burst and burst duration may be varied without affecting perception of frequency, provided the interval between the leading edge of successive pulses within a burst does not exceed 15 ms. As each spike is evoked based on a rapidly rising leading edge of the stimulus pulse, some variation in pulse shapes and length may also be allowed without affecting frequency and intensity encoding. It may be possible to also evoke spike responses on a rapidly falling edge of a pulse, enabling alternative variations of pulse trains.

An aspect of the present invention provides a stimulus sequence to evoke a controlled spike train pattern in nerve fibres. The stimulus sequence comprises a plurality of stimulus pulses arranged in a pattern of pulse bursts separated by time intervals. The plurality of stimulus pulses have substantially identical amplitude, and a pulse shape wherein the rising edge of the stimuli pulse is less than 3 milliseconds in duration. The plurality of stimulus pulses are arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds. Each burst comprises two or more stimulus pulses having a maximum time interval of 15 milliseconds between successive stimulus pulses within the pulse burst. The pattern of pulse bursts and time intervals is configured to convey a perception of physical sensation of which vibration is a part, the physical sensation having controlled properties of vibration frequency and intensity, to evoke a spike train pattern for perception of the sensation. The vibration intensity is conveyed by a number of stimulus pulses in each burst and burst duration. The vibration frequency is conveyed by time interval between bursts. The perceived frequency is the reciprocal of the time interval between bursts. Thus, perception of intensity is influenced by number of stimulus pulses and duration of a burst, and perception of vibration frequency is influenced by time intervals between successive pulse bursts. The perception of intensity of a natural stimulus translated into a vibratory pattern may be contributed to by many different tactile stimulus features, these include amplitude, wave shape, complexity of the pattern etc. In particular, vibration intensity may not be directly related to vibration amplitude. For example, there might be intense stimulus with low amplitude and vague slow stimulus with large amplitude. A real vibration having a smooth sinusoid may be perceived as having a different intensity to a vibration having an angular or complex wave shape even though these vibrations have the same frequency and amplitude. To consider an analogy: the same musical note played in tune with good tone on a clarinet may be perceived as less intense as the same note played in tune at the same volume but scratched by a beginner on a violin. Thus, vibrations that may have the same frequency and amplitude can be perceived as having a different intensity. It should be appreciated that in the stimulus sequence of the present invention the arrangement of bursts can be configured to influence intensity which is understood as a complex interplay between various perceptually and physically definable contributing factors including but not limited to amplitude, strength, texture, sharpness, complexity etc. In one system implementation the stimulus pulses are mechanical pulses of substantially identical shape and length. For example, uniform pulses produced by pin protractions. Preferred embodiments use short mechanical pulses with duration comparable to the refractory period of spike generation (about l-3ms; short enough to generate only a single spike). Each single mechanical pulse is a reproducible and uniform stimulation event with fixed speed and amplitude characteristics not influenced by the rate of recurrence, and so the same tactile receptors will be excited regardless of stimulation frequency. The inventors have reproduced and verified the same result with piezoelectric stimulators, dimorphs and voice coils using various software solutions. Where the mechanical pulse amplitude is up to about 5 microns fast adapting type I I (FAN) nerve fibres are selectively stimulated. For selective activation of Pacinian receptors and associated FAN nerve fibres, pulsatile stimuli are applied at amplitude about 5 μηη when no FAI would respond. The lowest FAI threshold in the most sensitive range is more than 10 μιη.

In some embodiments pulse amplitude for a stimulus sequence is controlled to selectively stimulate one or more types of nerve fibres. For example, in an embodiment the stimulus pulses are mechanical pulses and FAN nerve fibres are stimulated by pulses having mechanical pulse amplitude of 1 to 5 microns; and FAN and FAI fibres are stimulated by pulses typically having mechanical pulse amplitude of above 10 microns and below about 50 microns, further increase in amplitude will activate afferents signalling pressure followed (SAI) by afferents signalling skin stretch (SAM).

Preferably stimulus pulse duration is between 1 and 3 milliseconds.

Such spike train patterns can encode various aspects of sensory information transmitted to the central nervous system, which can be used to control conscious perceptual experiences and provide input to sensorimotor transformations when performing various tasks. Possible fields of application are prosthesis with sensory feedback, telesensory devices, haptic communication devices and brain- machine interfaces.

This technology enables development of certain spiking activity patterns to achieve the perception of intensity and frequency independently from one another by changing the temporal pattern of the spike train evoked in the same sensory nerve fibres. Prior to this invention there was no neurophysiological or practical knowledge available to exploit this approach for information transfer to the brain. The present invention provides knowledge to specify spike train pattern building principles. Further this is accompanied with non-invasive methods to evoke such spiking activity patterns in tactile sensory neurons.

While the focus of the inventors and above description has been to evoke such patterns non- invasively, the invention may also be advantageously applied to increase information throughput to the brain in case of electrical stimulation via microelectrodes inserted directly in the nerve or within central nervous system contacting single or a small number of sensory neurons.

The non-invasive technique of evoking well controlled spike trains in sensory nerve fibres and ability to exploit one neural communication channel by selectively activating FAN sensory nerve fibres without having an effect on other types of receptors has several advantages and specific applications: a) While in regard to vibrotactile frequency and intensity/amplitude encoding the function of different fast adapting afferent types may be similar, they may serve significantly different functions in different contexts, for example, sensorimotor control. The ability to create time-controlled spiking patterns selectively in FAN afferents may be crucial to achieve an adequate interpretation of tactile sensory feedback.

b) The information transfer using one sensory communication channel (FAN) may be beneficial in haptic communication devices as it would be able to transfer the information without interfering with the function of other tactile afferents.

At the heart of this non-invasive method is application of stereotypical pulsatile mechanical stimuli with a very short protraction time lasting only around 2 ms which is comparable to the refractory period of the action potential (spike). This ensures that each stimulation event generates only a single time-controlled spike in each responding receptor. Each single mechanical pulse is a reproducible and uniform stimulation event with fixed speed and amplitude characteristics not influenced by the rate of recurrence, and so the same population of receptors will be excited regardless of stimulation frequency. This method previously developed by inventors has been significantly advanced by being able to selectively stimulate only one single type of tactile sensory receptors. It has been used to selectively activate, only Pacinian corpuscle-associated FAN sensory nerve fibres. Using sinusoidal type stimuli FAN sensory nerve fibres cannot be selectively activated at low frequencies below about 60Hz. In contrast the method using pulsatile stimuli has enabled the inventors to selectively activate FAN sensory nerve fibres covering a whole range of frequencies. This approach is supported by recent neurophysiological discoveries of the inventors that FAN sensory nerve fibres even, if activated selectively, are capable of evoking conscious perception signalling low frequency vibrations and are able to readily detect small differences between stimuli with slightly different frequencies.

Possible fields of application are prostheses with sensory feedback, telesensory devices, haptic communication devices and brain-machine interfaces. In particular aspects of the invention may be of interest to prosthesis designers and manufacturers, haptic device designers etc.

Another aspect of the invention provides a method of selectively stimulating type I I fast adapting tactile afferents (FAN) across all frequencies, the method comprising:

applying the mechanical pulse generator to a skin region proximate to FAN nerve fibres; and driving the mechanical pulse generator to deliver a sequence of mechanical pulses, whereby each pulse evokes an electrical impulse spike in the FAN nerve fibre.

each burst comprising two or more stimulus pulses having a maximum time interval of 15 milliseconds between successive stimulus pulses within the pulse burst, the pattern of pulse bursts and time intervals being configured to convey a perception of sensation of which vibration is a part, the sensation having controlled properties of vibration frequency and intensity, to evoke a spike train pattern for perception of the sensation,

the vibration intensity being conveyed by a number of stimulus pulses in each burst and burst duration, and

the vibration frequency being conveyed by time interval between bursts,

whereby perception of intensity is influenced by number of stimulus pulses with a burst and bust duration, and

perception of vibration frequency time intervals between successive pulse bursts, and by varying time intervals.

Another aspect of the invention provides a neurological stimulation system comprising:

a stimulus sequence controller configured to generate a stimulus sequence for one or more vibrations each having a defined vibration frequency and intensity, the generated stimulus sequence comprising a plurality of stimulus pulses the plurality of stimulus pulses being arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds, each burst comprising two or more stimulus pulses having a maximum time interval of 15 milliseconds between successive stimulus pulses within the pulse burst, and the pattern of pulse bursts and time intervals being configured to convey a perception of sensation of which vibration is a part, the sensation having controlled properties of vibration frequency and intensity, to evoke a spike train pattern for perception of the vibration, the vibration intensity being conveyed by a number of stimulus pulses in each burst, and the vibration frequency being conveyed by time interval between bursts, whereby perception of intensity is influenced by burst duration and number of stimulus pulses within a burst, and perception of vibration frequency is influenced by time intervals between successive pulse bursts; and

a stimulus device configured to receive the generated stimulus sequence from the controller and deliver stimulus pulses to a subject in accordance with the stimulus sequence.

Embodiments of the present invention may be applied to provide sensory feedback in prostheses targeting one single type of receptors (Pacinian corpuscles) and associated FAN nerve fibres. The ability to achieve this effect using a simple mechanical actuator under software control may simplify and reduce cost to effectively integrate sensory feedback into prostheses.

Embodiments of the present invention enable one single type of receptors (Pacinian corpuscles) and associated FAN nerve fibres to convey information about stimuli associated with the whole spectrum of vibration frequencies. This increases possibilities for haptic communication via one sensory communication channel (FAN fibres) without interfering with the function of other sensory channels (types of tactile receptors) potentially leaving them available to convey independent information. It is also envisaged that embodiments may be applied to selectively stimulate any most sensitive nerve fibre in a target area. In some areas of the skin FAN tactile afferents may not be present and other nerve fibres may be the most sensitive in such areas. For example, it is believed that FAN afferents are absent from skin of some areas of the body, such as the face. Further in the case of amputees the types of nerve fibres effective may vary between different subjects, areas of the body and surgery techniques. The stimulus patterns described enable encoding of vibration frequency and intensity using bursts of pulses all of substantially identical shape. It is therefore envisages that stimulus pulses can be tuned to selectively stimulate the most sensitive nerve fibres available for a target area of a subject, by identifying the minimum pulse amplitude required to stimulate perception of a vibration (sensation) in the target area. Thus enabling stimulation of perception across all frequencies by applying different stimulus patterns using the tuned pulse amplitude. First a pulse generator is provided, the pulse generator being configured to deliver short pulses of around 1 to 3 millisecond duration, with substantially identical pulse shape. The amplitude of the pulses is however adjustable. The amplitude of the pulses generated by the pulse generator can then be tuned to determine a pulse amplitude for stimulating one type of nerve fibre. This process involves setting the adjustable amplitude of the pulse generator at an initial pulse amplitude. Typically this will be a low amplitude to reduce the risk of a pain response when applied to the subject. For example, if the pulse generator is a mechanical pulse generator the initial pulse amplitude may be 1 micron, for electronic pulses this amplitude may be 2 μ\/, the initial pulse amplitude and adjustment increments will vary depending on the type of pulse being generated, subject and stimulation area.

Stimulation is then applied to the stimulation site of the subject using the pulse generator as sequence of pulses at the initial pulse amplitude. The pulse sequence may be an arbitrary sequence of pulses. Feedback is received from the subject indicating sensation perception evoked by the applied pulse sequence. For example, the feedback may be from a monitored probe or verbal feedback from the patient. If the applied pulse sequence evoked no sensation then the pulse amplitude is incrementally increased, and the steps of applying stimulus, receiving feedback and incrementing the pulse amplitude repeated until a sensation is perceived, thus providing the tuned amplitude. If the initially applied pulse sequence evokes sensation, then the pulse amplitude is incrementally decreased and the steps of applying stimulus, receiving feedback and decrementing the pulse amplitude repeated until no sensation is perceived, then the pulse amplitude is incremented by one increment to provide the tuned amplitude. The tuned amplitude is therefore determined as a pulse amplitude where the subject's most sensitive sensory nerve fibres at the stimulation site are activated. Subsequently, the pulse generator can be driven at the tuned amplitude and slightly above to evoke sensation with clearly distinguishable properties. The sequence of pulses is delivered, in accordance with a stimulus sequence pattern to convey different frequency and intensity based on the stimulus pattern. As described above the stimulus patterns comprising a plurality of stimulus pulses arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds, each burst comprising two or more stimulus pulses having a maximum time interval of 15 milliseconds between successive stimulus pulses within the pulse burst. The pattern of pulse bursts and time intervals being configured for a vibration having controlled vibration frequency and intensity to evoke a spike train pattern for perception of the vibration, the vibration intensity being conveyed by a number of stimulus pulses in each burst, and the vibration frequency being conveyed by time interval between bursts. Thus, perception of intensity is influenced by burst duration and number of stimulus pulses within a burst, and perception of vibration frequency time intervals between successive pulse bursts, and by varying time intervals. This technique may be applied for various types of stimulus generators and is not limited to mechanical stimulation. Example

Demonstrating potential contribution of Pacinian corpuscle-associated FAN afferents to vibrotactile frequency perception within flutter frequency range:

The classical view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations - flutter (frequencies <60Hz) and vibratory hum (frequencies >60Hz). Electrophysiological investigations have demonstrated that two types of fast adapting tactile afferents, FAI and FAN, are activated preferentially within their characteristic frequency ranges resembling division between flutter and hum, respectively. This indicates that perception of vibrotactile frequency is rendered by two parallel neural processing channels subserved by different afferent types and specialised neural processing mechanisms.

The inventors investigated whether and to what extent FAN afferents can contribute to the perception of low frequency tactile stimuli. In particular the aim was to test whether detection thresholds are independent of the spiking rate in FAN afferents and whether FAN afferents have access to the neural circuits subserving perception of vibrotactile stimuli within flutter range frequencies.

In the first experiment, the detection thresholds were tested using the method of limits when pure frequency spike trains were evoked in FAN afferents at rate 6, 24, 100 and 200 spikes/second.

In the second experiment the two-alternative forced-choice paradigm was used to obtain psychometric functions of the frequency discrimination ability of FAN afferents within the flutter range. Six and fourteen subjects participated in the first and second experiments respectively.

Results proved that detection thresholds subserved by FAN afferents were not influenced by the discharge rate increasing from 6 to 200Hz, thus showing no effect of temporal summation over almost entire vibrotactile frequency range. The psychometric curves of frequency discrimination when FAN afferents were selectively activated were similar to those in the same subject, when activating the population of FAI and FAN afferents within flutter range.

The obtained data indicates that FAN afferents are capable of contributing to the frequency perception and discrimination within the low frequency flutter range.

Figure 5 is a graph showing detection thresholds as function of frequency for pulsatile and sinusoidal stimuli. This graph shows that judging by detection thresholds (around ~lum) the FAN afferents that are activated at 200 Hz by sinusoidal stimuli of ~1 um in amplitude can account for the detection of pulsatile stimuli regardless of frequency (as tested from 6 Hz up to 200 Hz). This figure also indicates that sinusoidal stimuli at low frequency range where FAI afferents show highest sensitivity have detection thresholds in average at about 10 microns with the most optimal vibrotactile stimulus. Thus it is unlikely that FAI afferents would respond to mechanical pulse amplitude below 10 microns which have acceleration and speed parameters outside their most sensitive range like with mechanical pulses compatible with sinusoidal stimuli of about 200Hz as proposed in current invention.

It will be understood to persons skilled in the art of the invention that many modifications may be made without departing from the spirit and scope of the invention. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

Claims

1. A stimulus sequence to evoke a controlled spike train pattern in neurons of the tactile sensory system, the stimulus sequence comprising:

the vibration frequency being conveyed by time interval between bursts,

2. A stimulus sequence as claimed in claim 1 wherein the stimulus pulses are mechanical pulses of substantially identical shape and length.

3. A stimulus sequence as claimed in claim 2 wherein the mechanical pulse amplitude of up to 5 microns to thereby selectively stimulate fast adapting type I I (FAN) nerve fibres.

4. A stimulus sequence as claimed in claim 1 wherein pulse amplitude is controlled to selectively stimulate one or more types of nerve fibres.

5. A stimulus sequence as claimed in claim 4 wherein the stimulus pulses are mechanical pulses having mechanical pulse amplitude within range 1-10 microns to stimulate FAN nerve fibres; and

having mechanical pulse amplitude of above 10 microns and below 50 microns to stimulate FAN and FAI fibres.

6. A stimulus sequence as claimed in claim 4 wherein the stimulus pulses are mechanical pulses having mechanical pulse amplitude of about 5 microns to selectively stimulate FAN nerve fibres.

7. A stimulus sequence as claimed in any one of the preceding claims wherein stimuli pulse duration is between 1 and 3 milliseconds.

8. A stimulus sequence as claimed in any one of the preceding claims wherein the property of intensity reflects a combination of perceptually and physically definable parameters including any one or more of amplitude, wave shape, texture, strength, sharpness and complexity.

9. A method of selectively stimulating type II fast adapting tactile afferents (FAN) across all frequencies, the method comprising:

10. A method as claimed in claim 9 wherein the mechanical pulse generator is driven in accordance with a stimulus sequence pattern comprising a plurality of stimulus pulses arranged in a pattern of pulse bursts separated by time intervals of more than 15 milliseconds,

the vibration frequency being conveyed by time interval between bursts,

11. A method of selectively stimulating one type of nerve fibres for a subject across all frequencies, the method comprising:

c) receiving feedback from the subject indicating sensation perception evoked by the applied pulse sequence, and

d) if the applied pulse sequence evoked no sensation incrementally increasing the pulse amplitude and repeating steps b, c and d until a sensation is perceived to provide the tuned amplitude; or e) if the applied pulse sequence evokes sensation incrementally decreasing the pulse amplitude and repeating steps b, c and e until no sensation is perceived, then incrementing the pulse amplitude once to provide the tuned amplitude,

and

the vibration frequency being conveyed by time interval between bursts,

12. A neuronal stimulation system comprising:

13. A neuronal stimulation system as claimed in claim 9 wherein the stimulus device is a mechanical stimulus device configured to deliver substantially identical pulses of duration between 1 to 3 milliseconds and amplitude between 1 to 5 microns.