WO2010127044A1 - Methods and systems for targeting, dosing and conducting neuronal stimulation protocols and detecting responses - Google Patents

Abstract

In one aspect, spectroscopic methods and systems determine thresholds at which neuronal target tissue sites respond detectably to various stimuli, and to determine and monitor appropriate stimuli parameters and stimulation protocols directed to neuronal target tissue sites. In another aspect, spectroscopic methods and systems are used to target the administration of stimuli and stimulation protocols to desired neuronal target sites, to detect and monitor responses to stimuli at the desired neuronal target site(s). Stimuli producing undesirable and/or unsafe responses may be detected, and automated alarms or shut-off protocols may be implemented to enhance the safety of stimulation protocols. TES, TMS, rTMS and other neuronal stimulation protocols, in combination with spectroscopic detection techniques, are used for functional mapping and localization of neuronal tissue. Integrated systems comprising one or more stimulation instruments, such as a magnetic coil, electrode or probe in combination with an optical source and an optical detector are provided.

Description

METHODS AND SYSTEMS FOR TARGETING, DOSING AND CONDUCTING NEURONAL STIMULATION PROTOCOLS AND DETECTING RESPONSES

FIELD OF THE INVENTION

The present invention relates to spectroscopic (i.e., optical) methods and systems that operate non-invasively, that is, without requiring any physical opening in the skull, to detect and monitor responses of neuronal target tissue sites to the administration of various stimuli, such as electrical stimuli, including electrical stimuli induced using magnetic coils.

BACKGROUND

Transcranial Electrical Stimulation (TES) protocols apply a brief, high voltage electric shock through the intact scalp. Application of TES over the primary motor cortex produces a brief, relatively synchronous muscle-evoked potential (MEP). TES has enjoyed limited clinical application because TES protocols are typically painful for the subject. Other methodologies for stimulating brain activity using electrical current, such as application of a low-level continuous electric current, referred to as transcranial direct current stimulation (tDCS), are being developed. The brain, and peripheral nerves, can also be stimulated non-invasively using electromagnetic stimulation protocols to induce electrical stimulation at target sites. Transcranial Magnetic Stimulation (TMS) and repetitive Transcranial Magnetic Stimulation (rTMS) protocols have been used for many years for stimulation of peripheral nerves and for investigational treatment of brain disorders. TMS has been shown to influence brain function if delivered repetitively, and is being developed for treatment of various central nervous system disorders. Several TMS and rTMS devices are approved for stimulation of peripheral nerves, and regulatory approval was recently announced for TMS treatment of adult patients with major depression who had previously received medication and not shown satisfactory improvement. Additional therapeutic applications of TMS may involve the use of TMS protocols in connection with Parkinson's disease, dystonia, stroke and seizures, as well as psychiatric conditions.

Because different neuronal tissue may be activated (and inhibited) with different electrical and magnetic stimuli at different doses and with different time courses, brain function may be studied and localized in both space and time using magnetic stimuli. Motor function, sensory and memory processes, and various cognitive functions have been mapped using TMS protocols.

TMS protocols use a brief, high current pulse produced in a magnetic coil to produce a magnetic field with lines of flux passing perpendicularly to the plane of the coil, which is generally positioned tangential to the scalp during treatment. Magnetic coils having different shapes are available: round coils are relatively powerful; figure eight-shaped coils are generally more focal, producing maximal current at the intersection of the two curved components; angled figure eight-shaped coils may increase the power at the intersection of the two curved components; and H-coils having complex windings provide a slower reduction of intensity of the induced field with depth.

In a homogeneous medium, current flows in loops parallel to the plane of the coil, which are predominantly tangential to the brain, and the loops with the strongest current are near the circumference of the coil. Neuronal elements are activated by the induced electric field. If the induced electric field is parallel to the neuronal element, the field is most effective where the intensity changes as a function of distance; if the field is not parallel to the neuronal element, activation occurs at bends in the neuronal elements. Because the brain is not a homogenous medium, because the surface conformation of the cranium is not flat and generally does not correspond to the surface conformation of the coil, and because neuronal elements are not arranged in regular patterns with respect to either the surface conformation of the coil or the surface conformation of the cranium, targeting and dosing of TMS stimuli is inexact at best.

There are several factors that make it difficult to appropriately dose and target electrical and magnetic brain stimulation protocols. Individual brains are highly individualistic and variable. Different brains require different intensities, patterns and durations of stimulation to elicit a detectable response, to achieve a desired level of activation (or inhibition), and to elicit the desired response. Physiological impacts, age, medications, and other factors make the responses of individual brains to equivalent stimuli protocols variable over time and depending on conditions. Variations in the spatial relationship of underlying brain structures to externally identifiable scalp locations provides a further challenge to accurately targeting the desired brain tissue.

Administering repeatable stimulation protocols, and treatments, is also challenging. Stimulation devices which provide non-invasive stimulation, such as electrical leads and magnetic coils, can only be "aimed" in a very gross manner. Leads or coils are positioned and "steered" by placing and orienting the stimulating device on the skull in a way that provides a focal stimulation at a desired target area by virtue of the geometry of the device as placed on the surface of the skull. Repeatability of the stimulation protocol from treatment to treatment thus depends on consistent placement of the stimulating device on the skull, which is difficult to reproduce accurately. Registration systems for aligning stimulation devices reproducibly with respect to an individual's brain are complex and expensive.

The intensity of individual stimuli, the effect of repeated stimuli, and the effect of single and multiple stimuli over time, are critical to any clinical treatment protocol. Because good methods for dosing electrical and/or magnetic stimuli are not available, most physicians and clinicians use ad hoc methods to determine intensity thresholds and select a stimulation intensity for treatment. One method for determining TMS stimuli thresholds involves administering a series of TMS stimuli having different, and generally increasingly "strong", parameters or combinations of parameters to motor cortex (e.g., hand motor cortex) to determine the minimum stimuli required to evoke an observable motor response. The minimum stimulation parameters required to evoke a motor response in motor cortex are then used as a reference point for determining a stimulation dose and protocol for treatment of a different, often non-motor, neuronal target site. Assessing neuronal responses to TMS stimuli and protocols that have no observable motor component is difficult, at best, and administering treatment courses reproducibly is not possible.

The magnetic field applied during a TMS protocol may reach about 2 Tesla, and magnetic stimulation pulses typically last for about 100 μs. Delivering a single pulse of TMS to the brain is considered to be very safe. rTMS can produce powerful effects, however, that outlast the period of stimulation, and rTMS has the potential to induce seizures. rTMS protocols must be carefully designed to avoid adverse effects and ensure patient safety. Safety guidelines prescribing limits for combinations of rTMS stimuli frequency, intensity and pulse train length have been developed and are being refined.

Several non-invasive methodologies for detecting and assessing neuronal activity for purposes of functional mapping and for evaluating the responses to various types of neuronal stimulation are available. EEG (electroencephalography) detection techniques measure voltage differences produced by transmembrane currents (e.g. postsynaptic potentials of apical dendrites of large pyramidal cells) from different sites on the scalp. Magnetoencephalography (MEG) detection techniques, which measure intracellular currents, provide direct measures of neuronal activity and generally provide measurements demonstrating good temporal resolution. The spatial resolution of these measurements, however, is generally not good and may even be ambiguous as a result of the non-homogenous nature of the underlying brain constituents and their arrangement with respect to the surface of the scalp (and the placement of the sensor). Imaging techniques such as Magnetic Resonance Imaging (MRI) and Positron

Emission Tomography (PET) are effective to take "snapshots" of anatomical features of the brain at given time periods. These detection modalities may be used at intervals to acquire images that allow a clinician to compare anatomical brain features over the course of relatively long time intervals or over the course of treatment. MRI and PET techniques, however, can't be effectively used in association with TMS or rTMS protocols as a result of electrical and/or magnetic interference issues.

Functional PET and functional MRI (fMRI) modalities are used for functional neuroimaging and provide good spatial resolution, but these detection modalities provide a low degree of temporal resolution and cannot be used in "real-time" in combination with TMS and rTMS stimulation protocols. In addition, all of these techniques may be more reliably used to detect neuronal excitation than neuronal inhibition. Various combinations of these modalities may be used in conjunction with one another. Their primary limitations are cost, lack of portability, lack of ability to carry out "real life" activities during scanning, and lack of availability. The neuronal activity detection modalities described above are used for research and mapping applications, as well as in clinical practice. Neuronal activity is assessed in connection with investigating the genesis of various pathologies, including, for example, seizures, movement disorders, Parkinson's disease, Huntington's disease, Tourette's syndrome, ataxia, migraine, and the like. These detection techniques are also used for investigating the efficacy and modes of action of therapeutic protocols, drugs and the like, and for monitoring status of conditions and diseases.

Spectroscopic detection and imaging techniques have been developed and used in numerous applications. Deoxy- and oxyhemoglobin absorb light differently at 660 nm and 950 nm, for example, and the ratio of spectral measurements acquired at these wavelengths provides a quantitative estimate of blood oxygenation; this is the basis of spectroscopic pulse-oximetry devices. Spectroscopic techniques for observing nerve activity and neuronal tissue are well-established. Hill and Keynes observed that the nerve from the walking leg of the shore crab normally has a whitish opacity caused by light scattering, and that opacity changes evoked by electrical stimulation of that nerve were measurable (J. Physiol. 108:278-281 (1949)). Since the publication of those results, experiments designed to learn more about the physiological mechanisms underlying the correlation between optical and electrical properties of neuronal tissue and to develop improved techniques for detecting and recording activity-evoked optical changes have been ongoing.

Intrinsic changes in optical properties of cortical tissue have been assessed by reflection measurements of tissue in response to electrical or metabolic activity. (Grinvald et al, "Functional architecture of cortex revealed by optical imaging of intrinsic signals," Nature 324:361-364 (1986); Grinvald et ah, "Optical imaging of neuronal activity," Physiological Reviews, 68:4 (1988)). Grinvald and his colleagues reported that some slow signals from hippocampal slices could be imaged using a CCD camera without signal averaging. A CCD camera was also used to detect intrinsic signals in a monkey model (Ts'o DY et al, "Functional organization of primate visual cortex revealed by high resolution optical imaging," Science 249:417-420, (1990)) The technique employed by Ts'o et al. would not be practical for human clinical use, since imaging of intrinsic signals was achieved by implanting a stainless steel optical chamber in the skull of a monkey and contacting the cortical tissue with an optical oil. Furthermore, in order to achieve sufficient signal to noise ratios, Ts'o et al. averaged images over periods of time greater than 30 minutes per image. Subsequent research efforts have referred to activity-evoked optical changes in cortical tissue as 'intrinsic optical signals' (IC¹S) and have provided high-resolution maps of functional and pathological brain areas in humans using spectroscopic techniques (Haglund et al, Nature 358:668-671 (1992)). The IOS in brain tissue are thought to be generated by at least three distinct physiological mechanisms: i) changes in blood volume, ii) changes in blood oxygenation, and iii) blood-independent light scattering changes resulting from ion fluxes associated with neuronal activity (Hochman, Neurosurgery Clinics of North America £:393-412 (1997)). By selecting the appropriate optical wavelengths, IOS imaging is capable of monitoring each of these physiological components independently. Compared to other brain-mapping modalities, IOS imaging is inexpensive and can provide significantly greater spatial and temporal resolution.

IOS imaging techniques have remained of limited clinical and laboratory use, however, for at least two reasons. First, incomplete knowledge about the physiological mechanisms that generate activity-evoked optical changes in brain tissue limits the ability to interpret IO S data. Second, there has been relatively little rigorous effort to determine how well IOS data correlates spatially and temporally to functional and pathophysiological brain activity in primates and humans. Intraoperative IOS imaging techniques provided dynamic maps of functional and epileptiform activity in cortex, with micron-level spatial resolution, but with poor temporal resolution (1-4 seconds/image; Haglund et al, Nature 358:668-671 (1992)).

When neurons fire action potentials (i.e., become active), they release several different molecules that diffuse through the extracellular space and cause nearby microscopic blood vessels to dilate, mediating large increases in blood volume and oxygenation which, in turn, alter the amount of light the active brain tissue absorbs. Since blood flow is related to the fourth power of vessel diameter, small changes in neuronal activity produce large changes in hemodynamics. The changes in brain tissue that can be detected spectroscopically are the consequences of: (1) alterations in blood volume, or the total amount of blood perfusing the tissue; and (2) changes in blood oxygenation (or in the ratio of oxygenated hemoglobin to deoxygenated hemoglobin, which have different absorption spectra). Thus, by illuminating the brain with light at specific wavelengths, changes in either (or both) blood volume or blood oxygenation can be detected and mapped, with high spatial and temporal resolution. For blood volume- specific optical changes, a wavelength is used at which Oxy-Hb and Deoxy-Hb absorb equal amounts of light (e.g., 535 nm); while for preferential detection of changes in blood oxygenation, imaging should be done with a wavelength at which the differences in absorption between Oxy-Hb and Deoxy-Hb are maximal (e.g., 660 nm), where changes in the proportion of Oxy-Hb to Deoxy-Hb generate the largest measurable optical changes (Hagland and Hochman, "Imaging of intrinsic optical signals in primate cortex during epileptiform activity, Epilepsia, 48 (Suppl. 4): 65 -74, (2007)). U.S. Patent 5,215,095 discloses methods and apparatus for real time imaging of functional activity in cortical areas of a mammalian brain using intrinsic signals. A cortical area is illuminated, light reflected from the cortical area is detected, and digitized images of detected light are acquired and analyzed by subtractively combining at least two image frames to provide a difference image. U.S. Patent 5,465,718 discloses a method for imaging tumor tissue adjacent to nerve tissue to aid in selective resection of tumor tissue using stimulation of a nerve with an appropriate paradigm to activate the nerve, permitting imaging (and thereby spatial location) of the active nerve. The '718 patent also discloses methods for imaging of cortical functional areas and dysfunctional areas, methods for visualizing intrinsic signals, and methods for enhancing the sensitivity and contrast of images. U.S. Patent 5,845,639 discloses optical imaging methods and apparatus for detecting differences in blood flow rates and flow changes, as well as cortical areas of neuronal inhibition.

Methods and systems for distinguishing neuronal tissue from surrounding tissue, for distinguishing functional neuronal tissue from dysfunctional or non-viable tissue, and for imaging of functional neuronal areas in cerebral cortex by non-invasively detecting changes in the optical properties of neuronal tissue following stimulation of neuronal activity are disclosed, for example, in U.S. Patents 6,196,226 and 6,233,480. Changes in neuronal activity that take place during development, neuronal trauma (e.g., seizure, stroke and the like), recovery from neuronal trauma, administration of therapeutic or diagnostic agents, and tissue transplantation and recovery may be monitored, in real time, using these types of optical imaging techniques. The disclosures of these patents are incorporated herein by reference in their entireties.

Localized increases in neuronal activity alter the distribution and oxygen content of blood within the surrounding brain tissue, and optical microscopy has been used, with optical techniques for examining neuronal activity, to map patterns of hemodynamic changes associated with neuronal activity (Haglund, M.M. and Hochman, D. W., Imaging of Intrinsic Optical Signals in Primate Cortex during Epileptiform Activity, Epilepsia, 48 (Suppl. 4):65-74, (2007)). Experimental evidence demonstrated that different spatial and temporal patterns of optical changes were elicited by similar stimuli; that, using appropriate wavelengths, maps can be generated using optical imaging data that represent changes predominately due to either blood volume (at 535 nm) or blood oxygenation (at 660 nm); that "negative" optical signals are negative only relative to a given optical wavelength and appear to be associated with more intense types of neuronal activation; and that optical imaging is useful for studying neocortical seizure activity in animal models.

SUMMARY

In one aspect, the present disclosure provides spectroscopic methods and systems to determine thresholds at which neuronal target tissue sites respond detectably to various stimuli, and to determine and monitor appropriate stimuli parameters and stimulation protocols directed to neuronal target tissue sites. In another aspect, the present disclosure provides spectroscopic methods and systems to target the administration of stimuli and stimulation protocols to desired neuronal target sites, to confirm that the stimuli are evoking a biological response at the desired neuronal target site(s), and to detect and monitor responses to stimuli at the desired neuronal target site(s). In yet another aspect, the present disclosure relates to methods and systems for non-invasively targeting, dosing and conducting stimulation protocols using direct transcranial electrical stimulation (TES), transcranial magnetic stimulation (TMS and rTMS), and other non-invasively administered neuronal stimulation protocols, and for detecting responses at target tissue sites resulting from TES, TMS, rTMS and other neuronal stimulation protocols. In still another aspect, the present disclosure relates to the use of TES, TMS, rTMS and other neuronal stimulation protocols, in combination with spectroscopic detection techniques, for functional mapping and localization of neuronal tissue.

As used herein, "stimulation" or "stimulation signal" refers to the application of an electrical, mechanical, magnetic, photonic, acoustic, chemical and/or biological signal to a neural (e.g., neuronal) structure in a subject's body. In most applications, the stimulation, or stimulation signal, is applied "non-invasively" from outside the body, e.g. from the surface of the skull. The stimulation of a neural or neuronal structure may elicit one or more biological response(s), and the effect of the stimulation signal may be excitatory or inhibitory. In one embodiment, the stimulation comprises an electrical signal or a magnetic pulse that produces an electrical signal at a target tissue site. The stimulation signal may induce afferent and/or efferent action potentials on the nerve, may block native action potentials, or may be applied at a sub-threshold level that neither generates nor blocks action potentials. Although the methods and systems of the present invention are described with reference to stimulation of neuronal tissue sites in the brain, it will be appreciated that similar stimulation protocols may be applied to tissue and structures forming part of the peripheral nervous system, and methods and systems of the present invention may also be used in connection with peripheral nervous system stimulation protocols.

The terms "spectroscopic" and "optical" are used interchangeably in this disclosure. Spectroscopic (or optical) detection, and spectroscopic (or optical) imaging, refer to the acquisition, processing, comparison (optional) and display (optional) of data representative of one or more optical properties of an area of interest that indicates neuronal activity or inactivity. Such optical detection techniques also generally provide an indication of the level of neuronal activity elicited by a stimulus. Spectroscopic techniques of the present invention detect neuronal activity, measured as changes in optical responses in the target tissue, and are generally highly sensitive to changes in neuronal activity at a target site. Optical properties that may be detected using methods and systems of the present invention include but are not limited to scattering (Rayleigh scattering, reflection/refraction, diffraction, absorption and extinction), birefringence, refractive index, Kerr effect, and the like. Methods and systems of the present invention employ spectroscopic techniques to non-invasively detect and monitor changes in optical properties of tissue in response to stimuli, such as changes in blood flow and blood oxygenation, which are indicative of changes in neuronal activity in neuronal cortex.

Methods and systems disclosed herein are directed to spectroscopic techniques that can be used to determine threshold stimulation doses that elicit detectable responses in target neuronal regions of individual subjects, and that provide dosing and targeting guidance for various types of neuronal and peripheral nerve stimulation protocols. The determination of accurate threshold stimulation parameters required (and effective) to elicit a response, e.g., a therapeutic response, enhances the safety and efficacy of therapeutic stimulation protocols. The intensity and/or duration of stimulation required to elicit observable motor activity, for example, is higher than that required to elicit neuronal activity observable using spectroscopic techniques of the present invention. Spectroscopic techniques of the present invention thus provide highly sensitive methods and systems for determining stimulation thresholds, designing stimulation protocols, targeting stimulation pulses, dosing stimulation pulses, and monitoring the biological activity elicited by and the effects of stimulation pulses and protocols.

Because there are individual-specific and tissue-specific responses, methods disclosed herein may include a preliminary subject- and/or tissue-specific evaluation or calibration performed prior to a stimulation protocol. In one embodiment, for example, a neuronal target site may be stimulated using electrical (or magnetic) pulses of progressively increasing intensity to identify a threshold at which a biological response is elicited and is detectable using spectroscopic techniques of the present invention. The effect of other stimulation parameters, such as duration of the pulse, pulse repetition frequency, and the like, may similarly be evaluated by progressively increasing the duration, pulse repetition frequency, and the like, to establish a threshold at which a biological response detectable using spectroscopic techniques is elicited. Using spectroscopic techniques for establishing stimulation thresholds and designing stimulation protocols provides considerably higher detection sensitivity than conventional threshold determination techniques, which generally require stimulation of motor cortex and observation of a motor response. The use of spectroscopic detection techniques also allows the determination of threshold stimulation parameters in target neuronal tissue sites other than motor cortex.

Establishing and frequently re-evaluating stimulation thresholds and safe stimulation levels is particularly important in the patient population generally treated using therapeutic stimulation protocols. Pharmacological and other types of treatment agents affect the CNS and neuronal tissue in different, and sometimes unpredictable, ways. Different treatment agents, different doses of treatment agents, and different combinations of treatment agents may also affect individuals differently. Neuronal excitability may be affected, for example, during or following exposure to pharmacotherapeutic treatments for epilepsy, migraine, anxiety, depression, psychiatric disorders, and the like. A given individual may react differently to stimulation protocols before, during and after treatment with such agents. Changes in medication, doses, regimen, etc., may also produce different responses to stimulation protocol and are monitored using spectroscopic techniques of the present invention to improve the safety and efficacy of stimulation protocols.

In another aspect, methods are provided for calibrating a stimulation treatment protocol, for assessing the suitability of different stimulation devices (e.g. electrodes, various TMS coils, and the like) for use in different stimulation protocols and/or with different individuals, or for determining and assessing appropriate stimulation target sites and/or doses for individual subjects. Stimulation devices, such as TMS coils, for example, may be placed on the skull in different places and operated to test "aiming" or targeting of the coil by evaluating the optically detected neuronal activity elicited. Different stimulation devices, such as TMS coils, may also be tested at different output levels, such as % maximum output, pulse duration, pulse repetition frequency, and the like, to assess the biological response of the target tissue by evaluating the neuronal activity detected optically. This type of evaluation is useful in establishing suitable dosing ranges and stimulation protocols, and for assessing responses to stimulation protocols.

Using spectroscopic techniques, the effects of stimulation protocols, including the magnitude of the response(s), the duration of the response(s), the character of the response(s), and the like, may be assessed in real-time. The safety of stimulation protocols may be monitored and confirmed on a real-time basis, and stimulation protocols may be modified "in real-time" when adverse and/or unsafe responses are detected. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. IA is a schematic diagram of a system of the present invention integrating emr sources and detectors with a stimulation device in a common housing.

Fig. IB is a schematic diagram illustrating an experimental system of the present invention incorporating multiple emr sources and detectors, and a stimulation device. Fig. 2 is a graph showing the optical response of a subject's brain to a series of

TMS stimuli at a level previously demonstrated to be sufficient to elicit thumb movement (45% magnet strength).

Fig. 3 is a graph showing a subset of the optical raw data displayed in Fig. 2.

Fig. 4 is a graph showing the time scale and course of the optical data displayed in Fig. 3.

Fig. 5 is a graph showing spectroscopic data collected using two optical detectors, each detecting optical signals at 830 nm.

Fig. 6 is a graph showing the time scale and course of optical data obtained during magnetic stimulation of frontal motor cortex at a stimulation level below that required to elicit a motor response.

Fig. 7 is a graph showing the optically detected response of a subject's brain to a series of TMS stimuli at 20% magnet strength.

Fig. 8 is a graph showing the optically detected response of a subject's brain to a series of TMS stimuli at 20% magnet strength over a longer time course. Figs. 9 and 10 are graphs showing the optically detected response of a subject's brain to a series of TMS stimuli at 40% magnet strength.

DETAILED DESCRIPTION

Methods and systems disclosed herein provide spectroscopic techniques that can be used to identify the neuronal region in which a biological response(s) is evoked by the stimulation protocol and to determine the spatial extent of the evoked response. By changing the position and/or orientation of the stimulating devices (e.g. electrode, probe, magnetic coil or the like) in response to the data on a real-time basis, and administering stimulation protocols to evoke a response, the stimulating device(s) may be targeted to one or more desired target regions, and effective delivery of the stimuli to the target region can be confirmed. This provides effective targeting of stimuli, in real time and also provides targeting of sites in a reproducible manner over time and over the course of many different (e.g. successive) stimulation protocols. In another protocol, target neuronal sites anticipated to be "normal," or having a known or reliably predictable level of activity, may be used to calibrate a spectroscopic detection system. In this scenario, neuronal stimulation protocols known to elicit a predictable response are administered and biological responses are monitored spectroscopically to initially calibrate the system and, optionally, to assess the sensitivity of the subject to stimulation in general, or to a specific stimulation protocol. Stimulation responses and values may be normalized from subject to subject, if desired, using known techniques. In one embodiment, for example, changes in neuronal stimulation observed during the course of a stimulation protocol may be expressed as a percentage increase or decrease in neuronal activity compared to the activity observed/detected prior to stimulation or to the activity observed at a specified target site and under specified conditions.

Methods and systems of the present disclosure may also be used to evaluate a patient's progression during and over the course of a neuronal stimulation treatment. Data relating to responses to individual stimuli and responses over the course of a stimulation protocol may be stored, accessed and compared to data collected while administering the same or a different protocol to the same individual at a different time period, for example. Data collected from multiple individuals may also be compared.

Methods and systems disclosed herein may also be used to detect afterdischarge and other undesirable, or unsafe, neuronal activity characterized by a distinctive and detectable optical response, and produced during, or as a result of, stimulation protocols. Data monitoring techniques may be applied in "real time" to automatically detect undesirable or unsafe responses to stimulation protocols, and alert the operator. Appropriate alarms and stimulation inactivation or modification routines may also be applied in "real time" to enhance the safety of stimulation protocols and reduce or prevent application of unsafe or damaging stimuli to the subject. Methods and systems of the present invention thus provide significant safety benefits.

With improved ability to determine appropriate stimuli thresholds and to target and dose stimuli protocols using spectroscopic techniques as disclosed herein, additional applications for electrical and magnetic stimuli protocols have been identified. In one embodiment, electrical or magnetic (e.g., TMS) stimuli are applied and monitored using spectroscopic techniques to provide increased signal-to-noise for functional mapping and localization of neuronal tissue. The detection limits for detecting optical signals indicating neuronal activity are very low, which makes it quite difficult to accurately localize functional neuronal tissue for purposes of functional mapping and localization of functional tissue during surgeries. The optical signals elicited by TMS stimulation, even at low stimulation levels, are much larger than the functionally evoked optical signals.

A method for using TMS in combination with optical detection techniques to enhance the localization of function using the following methodology are therefore desirable. Functional mapping of neuronal tissue is important for research, treatment and surgical applications. Optical detection techniques, as described herein, may first be applied to determine a threshold stimulus (e.g. TMS-induced stimulation current) required to G^ust) elicit afterdischarge activity. In general, functional mapping protocols use stimuli that are below the threshold required to elicit afterdischarge activity. In one functional mapping protocol, the biological response of a neuronal target region to a TMS stimulus is detected using optical detection techniques while the subject is at rest and not engaged in any conscious functional or cognitive task. Second, the biological response of the neuronal target region to an equivalent TMS stimulus is detected while the subject is engaged in a functional or cognitive task, such as naming objects (for localization of language cortex). The differences in the biological responses of the neuronal target region detected using optical techniques as described herein under the two conditions described above are expected to be much larger than the optical signal generated by functional activation alone. This makes it possible to localize and detect functional activation of brain regions that might otherwise not be detectable, and it also allows the use of stimulation protocols that are less powerful (and magnetic coils that are smaller) for functional imaging tasks than those required for administration of therapeutic stimulation protocols.

The systems of the present invention employ one or more electromagnetic radiation (emr) optical source(s) for illuminating an area of interest (i.e., an area to be screened or treated with a stimulation protocol, such as a TMS protocol) and one or more optical detector(s) capable of detecting and acquiring data relating to one or more optical properties of the area of interest. The optical source(s) and detector(s) may be selected and located to acquire data relating to optical properties of an area of interest that is exposed, or that underlies skin, tissue, bone, dura, or the like. "Non-invasive" optical detection systems that detect biological responses to stimuli at neuronal target sites from the surface of the skull, employing epi-illumination and reflective detection, are preferred for many applications. The optical detection system may be used to acquire data for analysis in a static mode, or multiple data sets may be acquired at various time intervals for comparison in a dynamic mode. The optical detection system may, for example, acquire control data representing the "normal" or "background" optical properties of an area of interest, and then acquire subsequent data representing the optical properties of an area of interest during and/or following administration of a stimulus, or during a monitoring interval. The subsequent data may be compared to the control data, or to empirically determined standards, to identify changes in optical properties of corresponding spatial locations in the data set that are representative of normal and abnormal blood volume, blood oxygenation and/or neuronal activity in the area of interest. In one aspect, the systems disclosed herein comprise at least one optical source adapted for placement on a surface of the skull and operably connected to a source(s) of electromagnetic radiation (emr) for providing illumination of a selected target site or region at one or more wavelengths in a continuous or pulsed format. Such systems additionally comprise at least one optical detector adapted for placement on a surface of the skull and operably connected to an emr detector(s) for detecting illumination at a selected target site or region at one or more wavelengths in a continuous or pulsed format. Multiple sources and detectors may be provided for illuminating a target region and detecting illumination at a target region at one or multiple wavelengths.

Optical source(s) may provide continuous or non-continuous illumination. For some applications, emr sources providing continuous, uniform illumination are preferred, while non-continuous illumination using time domain or frequency domain illumination sources are preferred for some applications. Optical sources are high intensity emr sources, e.g. lasers, light emitting diodes, and the like. Tunable IR diode lasers may be used in some applications, in combination with an IR detector. Cutoff filters may be used to select emr having certain wavelengths when a broad spectrum emr source is used. Emr can be provided through strands of fiber optic material using a beam splitter controlled by a regulated power supply. Short pulse (time domain), pulsed time, and amplitude modulated (frequency domain) illumination sources may be used with suitable detectors. Frequency domain illumination sources typically comprise an array of multiple source elements, such as laser diodes, with each element modulated out of phase (e.g. 180°) with respect to other elements. Two-dimensional arrays comprising emr sources in two planes may be employed, as is known in the art. Various types of optical detectors may be used, depending on the emr source(s) used, the optical property being detected, the type of data being collected, certain properties of the area of interest, the desired data processing operations, the format in which the data is displayed, and the application. In general, any photon detector may be used, e.g. photodiodes, photomultiplier tubes, cameras, charge coupled devices (CCD), and the like.

In one embodiment, each optical source comprises a fiber optic cable coupled to at least two different light sources having different properties, e.g. wavelength. In one embodiment, each optical source comprises a fiber optic cable coupled to two lasers, each laser emitting emr at a distinct wavelength, e.g. 690 and 830 nm. Emr from each laser is conducted through the single source fiber optic cable in a rapid on-off manner, so that one wavelength of emr is passed through the cable, then the other wavelength, and so on. One or more optical detectors is provided, each optical detector comprising a photodiode, for example, attached to a fiber optic cable, and positioned somewhere on the scalp to collect backscatter or other optical measurements. The electronics controlling the sources and detectors may be synchronized so that near-simultaneous monitoring of activity- evoked cortical changes at two or more wavelengths is possible from a given location on the scalp.

For most surgical, diagnostic and monitoring uses, the optical detector preferably provides data having a high degree of spatial resolution at a magnification sufficient to precisely locate the areas of neuronal activity and changes in neuronal activity, blood characteristics, blood flow and/or blood oxygenation. Multiple data sets are typically acquired over a predetermined time period and combined, such as by averaging, to provide data sets for analysis and comparison. Methods and systems disclosed herein may be used in a static mode that provides a comparison of optical properties of different spatial locations in an area of interest, to spatially locate areas showing differential optical properties and thereby locate areas of differential blood characteristics, blood flow, and/or blood vessels.

The sensitivity of the present optical detection methods and systems is improved when the optical source(s) and detector(s) are stationary and provided in a fixed position with respect to one another. Improvements are also provided when the optical source(s) and detector(s) are also stationary and provided in a fixed position with respect to the stimulation source(s) (e.g. TMS coil(s), electrode(s), or the like). In one embodiment, the present systems thus comprise a stimulation device mounted or mountable in a common housing with, or mounted in a fixed mechanical relationship to, at least one optical source and at least one optical detector. In another embodiment, the positions of the optical source(s) and detector(s), and the stimulation source(s), are fixable and stationary during stimulation protocols and data collection, but the relative positions of the optical source(s) and detector(s), and the stimulation source(s) are adjustable with respect to one another to provide numerous geometries for stimulation protocols and data collection. This permits accurate and consistent registration of the optical source(s), detector(s) and stimulation source during stimulation protocols and over the course of successive stimulation protocols. The stimulation device may comprise a magnetic coil, an electrical lead, electrode or probe, or the like. In one embodiment, at least one optical source and at least one optical detector are provided in a common housing with a TMS magnetic coil. In another embodiment, at least one optical source, at least one optical detector, a TMS coil, and an electrical lead, electrode or probe are provided in a common housing.

In one embodiment, the housing is preferably rigid or semi-rigid and conforms generally to an area of the skull. In another embodiment, the housing is initially provided in a moldable condition and is molded to conform to the surface contours of an individual's skull and then hardened to a rigid condition to provide an individualized, subject-specific stimulation and detection apparatus. In another embodiment, a housing for a stimulation device is generally rigid and is provided with a cavity or another mechanical system that mates with one or more optical source(s) and detector(s). Optical source(s) and detector(s) may thus be provided in a rigid, semi-rigid or flexible housing that mates reliably and positively with a stimulation device so that the stimulation device, the optical source(s) and the optical detector(s) are stationary with respect to one another during stimulation protocols. Optical source and detector components may be provided in different configurations, formats, and the like to cooperate with different configurations and types of stimulation devices.

It is important to ensure that the stimulation device and the optical source(s) and detector(s) remain stationary with respect to the neuronal target site during stimulation, during a stimulation protocol, and over the course of successive stimulation protocols. In one embodiment, therefore, the housing is generally mountable to a subject's skull using a mounting device, straps, bands, a helmet-type device, or the like to position the housing firmly on the skull during a stimulation protocol. Marking and positioning systems may also be provided to provide consistent mounting of the housing on an individual's skull over the course of successive stimulation protocols. Fig. IA schematically illustrates an exemplary system having a detection component placed on a subject's skull that communicates with controller and/or display components. In this embodiment, a plurality of optical sources (12A, 12B) and a plurality of optical detectors (14A, 14B) are provided in a stimulation device housing 16. Optical sources 12A, 12B, etc. comprise fiber optic cables that transmit photons having a certain wavelength emitted by optical sources such as lasers. Each of the source fiber optic cables may be attachable to a plurality of different optical sources (e.g., lasers), each source emitting photons at a different wavelength. In one system, for example, each optical source 12A, 12B, etc., is attached to two different laser optical sources - one emitting at 690 nm and one emitting at 810 nm. Optical sources are in communication with a source controller 22 and optical detectors are in communication with a detector controller 24.

Stimulation device housing 16 may incorporate an electrical stimulation device, or a TMS or rTMS stimulation device, such as a magnetic coil 18. Other types of neuronal stimulation devices may also be used. Magnetic coil 18 is in communication with, and is controlled by, stimulation controller 20. Both the source and detector controllers 22 and 24, respectively, and the stimulation controller 20 may be in communication with or incorporated in a system controller and data processing module 26. A data display device 28 may be incorporated in or provided separately from system controller and data processing module 26. It will be appreciated that additional components, controllers, data processing systems and the like may be used with and incorporated in the disclosed systems.

Fig. IB illustrates a prototype non- invasive optical detection system positioned on a subject. The system has two light sources that pass photons through fiber optic cables (30A, 30B) and four detectors that receive photons collected from the neuronal site through cables 32A, 32B, 32C and 32D. A larger array having more sources and detectors may also be employed An optical-TMS device would have a stimulation device (e.g. TMS coil) placed over the pad of optical sources/detectors.

Optical detection techniques may be used to "image" the administration of stimuli, to localize biological responses to stimuli spatially and temporally, and to detect biological responses, e.g. neuronal excitation and/or inhibition, blood volume changes in the target area, blood oxygenation changes in the target area, etc. Blood volume and/or oxygenation changes may be used as surrogate markers for neuronal activity/inhibition. The optical detection techniques may be used, for example, to characterize and/or map target tissues and sites prior to stimulation, to identify and/or map the target tissues and sites evoking biological responses, and to evaluate and/or quantitate the biological responses evoked by stimulation. In addition to providing identification and/or mapping of sites evoking biological responses, identified sites may be identified and marked (e.g., electronically) for follow-up, additional evaluation, treatment, or the like. In one application, for example, target sites for EMS and/or TMS treatment may be identified and marked so that consistent treatment of a desired target site may be provided at different times. According to some embodiments, records (e.g., electronic records) preserving and identifying sites examined and/or marked, and the responses evoked by stimulation during stimulation protocols and over time, may be generated and saved, for example, for follow-up, additional diagnostic evaluation, for comparative purposes, or for further treatment.

According to one embodiment, optical detection techniques are used to collect data and evaluate a target area of interest prior to, during or following stimulation by: (a) illuminating the target area of interest with at least two different wavelengths of emr; (b) obtaining control data sets corresponding to the optical properties/response of the target area at each wavelength of emr prior to an intentional stimulation; (c) stimulating the target area (e.g. using TMS or another type of electrical stimulation, administering a paradigm, etc.); and (d) obtaining a sequence of subsequent optical data sets for each wavelength of emr during and/or following the stimulation. Optionally, comparisons of the optical data collected pre-, during and post-stimulation may be made by, for example, obtaining a series of comparison data sets for each wavelength of light by subtracting the control data set from the subsequent data set. Changes in neuronal stimulation observed during the course of a stimulation protocol or multiple stimulation protocols may also be expressed as a percentage increase or decrease in neuronal activity compared to the activity observed/detected prior to stimulation or at a specified target site and under specified conditions, or compared to standardized reference data.

Changes in the optical source(s) and detector(s) systems, or changes in the positioning of the optical source(s) and detector(s) relative to the stimulation source, target area or skull, may produce different absolute values of optical signals and make comparison of results difficult. In one embodiment, an absolute baseline may be established prior to initiation of each stimulation protocol to provide a basis for comparison of data collected using different stimulation and optical detection systems, and for comparison of optical data to standards or from subject-to-subject. A reference baseline may be established prior to each stimulation protocol, for example, by gradually increasing the magnitude of the stimulation until the detected response reaches a plateau, which indicates maximal neuronal firing. The response observed at the plateau is recorded and stimulation is then scaled back for data collection during stimulation at sub- plateau levels. Scaling the observed responses to the maximal response (the response at the plateau) by plotting data, for example, as the percentage of the maximal response, allows for comparison of data acquired under different circumstances to empirically established standards, from subject to subject, and the like.

Optical contrast enhancing agents may be used in methods and systems of the present invention to enhance detection of optical responses to stimulation protocols. The use of optical contrast enhancing agents is described, for example, in U.S. Patents 5,465,718, 5,845,639 and 6, 196,226, which are cited and incorporated by reference herein in their entireties. Additional patent and literature publications disclose suitable optical contrast enhancing agents, methods for identifying such agents, methods for administering such agents, and the like. Data corresponding to three dimensional spatial locations may also be acquired using multiple agents having different spectral properties, and by employing optical tomography techniques. Specifically, photon time-of-flight techniques and frequency domain methods may also be used.

Data Analysis

Removing respiration, heart beat and movement artifacts from optical data is important, particularly because the amplitude of optical changes being detected is generally small. Performing an analysis of the statistical error and removing artifacts from the optical data increase the precision and resolution of the detection and data analysis and allow observation of small changes in that data. The use of dynamic linear models (DLM) for data analysis is one way to provide this type of data analysis.

The following experimental observations and data are provided to support the subject matter disclosed herein and are not intended to limit the invention in any way. Sensitivity of Spectroscopic Detection Techniques for Establishing Safe Stimulation Intensities and Protocols

Neurosurgeons establish a threshold current for safe stimulation during neurosurgeries to map functional brain regions by stimulating the brain with increasing currents while recording EEG measurements until "afterdischarge" activity is observed as spiking activity that persists after the stimulation-current has been inactivated. Functional areas are then stimulated using currents that are just below the current required to elicit afterdischarge activity. Hand motor cortex is typically stimulated to establish a threshold current for safe stimulation in TMS therapeutic protocols. Hand movements (e.g., twitching) is observed, in these protocols, as the manifestation of afterdischarge activity following cessation of stimulation-current that evokes a response. This activity may also be detected, and recorded, using electromyelography (EMG) from the hand muscles, where one would also observe EMG activity following cessation of the stimulation- current.

Electrical stimulation of the cortex at varying currents has been used previously in primate and human subjects to correlate optical signals detected to the magnitude of cortical activation (Haglund and Hochman, 2004, 2005, 2007, citations provided supra). The cortex is stimulated with a bipolar electrode placed on the cortical surface and the current is gradually increased until a current is found that is just sufficient to consistently elicit an episode of afterdischarge (epileptoform) activity that persists after the stimulation period has ended. During primate studies, afterdischarge thresholds for hand motor cortex of individual animals were identified as the minimal stimulation current that was just sufficient to elicit epileptiform activity that reliably elicited an episode of afterdischarge activity of similar duration and intensity following each stimulation. Ongoing hand-twitching movements were clearly observed that had the same duration as the afterdischarge activity. In eight primates studied, afterdischarge thresholds varied from 4 mA to 16mA (Haglund and Hochman, Epilepsia, 2007, supra). These studies also showed that a small change (1 mA) in the magnitude of stimulation current determined whether or not a prolonged period (>10s) of afterdischarge activity occurs. This indicates that small changes in electrical stimulation over threshold values may produce serious, and lasting, effects. This is particularly a concern when subjects may experience variable thresholds over time or at different CNS target sites as a result of medications, lesion(s) or epileptiform propensity. In the course of conducting primate seizure studies, we monitored the hand motor cortex using EEG electrodes and the hand muscles using highly sensitive needle EMG electrodes while targeted neuronal regions were electrically stimulated, and while epileptic activity was stimulated by administration of pharmacological agents. Spectroscopic techniques were also used to monitor neuronal activity, as described in Haglund and Hochman, Epilepsia 2007 (supra). In many cases, afterdischarge activity was observed using the optical detection techniques, while there were no observable hand motor movements or detectable EMG activity.

These studies suggest that observation of elicited EMG measurements and motor movements alone, using currently practiced techniques, is not sufficiently sensitive to consistently detect neuronal activity producing afterdischarge activity, which may result in hyperexcitability or epileptic activity. Identifying and implementing improved methods and systems for determining stimuli thresholds and designing stimuli protocols suitable for individual subjects is a paramount safety concern and also contributes significantly to the efficacy of therapeutic stimulation protocols. The optical detection techniques described herein are highly sensitive to detection of afterdischarge activity directly from the cortex, which provides a substantial safety advantage and heightened detection sensitivity compared to the sensitivity of EMG and visual monitoring of motor responses in TMS and neurosurgical applications. Although the optical detection techniques used experimentally in many of the cited publications employed an invasive optical window to monitor neuronal activity from a position in close proximity to the cortical surface, the methods and systems described herein may be used non-invasively, as described, with the optical sources and detectors placed on the surface of the skull. Optical detection techniques applied non-invasively, as described herein, generally have lower signal resolution and lower spatial resolution than optical detection techniques employed "invasively," but they provide high sensitivity and high spatial resolution compared to other detection techniques.

There are many different techniques available for conditioning and processing data collected using optical detection techniques. In general, data conditioning and processing techniques described in the Hochman and Haglund patent and literature publications cited herein may be used with methods and systems of the present invention. Many other data conditioning and processing techniques are known in the art and would be suitable for use in methods and systems of the present invention. Determination of TMS Stimulation Intensities on Thumb Motor Cortex

A preliminary experiment was conducted to determine the threshold TMS stimulation intensity required to elicit motor thumb movements. Stimulation was carried out with a MagStim "Rapid" TMS device using a figure eight coil where the two loops were angled in an inverted v (^A) configuration. The TMS coil was first placed on the human subject's scalp at a location predicted to be generally over hand motor cortex (left side for right hand). The power of the coil output was started at a very low level (approximately 10% of maximal power, where a motor response is unlikely) and was gradually increased until involuntary hand movements (twitching) of the subject's thumb were observed. If no motor response was observed with power increasing to approximately 75% of the maximum power output of the coil and stimulation device, the coil was moved to an adjacent location and the stimulus output was again titrated upward from 10% of the maximum output until either involuntary movement of the thumb was elicited or 75% of the maximum output was reached. This procedure was repeated at a series of locations in proximity to the predicted skull location overlying the thumb motor cortex until an involuntary movement of the hand was reliably elicited.

This location on the skull was marked as corresponding to the thumb motor cortex and further testing was conducted to fine tune the determination of the stimulation "power" required to evoke a detectable response. Using the MagStim "Rapid" TMS device with the figure eight coil, biphasic pulses of approximately 250 μsec duration at 45% of the maximum power was just sufficient to induce thumb movements on the tested subject. Adjusting the power slightly below 45% resulted in no observable thumb movement. Thus 45% of the maximum power was defined as the threshold to elicit motor movements. This is similar to procedures used to determine threshold stimulation "power" for therapeutic TMS and rTMS protocols.

TMS Stimulation and Optical Observation of Thumb Motor Cortex above and below Motor Thresholds

Optical source-and-detector pairs were placed on the scalp of the human subject for whom the threshold power determination was made, as described, in proximity to the skull location identified as targeting thumb motor cortex (above). Optical signals were then recorded prior to, during and following stimulation using the magnetic coil and TMS-stimulator described above. Optical detection was carried out using the NIRS2 system from TechEn, Inc. (Milford, MA 01757). Each optical detector, consisting of a photodiode attached to a fiber optic cable, was placed about 1 cm from an optical source on the scalp. Each optical source consisted of a fiber optic cable that was coupled to two lasers. Each laser emitted light at a different wavelength so that two different wavelengths were passed through each source fiber optic cable: 690 nm, which selects for changes in blood oxygenation, and 830 nm, which selects for changes in blood volume. Light from each laser was passed through the single source fiber optic cable in a rapid on-off manner so that one wavelength of light from one laser alone was passed through the filter for a brief period of time, then the other, and so on. The electronics controlling the illumination was synchronized with that controlling the detector so that near-simultaneous monitoring of activity-evoked cortical changes at two wavelengths was possible from a given location on the scalp.

Data was acquired at 45% (threshold to elicit motor activity) and 20-25% (well below the threshold to elicit motor activity). The brain was stimulated for short intervals with the TMS device and the brain was allowed to recover for several seconds following each stimulation trial (intervals of stimulation and recovery are indicated in the figures). Optical data was continuously acquired throughout the experiment so that data was acquired both during the stimulation and recovery phases.

Data analysis: To aid in visualization, a 60-degree polynomial cubic spline was interpolated through the raw optical data to produce the smooth curves shown in the figures. For some experiments, data from several stimulation-recovery trials were aligned with respect to the start-time of the stimulation, and then averaged to increase the signal- to-noise profile.

Fig. 2 shows the optical response of the subject's brain to a series of TMS stimuli at 45% magnet strength previously demonstrated to be sufficient to elicit thumb movement at the skull location previously demonstrated to correspond to thumb motor cortex. The broken vertical lines indicate stimulus onset, and the solid vertical lines indicate termination of the magnetic stimulus. The optical response was monitored at 830 nm, which provides data indicative of changes in blood volume. The negative-going deflection following administration of the magnetic stimulus that continues for a second or two following termination of the stimulus is consistent with the optical (blood volume) data collected using invasive optical monitoring.

Fig. 3 shows a subset of the optical raw data collected at 830 nm and displayed in Fig. 2. This figure shows l/40^th of the raw data points plotted, and the smoothed spline interpolation through the points to give a smooth curve approximation of the results. Fig. 4 illustrates the time scale and course of optical data displayed in Fig. 3, with the lighter curve showing the optical results obtained at 830 nm, reflecting changes in blood volume, and additionally showing, in the darker curve, optical results obtained simultaneously at 690 nm (scaled), reflecting changes in blood oxygenation. The 690 nm (darker) curve, as illustrated, is inverted (multiplied by -1) to allow comparison to the 830 nm curve and, in its non-inverted condition, would generally mirror the optical results obtained at 830 nm. This illustrates that the magnetic stimulation produces a transient decrease in blood volume and a transient increase in blood oxygenation.

Fig. 5 shows spectroscopic data collected using two optical detectors, each detecting optical signals at 830 nm. The source-2 (darker curve) optical signal was obtained from an optical detector substantially aligned with the location of the TMS stimulator and the stimulation site in the brain. The source- 1 (lighter curve) optical signal was obtained from a detector located a couple of centimeters away from the location of the TMS stimulator, with the magnitude of optical signals from this detector amplified by 10X. These results demonstrate that different levels of brain activity at different locations with respect to the TMS stimulus can be mapped and quantified.

Fig. 6 illustrates the time scale and course of optical data obtained during magnetic stimulation of frontal motor cortex that was below the stimulation level required to elicit a motor response. The darker curve shows the optical results obtained at 830 nm from an optical detector substantially aligned with the location of the TMS stimulator and the stimulation site in the brain. The source- 1 (lighter curve) optical signal was obtained at 690 nm from a detector located a couple of centimeters away from the location of the TMS stimulator and collected data at 690 nm. The magnitude of these detected signals was amplified 10OX. The 690 nm (lighter) curve, as illustrated, is inverted (multiplied by -1) to allow comparison to the 830 nm curve and, in its non- inverted condition, would generally mirror the optical results obtained at 830 nm. These results demonstrate that different levels of brain activity at different locations with respect to the TMS stimulus can be mapped and quantified.

Fig. 7 shows the optically detected response of the subject's brain to a series of TMS stimuli at 20% magnet strength. This level of magnetic stimulation was previously demonstrated to be insufficient to elicit thumb movement and produces no response that is detectable functionally. The first vertical line indicates the onset of magnetic stimulation and the second vertical line indicates the termination of magnetic stimulation. This figure shows the optical data collected at 830 nm during and following three (3) consecutive stimuli at 20% magnetic strength, averaging the data collected during the stimulations. Fig. 8 shows the full data set collected as optical responses (830 nm) of the subject's brain to the series of TMS stimuli at 20% magnet strength described with respect to Fig. 7 - and over a much longer time course. This data demonstrates that optical signals indicative of neuronal stimulation are detectable when the magnetic stimulation is insufficient to elicit detectable motor responses.

Figs. 9 and 10 also illustrate data collected during TMS stimulation of the frontal cortex, wherein it is not possible to elicit an observable behavior (e.g., a motor or language response) from the subject. These data were collected using TMS stimulation at approximately 40% magnet strength, which is slightly below the magnet strength required to elicit motor behavior in the subject's motor cortex. The stimuli were administered relatively frequently, without allowing the target neuronal tissue to return to baseline between stimuli. Figs. 9 and 10 show different representations of the same data. The lower trace in each is optical data collected at 830 nm; the upper trace in each is optical data collected at 690 nm. The vertical lines show when the TMS stimuli were administered.

The lower trace (830 nm) trends downwardly (toward negative) during stimulation evoking (neuronal) activity-related changes, indicating that blood volume is decreasing at higher levels of activity compared to lower neuronal activity levels. The upper trace (690 nm) trends upwardly (toward positive) during stimulation evoking neuronal activity- related changes, indicating that blood oxygenation is increasing at higher levels of activity compared to lower. These data illustrate that optical responses to neuronal stimuli are observable, in real-time, even when the neuronal stimuli are below the threshold required to elicit an observable response, and even when stimulation of the target neuronal tissue site does not elicit an observable response, regardless of the magnitude of the stimuli.

Illustrative embodiments of the invention are described herein. In the implementation of specific embodiments, many design-specific and application-specific decisions will be made, which will vary from implementation to implementation. It will be appreciated that such a development effort, while time-consuming and potentially arduous, would nevertheless be a routine undertaking for persons of ordinary skill in the art in light of the disclosures provided herein. All of the patent and literature references cited herein are incorporated by reference in their entireties.

Claims

We Claim:

1. A method for determining a threshold dose at which neuronal stimulation is evoked, comprising: administering a neuronal stimulation protocol to a neuronal target site using an electrical and/or magnetic stimulation protocol; detecting changes (or not) in neuronal tissue at the target site using optical detection techniques; administering modified neuronal stimulation protocols to the neuronal target site by changing at least one parameter of the electrical and/or magnetic stimulation protocol; detecting changes (or not) in neuronal tissue at the target site using optical detection techniques; and analyzing the changes detected in neuronal tissue at the target site to identify threshold dose parameters that elicit a response in neuronal tissue that is detectable using the optical detection techniques.

2. The method of claim 1, wherein the modified parameters of the electrical and/or magnetic stimulation protocol are selected form the group consisting of: stimulation amplitude; stimulation pulse duration; time between stimulation pulses; number of pulses administered; and duration of protocol.

3. A system for stimulating and detecting stimulation of neuronal tissue, comprising: a magnetic coil suitable for use in a transcranial magnetic stimulation protocol; at least one optically conductive fiber in communication with an optical source for transmitting an optical signal to a target neuronal stimulation site; and at least one optical detector for detecting an optical signal emitted from the target neuronal stimulation site, wherein the magnetic coil, an optical signal transmission portion of the optically conductive fiber, and an optical signal detection portion of the optical detector are mounted in a stationary location with respect to one another.

4. The system of claim 3, wherein the magnetic coil, the at least one optically conductive fiber, and the at least one optical detector are "hard" mounted in a common housing.

5. The system of claim 3, wherein the magnetic coil is mounted in a housing and the optical signal transmission portion of the optically conductive fiber and the optical signal detection portion of the optical detector are mountable in pre-determined receiving ports in the housing that are in a fixed location with respect to the magnetic coil.

6. The system of claim 3, comprising at least two optically conductive fibers, each of the optically conductive fibers being in communication with an optical source emitting photons at a different wavelength.

7. The system of claim 3, wherein the optically conductive fiber is in communication with a plurality of optical sources and can switch from source to source.

8. The system of claim 7, wherein one of the optical sources emits at a wavelength that is sensitive to changes in blood oxygen.

9. The system of claim 7, wherein one of the optical sources emits emr at a wavelength between about 650 nm and 730 nm.

10. The system of claim 7, wherein one of the optical sources emits at a wavelength that is sensitive to changes in blood volume.

11. The system of claim 10, wherein one of the optical sources emits emr at a wavelength between about 780 nm and 840 nm.

12. The system of claim 3, further comprising at least one EEG electrode mounted in a stationary location with respect to the magnetic coil and the optical signal transmission and detection elements.