Methods and apparatus for effectuating a lasting change in a neural-function of a patient

ES 2 274 014 T3

DESCRIPTION

Methods and devices for producing a lasting change in a patient's neural function.

The application claims the benefit of Provisional Application US 60 / 217,981, filed July 31, 2000, which is incorporated herein in its entirety.

Various embodiments of methods and devices according to the invention are related to the electrical stimulation of a region of the cortex or other areas of the brain to produce a lasting change in a physiological function and / or a mental process of a patient.

A wide variety of mental and physical processes are known to be controlled or influenced by neural activity in particular regions of the brain. In some areas of the brain, such as the sensory or motor cortices, the organization of the brain is similar to that of a map of the human body; this is called the "somatotopic organization of the brain." There are many other areas of the brain that appear to have different functions and are located in specific regions of the brain in most individuals. For example, areas of the occipital lobes refer to vision, regions of the left lower frontal lobes refer to language in most people, and regions of the cerebral cortex appear to be involved in consciousness, memory and the intellect. This type of area-specific functional organization of the brain, in which there is a statistical probability that certain discrete areas of the brain control particular mental or physical functions in normal individuals, is here called the "functional organization of the brain."

Many problems or abnormalities in bodily functions can be caused by brain damage, pathology, and / or disorders. Stroke, for example, is a very common clinical condition that causes brain damage. Strokes are usually caused by emboli (eg, obstruction of a tract vessel), hemorrhage (eg, rupture of a vessel), or thrombi (eg, clot) in the vascular system of a specific region of the cortex. , which in turn usually cause the loss or deterioration of neural function (eg. neural functions related to facial muscles, limbs, speech, etc.). Stroke patients are usually treated using physical therapy to rehabilitate the loss of function of a limb or any other affected body part. For most patients, little can be done to improve the function of the affected limb other than recovery that occurs naturally without intervention. An existing physical therapy technique for the treatment of stroke patients requires the use or reduction of the use of a part of the healthy body of the patient to force him to use the affected body part. For example, loss of use of one limb is treated by limiting the movement of the other. Although this type of physical therapy has shown some experimental efficacy, it is expensive, long and little used. Stroke patients can also be treated using physical therapy and complementary therapies. For example, some types of drugs, such as amphetamines, which increase the activation of neurons in general, seem to enhance neural networks; however, these drugs have limited efficacy, as their mechanism of action is not selective and cannot be administered directly in high concentrations to the site where they are needed. Consequently, there is a need to develop effective treatments for the rehabilitation of stroke patients and patients who have suffered from other types of brain damage.

Other brain disorders and pathologies are also difficult to treat. It is well known, for example, that Alzheimer's disease affects parts of the cortex, although it is not fully understood what causes Alzheimer's disease and how it alters neural activity in the cortex. Similarly, the neural activity of brain disorders (eg, depression and obsessive-compulsive behavior) is also not fully understood. Therefore, it is also necessary to develop more effective treatments for other disorders and pathologies of the brain.

Neural activity in the brain can be influenced by electrical energy, which is supplied from an external source outside the body. Thus, various neural functions can be enhanced or interrupted by applying an electrical current to the cortex or to another region of the brain. As a result, the search for treatment for brain damage, pathologies and disorders has focused research on the use of electricity or magnetism to control brain functions.

One type of treatment is transcranial electrical stimulation (TES), which involves placing an electrode on the outside of the scalp and applying an electrical current to the brain through the scalp and skull. Among the patents dealing with TES, we can cite US patent 5,540,736 issued to Haimovich et al (to provide analgesia), US 4,140,133, issued to Katrubin et al (to provide anesthesia), US 4,646,744 issued to Capel ( to treat drug addiction, appetite disorders, stress, insomnia and pain) and US 4,844,075 granted to Liss et al (to treat pain and motor dysfunction associated with cerebral palsy). However, the use of TES has not become widespread because patients experience a lot of pain and the electric field is difficult to direct and focus accurately.

Another type of treatment is transcranial magnetic stimulation (TMS), which consists of producing a high-power magnetic field, adjacent to the outside of the scalp, over an area of ​​the cortex. TMS does not cause the painful side effects of TES. Since 1985, TMS has been used primarily for brain mapping research. Recently however, potential therapeutic applications have been proposed, primarily for the treatment of depression. In a small number of clinical trials, TMS has been shown to be effective in treating depression when used to stimulate the left prefrontal cortex.

ES 2 274 014 T3

TMS treatment has been studied with promising results in a few other groups of patients, eg. ex. people with Parkinson's disease and hereditary hawthorn cerebellar degeneration. Among the published patents and patent applications dealing with TMS, mention may be made of the published international patent application WO 98/06342 (which describes a transcranial magnetic stimulator and its use in brain mapping studies and in the treatment of depression) ; US Patent 5,885,976 issued to Sandyk (describing the use of transcranial magnetic stimulation to treat a variety of disorders purportedly related to deficient serosonin neurotransmission and altered pineal melatonin functions); and US Patent 5,092,835 issued to Schurig et al, which describes the treatment of neurological disorders (such as autism), the treatment of learning disabilities, and the enhancement of the mental and physical abilities of "normal" people through a combination of stimulation. transcranial magnetic and peripheral electrical stimulation.

Independent studies have also shown that TMS can produce a lasting change in neural activity within the cortex, which occurs over a period of time after the termination of TMS treatment ("neuroplasticity"). For example, Ziemann et al., Modulation of Plasticity in Human Motor Cortex after Forearm Ischemic Nerve Block, 18 J Neuroscience 1115 (February 1998) describes that TMS at subliminal levels (eg. at levels where movement was not induced) in neuroblock models that mimic amputation, it could modify the long-lasting changes in normal activity that often accompany amputation. Similarly, Pascual-Leone et al., (Submitted for publication) describe that the application of TMS on the contralateral motor cortex in normal subjects subjected to immobilization of a hand in plaster for 5 days, can avoid the reduction of excitability of the motor cortex normally associated with immobilization. Other researchers have proposed that the ability of TMS to produce desired changes in the cortex can be used to enhance neuro-rehabilitation after brain trauma such as stroke, although no published study exists to date.

Other publications related to TMS are those of Cohen et al., Studies of Neuroplasticity With TRanscrananial Magnetic Stimulation, 15 J. Clin. Neurophysiol 305 (1998), Pascual-Leone et al., Transcranial magnetic Stimulation and Neuroplasticity, 37 Neuropsychology 207 (1999); Stefan et al., Induction of Plasticity in the Human Motor Cortex by Paired Associative Stimulation, 123 Brain 572 (2000); Sievner et al., Lasting Cortical Activation after repetitive TMS of the Motor Cortex, 54 Neurology 956 (February 2000); Pascual-Leone et al., Study and Modulation of Human Cortical Excitabilty With Transcranial Magnetic Stimulation, 15 J. Clin. Neurophysiol. 333 81998); and Boylan et al., Magnetoelectric Brain Stimulation in the Assessment Of Brain Physiology And Pathophysiology, 111 Clin. Neurophysiology 504 (2000).

Although TMS appears to be able to produce a change in the underlying cortex beyond the time of actual stimulation, TMS is currently not effective for the treatment of many patients, as existing delivery systems are not practical to apply the stimulation. stimulation for an appropriate period of time. TMS systems, for example, are relatively complex and require stimulation treatments by a healthcare professional in a hospital or doctor's office. TMS systems may not be reliable for long-term therapies, as it is difficult to (a) precisely locate the stimulation region in a reproducible way, and (b) keep the device in the correct position on the skull for a period of long time, especially when the patient is moving or during rehabilitation. Furthermore, current TMS systems often do not focus electromagnetic energy sufficiently in the desired region of the crust for many applications. The potential therapeutic benefit of TMS as such, using existing equipment, is relatively limited.

Direct and indirect electrical stimulation of the central nervous system has also been proposed to treat a whole series of disorders and clinical pictures. For example, US Patent 5,938,688, issued to Schiff, states that the phenomenon of neuroplasticity can be harnessed and enhanced to treat cognitive disorders related to brain trauma caused by trauma or stroke. The Schiff implant is designed to increase the level of brain activation in a comatose patient by stimulating deep centers in the brain that are involved in consciousness. To this end, Schiff's invention comprises the electrical stimulation of at least a part of the intra-laminar nuclei (i.e. the deep brain) using, for example, an implantable multipolar electrode and an implantable pulse generator or a radio-frequency controlled pulse generator. external. The Schiff deep brain implant is however aggressive and could cause serious complications for the patient.

US Patent 6,066,163, issued to John also recognizes the ability of the brain to overcome some of the results of trauma, due to neuroplasticity. John also cites a number of skills that demonstrate that direct electrical stimulation of the brain can reverse the effects of traumatic injury or stroke at the level of consciousness. The system described in this document stimulates the patient and modifies the stimulation parameters based on the result of comparing the current state of the patient with a baseline state, in an effort to

ES 2 274 014 T3 optimize the results. But, as with Schiff, the invention described by John focuses on a highly aggressive deep brain stimulation system.

Another device for stimulating a region of the brain is that described by King in US Patent 5,713,922. King describes a device for stimulation of the cortical surface, which has electrodes mounted on a paddle implanted under the patient's scalp. The electrodes are implanted on the surface of the brain in a fixed position. King's electrodes therefore cannot move to accommodate changes in the shape of the brain. King also describes that the electrical impulses are generated by a pulse generator that is implanted in the patient away from the skull (eg subclavicular implantation). The pulse generator is not directly connected to the electrodes but is electrically coupled to the electrodes via a wire extending from the furthest implanted pulse generator and the electrodes implanted in the skull. The lead described by King runs from the paddle, around the skull and down the neck to the subclavicular location of the pulse generator.

King describes implanting the electrodes in contact with the surface of the cortex to create paresthesia, which is a vibrating or "buzzing" sensation experienced by a patient. More specifically, King describes the induction of paresthesia in wide areas, applying electrical stimulation to a higher element of the central nervous system (for example the cortex). King describes the placement of the electrodes against particular regions of the brain to induce the desired paresthesia. The goal of creating paresthesia in a body region is to create a distracting stimulus that effectively reduces the perception of pain in the body region. It therefore appears that King requires a stimulation in excess of the activation levels.

Although King describes a device that stimulates a region on the cortical surface, this device is considered to have several drawbacks. First, it is expensive and time consuming to implant the pulse generator and lead into the patient. Second, it appears that the electrodes are held at a fixed elevation that does not compensate for anatomical changes in the area of ​​the brain relative to the skull, which makes it difficult to precisely apply electrical stimulation to a desired area of ​​the cortex. specific and precise mode. Third, King describes the direct activation of neurons to cause paresthesia, and presumably this may cause training / entrainment of activity in the stimulated population of neurons with other forms of therapy or adaptive behavior such as occupational therapy. or physical. Accordingly, King's disclosure is considered to have several drawbacks.

It is assumed that both King's description and the other references above have difficulties in producing the desired neural activity, since these references generally apply to therapy of the brain region responsible for physiological function or mental process depending on the organization functional brain. In the case of trauma or brain pathology, however, the region of the brain associated with impaired physiological function or cognitive process may not respond to stimulation therapies. Therefore, existing techniques may not produce adequate results that are sustained beyond the stimulation period.

In the present invention, a device is described to achieve a neural function of a patient, associated with a first location of the brain of the patient, comprising:

a diagnostic system capable of identifying a stimulation zone in the patient's cerebral cortex, determining a region of the brain in which a predicted neural activity is present in response to the generation of the predicted neural activity, remotely, from the first location of the brain; and a stimulation system comprising a compressible or flexible support element, an electrode on the support element configured to be implanted in the stimulation zone between the skull and the surface of the pia mother of the brain, and a pulse generator to provide a electrical potential to the electrode.

Other aspects of the invention are set forth in the appended subclaims.

The following part of the description (up to "brief description of the figures") constitutes additional material and is not to be considered an integral part of the claimed invention.

The present description focuses on various devices and methods for achieving neural function in a patient. One aspect of the description is focused on a device for achieving a neural function of a patient associated with a first location of the patient's brain. This device comprises a diagnostic system capable of identifying a stimulation zone, determining a region of the brain in which a predicted neural activity is present, in response to the generation of the predicted neural activity, remotely, from the first location of the brain. This device may include a stimulation system comprising an electrode configured to be implanted in the stimulation site and a pulse generator to provide an electrical potential to the electrode.

Another aspect of the description focuses on a device for treating the loss of neural function at a first cortical location in the brain of a patient. Several examples of such an aspect include a diagnostic system capable of choosing a stimulation zone in the cortical region of the brain in which neural activity is expected to occur to compensate for the loss of neural function in the first cortical location of the brain.

ES 2 274 014 T3

These examples can also include a stimulation system having first and second electrodes. The stimulation system is generally configured to be implanted in the patient, close to the pia mater in the cortical region, so that the first electrode is in a first area of ​​the stimulation zone and the second electrode is in a second area. of the stimulation zone.

Another aspect of the description focuses on a device for treating a neural function in the brain of a patient. In this aspect, one embodiment comprises a diagnostic system that determines an electrical stimulation threshold to induce a response in cells in a stimulation zone in the cortical region of the patient's brain. This device may also comprise a stimulation system having a first electrode, a second electrode, and a controller coupled to the first and second electrodes. The first and second electrodes are configured to be implanted close to the pia mater of the patient's brain. The controller is configured to apply electrical stimulation at an intensity below the stimulation threshold between the first and second electrodes. The controller can therefore apply a stimulation with an intensity below the threshold, below the activation threshold for a population of neurons in the stimulation zone.

Other aspects of the devices of the present disclosure focus on various characteristics of the stimulation systems. One of the aspects focuses on a device to apply electrical stimulation in a region of the brain of a patient. In one of the examples, the device comprises an implantable support member configured to be implanted in the patient, at least partially, within the patient's skull. This device can also comprise a pulse system that rests on the support element, a first electrode that rests on the support element and a second electrode that also rests on the support element. The first and second electrodes are coupled to the pulse system.

Another example focuses on a device that comprises an implantable support element, configured to be implanted in the patient, close to the patient's skull. The support member may comprise a fixation member to secure the support member to the skull. The device may also comprise a pulse system resting on the support member, and a first and a second electrode located in a first and a second region of the support member, respectively. The first and second electrodes are coupled to the pulse system.

Other examples of the device of the present disclosure have a first and a second electrode, directly coupled to the pulse system within the support element, so that the stimulation system is an integrated unit that can be implanted entirely within or on the skull of the patient. patient. Other aspects include a device in which the support member has a biasing member and the electrodes rest on the biasing member.

Various aspects of the methods of the present disclosure focus on causing neural function to occur in a patient. An example of a method of achieving a patient's neural function associated with a first location in the patient's brain comprises identifying a stimulation zone, generating a predicted neural activity, remotely, from the first location, and then determining a region of the brain in which the generated neural activity is present. This method can be continued by placing at least a first electrode in the stimulation zone, then applying an electrical potential to pass a current through the first electrode.

Another example of a method of achieving neural function in a patient involves identifying a zone of stimulation in and / or on the brain, where neural activity has changed in response to a change in neural function in the first brain location. This method may comprise placing the first and second electrodes in the stimulation zone, then applying an electrical potential between the first and second electrodes.

Other aspects of the methods focus on methods for treating loss of neural function at a first cortical location in the brain of a patient. An example comprises the selection of a stimulation zone in a cortical region of the brain, in which neural activity is expected to occur to compensate for the loss of neural function in the first cortical location of the brain. These examples may comprise placing a first electrode in a first area of ​​the stimulation zone, close to the pia mater in the cortical region, and also placing a second electrode in a second area of ​​the stimulation zone, close to the pia madre in the cortical region. The method may also comprise applying an electric potential between the first and second electrodes.

Other aspects of the methods of the present disclosure focus on treating a neural function in the brain of a patient using less than threshold stimulation. In one of the examples, the method comprises selecting a stimulation zone in a first cortical region of the brain, and subsequently determining an electrical stimulation threshold to induce a response in cells in the stimulation zone. This method further comprises the application of an electrical stimulation between the first and second electrodes in a location close to the pia mater of the first cortical region of the brain and with an intensity below the stimulation threshold.

Figure IA is a schematic view of neurons.

ES 2 274 014 T3

Figure 1B is a graph illustrating the performance of a normal.

'action potential' associated with neural activity

Figure 1C is the flow chart of a method for producing a neural function of a patient, associated with a location in the brain.

Figure 2 is a top view of a part of a brain illustrating neural activity in a first brain region associated with neural function of the patient according to the somatotopic organization of the brain.

Figure 3 is a top view of part of the brain illustrating a loss of neural activity associated with the neural function of the patient.

Figure 4 is a top image of the brain of Figure 3 showing a change in the location of neural activity associated with the patient's neural activity. Figures 5A and 5B are schematic illustrations of an implant procedure.

Figure 5C is a graph illustrating the performance of an "action potential" associated with stimulated neural activity.

Figure 6 is an isometric view of an implantable stimulation device.

Figure 7 is a sectional view schematically illustrating a part of an implantable stimulation device.

Figure 8 is a schematic illustration of a pulse system.

Figure 9 is a schematic illustration of an implanted stimulation device and external controller.

Figure 10 is a schematic illustration of an implantable stimulation device having a pulse system and an external controller.

Figure 11 is a sectional view schematically illustrating a part of an implantable stimulation device.

Figure 12 is a schematic illustration of an implantable stimulation device having a pulse system and an external controller.

Figure 13 is a sectional view schematically illustrating a part of an implantable stimulation device having a pulse system and an external controller.

Figure 14 is a bottom view and Figure 15 is a sectional view illustrating an electrode configuration for an implantable stimulation device.

Figure 16 is a bottom view and Figure 17 is a sectional view of an electrode configuration for an implantable stimulation device.

Figure 18 is a bottom view and Figure 19 a sectional view of an electrode configuration.

Fig. 20 is a bottom view of an electrode configuration for an implantable stimulation device.

Fig. 21 is a bottom view of an electrode configuration for an implantable stimulation device.

Figure 22 is a bottom view of another electrode configuration.

Figure 23 is a bottom view and Figure 24 a sectional view of the electrode arrangement.

Figure 25 is an isometric view schematically illustrating a portion of an implantable stimulation device with a mechanical biasing element.

Figure 26 is a sectional view of a stimulation device having a mechanical deflection element implanted in the skull of a patient.

Figure 27 is a sectional view schematically illustrating a part of a stimulation device having a biasing element.

Figure 28 is a sectional view of a stimulation device having a biasing element.

ES 2 274 014 T3

Figure 29 is a sectional view of a stimulation device having a biasing element.

Figure 30 is a sectional view of a stimulation device having a biasing element.

Figure 31 is a sectional view schematically illustrating a part of an implantable stimulation device having an external power source and a pulse generator.

Figure 32 is a sectional view schematically illustrating a part of an implantable stimulation device having an external power source and a pulse generator.

Figure 33 is a sectional view illustrating in greater detail a portion of the implantable stimulation device of Figure 32.

Figure 34 is a sectional view schematically illustrating a part of an implantable stimulation device and an external controller.

Figure 35 is a sectional view schematically illustrating a part of an implantable stimulation device and an external controller.

Fig. 36 is a sectional view schematically illustrating a part of an implantable stimulation device according to an embodiment of the invention.

Figure 37 is an isometric view and Figure 38 a sectional view illustrating an implantable stimulation device according to one embodiment of the invention.

FIG. 39 is a sectional view illustrating an implantable stimulation device according to another embodiment of the invention.

Figure 40 is a schematic illustration of an implantable stimulation device according to one embodiment of the invention.

The following description presents various methods and devices for intracranial electrical stimulation in order to treat or otherwise produce a change in the neural functions of a patient. Various method embodiments are focused on enhancing or otherwise inducing neuroplasticity to achieve a particular neural function. Neuroplasticity refers to the brain's ability to change or adapt over time. It has been thought for some time that adult brains become relatively "hard wired" so that functionally significant neural networks could not change markedly over time or in response to trauma. It has become increasingly clear that these neural networks can change and adapt over time, so that important functions can be restored in response to head trauma. One aspect of various method embodiments is to provide suitable activators to achieve adaptive neuroplasticity. These suitable activators appear to cause or allow greater synchronism in functionally significant populations of neurons in a network.

Electrically enhanced or induced neural stimulation according to various embodiments of the invention excites a part of the neural network involved in a functionally significant task, so that a given population of neurons can be more strongly associated with said network. Because such a network supports a functionally important task such as motor learning, the changes are more likely to be long-lasting, as they are continually reinforced by mechanisms of natural use. The nature of stimulation according to various embodiments of the invention ensures that the stimulated population of neurons connects with other neurons in the functional network. This is expected to occur since the action potentials are not actually caused by the stimulus but rather with interactions with other neurons in the network. Various aspects of electrical stimulation according to particular embodiments of the invention simply allow this to occur with greater probability when the network is activated by means of favorable activities such as rehabilitation or use of the extremities.

The methods can be used to treat brain damage (eg stroke, trauma, etc.), brain pathologies (eg Alzheimer's, Pick's, Parkinson's disease, etc.) and / or brain disorders (eg epilepsy, depression, etc). The methods can also be used to enhance healthy normal brain functions (eg learning, memory, etc.) or to control sensory functions (eg pain).

Certain method embodiments electrically stimulate the brain in a stimulation zone where neuroplasticity occurs. The area of ​​stimulation may be different from the area of ​​the brain where neural activity is usually present to perform the particular function depending on the functional organization of the brain. In an embodiment where neuroplasticity relative to neural function occurs in the brain, the method may include identifying the location where such neuroplasticity is present. This particular procedure can therefore enhance a change in normal activity to help the brain perform neural function. In an alternative embodiment where neuroplasticity does not occur in the brain, one of the aspects is to induce neuroplasticity in a zone of stimulation where it is expected to occur. The particular procedure can therefore induce a change in neural activity to enhance the performance of neural function. Expected

ES 2 274 014 T3 that various embodiments of these methods produce a lasting effect on the anticipated neural activity in the area of ​​stimulation.

Figures 1A-40 allow a person of ordinary skill in the art to understand these embodiments well. More specifically, the invention is illustrated initially with reference to Figures 1-5C, and then various embodiments of devices for stimulating the cortical and / or deep brain regions are described with reference to Figures 6-40. Any person skilled in the art will understand that the present invention may have additional embodiments or that the invention may be practiced without various of the details described below.

A. Methods for Electrically Stimulating Regions of the Brain

1. Performances of electrical enhancement of neural activity

Figure 1A is a schematic representation of various N1-N3 neurons and Figure 1B is a graph illustrating an "action potential" relative to neural activity in a normal neuron. Neural activity is governed by electrical impulses generated in neurons. For example, neuron N1 can send excitation inputs to neuron N2 (eg times ti, t₃ and t₄ in Figure 1B) and neuron N3 can send inhibitory inputs to neuron N2 (e.g. time t₂ in Figure 1B). Neurons receive / emit excitation and inhibition inputs from / to a population of other neurons. The excitation and inhibition inputs can produce "action potentials" in neurons, which are electrical impulses that travel through neurons changing the flux of sodium (Na) and potassium (K) ions across the cell membrane. An action potential occurs when the resting membrane potential of neurons exceeds a certain threshold. Once this threshold is reached, an "all" or "nothing" action potential is generated. For example, as shown in Figure 1B, the excitation input at time t₅ it causes the N2 neuron to “fire” an action potential because the input exceeds the threshold-level to generate the initial action potential. Action potentials propagate down the length of the axon (the long process in the neuron that makes up nerves or neural tracts) to produce the release of neurotransmitters from that neuron, which will then influence adjacent neurons.

Figure 1C is a flow chart illustrating a method 100 for achieving neural function in a patient. Neural function, for example, can control a mental process or a specific physiological function such as a motor function or a particular sensory function (eg movement of a limb) normally associated with neural activity in a "normal" area of ​​the brain depending on the functional organization of the brain. In various embodiments of method 100, at least some neural activity related to neural function may occur in one area of ​​the brain. The zone of neural activity may be in the normal location where neural activity usually occurs to perform neural function according to the functional organization of the brain, or the zone of neural activity may be in a different location where the brain has recruited material to perform neural activity. In either situation, one aspect of the embodiments of method 100 is determining the area of ​​the brain in which this neural activity is present.

Method 100 comprises a diagnostic method 102 that consists of identifying a stimulation zone at a location in the brain where there is predicted neural activity related to neural function. In one embodiment, the diagnostic method 102 comprises generating the predicted neural activity in the brain from a "peripheral" location away from the normal location, then determining where in the brain the predicted neural activity is now present. In an alternative embodiment, the diagnostic procedure 102 can be performed by identifying a stimulation zone in which neural activity has changed in response to a change in neural function. Method 100 continues with an implantation procedure 104 that consists of positioning a first and a second electrode in the identified stimulation zone, and a stimulation procedure 106 that consists of applying an electrical current between the first and second electrodes. Many embodiments of the implantation procedure 104 place two or more electrodes in the stimulation zone, although other embodiments of the implantation procedure consist of placing only one electrode in the stimulation zone and another electrode remote from the stimulation zone. The implantation procedure 104 of method 100 as such may comprise implanting at least one electrode in the stimulation site. Procedures 102106 are described in more detail below.

Figures 2-4 illustrate one embodiment of diagnostic procedure 102. Diagnostic procedure 102 can be used to determine the region of the brain where stimulation is likely to achieve the desired function, such as rehabilitation of a loss of neural function. caused by stroke, trauma, pathology or other circumstance. Figure 2, more specifically, is the image of a normal, healthy brain 200 having a first region 210 in which predicted neural activity occurs to achieve a specific neural function in accordance with the functional organization of the brain. For example, neural activity in the first region 210 shown in FIG. 202 is generally associated with movement of a patient's fingers. The first region 210 may have a high intensity zone 212 and a low intensity zone 214 in which different levels of neural activity occur. It is not necessary to have an image of the neural activity in the first region 210 shown in Figure 2 to perform the diagnostic procedure 102 but rather serves to show an example of neural activity that usually occurs in a "normal location" according to the functional organization of the brain 200 for a large population of people with normal brain function. It will be appreciated that the actual location of the first region 210 will generally vary from patient to patient.

ES 2 274 014 T3

However, neural activity in the first region 210 may deteriorate. In a typical application, the diagnostic procedure 102 begins by taking an image of the brain 200 that is capable of detecting neural activity to determine whether the predicted neural activity associated with the particular neural function of interest is occurring in the brain region 200 in the region. that usually occurs according to the functional organization of the brain. Figure 3 is an image of the brain 200 after the first region 210 has been affected (eg, by stroke, trauma, or other cause). As shown in Figure 3, the neural activity that controlled neural function to stop moving the fingers occurs in the first region 210. The first region 210 is therefore "inactive", and it is expected that the result of this is the corresponding loss of movement and / or sensation in the fingers. In some cases, damage to the brain 210 may result in only a partial loss of neural activity in the damaged area. In any case, the image shown in Figure 3 establishes that the loss of neural function is related to the decrease in neural activity in the first region 210. The brain 200 may therefore recruit other neurons to carry out the neural activity of the affected neural function (ie, neuroplasticity), or the neural activity may not be present anywhere in the brain.

Figure 4 is an image of brain 200 illustrating a plurality of potential stimulation zones 220 and 230 to perform neural function that was originally performed in the first region 210 shown in Figure 2. Figures 3 and 4 show an example of neuroplasticity in which the brain compensates for a loss of neural function in one region of the brain by recruiting other regions of the brain for neural activity to carry out affected neural function. Diagnostic procedure 102 uses neuroplasticity that occurs in the brain to identify the location of a stimulation zone that is expected to best account for the results of an electrical, magnetic, sonic, genetic, biological, and / or pharmaceutical procedure to achieve desired neural function.

One embodiment of the diagnostic method 102 involves generating the predicted neural activity away from the first brain region 210 then detecting the location in the brain where the predicted neural activity has been generated. Predicted general activity can be generated by applying an input that produces a signal that is sent to the brain. For example, in the case of a patient who has lost the use of a limb, the affected limb is moved and / or stimulated while the brain is scanned using a known imaging technique that can detect neural activity (eg. eg functional MRI, positron emission tomography, etc). In a specific embodiment, the affected limb can be moved by a physician or by the patient, stimulated by sensory tests (eg. puncture) or subjected to peripheral electrical stimulation. Movement / stimulation of the affected limb produces a limb peripheral neural signal that is expected to generate responsive neural activity in the brain. The location in the brain where responsive neural activity is present can be identified using the imaging technique. Figure 4, p. ex. It can be created by moving the affected fingers and then noting where neural activity occurs in response to peripheral stimulus. By peripherally generating predicted neural activity, this embodiment can accurately identify where the brain has recruited (ie, zones 220 and 230) to perform predicted neural activity associated with neural function.

An alternative embodiment of the diagnostic method 102 is to identify a stimulation site in a second location in the brain where neural activity has changed in response to a change in the patient's neural function. This embodiment of the method does not necessarily require that the predicted neural activity be generated by peripheral actuation or stimulation of a part of the body. For example, the brain can be scanned for neural activity associated with impaired neural function when a patient regains use of an affected limb or learns a task over a period of time. This embodiment may however also comprise the peripheral generation of the anticipated neural activity away from the brain, as indicated above.

In another embodiment, the diagnostic method 102 consists of identifying an identification zone at a location in the brain where predicted neural activity is developing to perform neural function. This embodiment is similar to the other embodiments of the diagnostic procedure 102 but can be used to identify a stimulation zone in (a) the normal region of the brain in which predicted neural activity is expected to occur based on the functional organization of the brain and / or or (b) a different region in which neural activity occurs because the brain is recruiting additional material to perform neural function. This particular embodiment of the method is to monitor and track neural activity at one or more locations where neural activity occurs in response to the particular neural function of interest. For example, to enhance the ability to learn a particular task (eg to play a musical instrument, memorize, etc.), neural activity can be monitored and followed while a person performs the task or plans to perform it. Stimulation zones can be defined by the areas of the brain in which neural activity has the maximum intensity, the greatest increases, and / or other parameters that indicate areas of the brain that are being used to perform the particular task.

Figures 5A and 5B are schematic illustrations of the implantation procedure 104 described above with reference to Figure 1C for positioning the first and second electrodes relative to a portion of a patient's brain 500. Referring to Figure 5A, a stimulation zone 502 in accordance with one embodiment of diagnostic procedure 102. In one embodiment, a section of skull 504 from patient 500 is removed adjacent to stimulation site 502. Skull section 504 may be removed by drilling a hole in the skull, in known manner, or a much smaller hole may be formed. in the skull using drilling techniques known in the state of the art. In general, the hole can have a diameter of 0.2 to 4.0 cm. Referring to FIG. 5B, an implantable stimulation device 510 may be implanted in patient 500 that

ES 2 274 014 T3 has first and second electrodes 520. Medical personnel skilled in the art are familiar with the appropriate techniques associated with the implantation procedure. Once stimulation device 510 has been implanted in patient 500, a pulse system generates electrical impulses that are transmitted to stimulation zone 502 by first and second electrodes 520. With reference to Figures 6-40, stimulation devices for carrying out embodiments of the aforementioned methods are described below in more detail.

Various embodiments of methods for enhancing neural activity are expected to offer lasting results that promote desired neural function. Prior to the present invention, electrical and magnetic stimulation techniques used to stimulate normal brain locations where neural activity related to neural functions occurred according to the functional organization of the brain. These conventional techniques however cannot be effective as neurons in "normal locations" in the brain may not be able to perform neural activity due to brain damage, disease, disorder and / or due to specific location variations. of individual patients. Various embodiments of methods for enhancing neural activity overcome this drawback by identifying a zone of stimulation based on neuroplastic activity that appears to be related to neural function. By first identifying a location in the brain that is being recruited to perform neural activity, therapies (eg. electrical, magnetic, genetic, biological and / or pharmaceutical) applied to this location are more effective than conventional techniques. This is because the location that the brain is recruiting for neural activity may not be the "normal location" where neuroactivity normally occurs based on the functional organization of the brain. Accordingly, various embodiments of methods for enhancing neural activity are expected to provide lasting results because the therapies are applied to the part of the brain where neural activity to perform neural function actually occurs in the particular patient.

2. Electrical induction of desired neural activity

The method 100 for achieving neural function can also be used to induce neural activity in a region of the brain where such neural activity is not present. Contrary to the embodiments of method 100 described above for enhancing existing neural activity, embodiments of methods 100 for inducing neural activity initiate neural activity in a zone of stimulation where neuroplasticity is expected to occur. In this particular situation, an image of the brain attempting to locate the site of neuroplasticity may be similar to that depicted in Figure 3. Therefore, one aspect of inducing neural activity is to develop a procedure to determine where neuroplasticity is likely to occur.

A zone of stimulation can be identified by estimating where the brain is likely to recruit neurons to perform neural function. In one embodiment, the location of the stimulation zone is estimated by defining a region of the brain close to the normal location where neural activity related to neural function is usually present according to the functional organization of the brain.

An alternative embodiment for locating the stimulation zone is to determine where neuroplasticity has commonly occurred in patients with similar symptoms. For example, if the brain typically recruits a second region of the cortex to compensate for a loss of neural activity in the normal region of the cortex, then the second region of the cortex can be chosen as the stimulation zone with or without imaging of the brain. neural activity in the brain.

Various embodiments of methods for inducing neural activity are expected to provide long-lasting results that initiate and promote a desired neural function. By first calculating the location of a stimulation zone in which the desired neuroplasticity is expected to occur, therapies applied to this location may be more effective than conventional therapies for reasons similar to those discussed above in enhancing neural activity. In addition, methods for inducing neural activity may be easier and cheaper to implement as they do not require generation of neural activity and / or imaging of the brain to determine where anticipated neural activity occurs prior to application. the therapy.

3. Applications of methods to electrically stimulate regions of the brain

The above methods for enhancing existing neural activity or inducing new neural activity may be useful, it is hoped, for various applications. As discussed above, various embodiments of method 100 consist of determining an effective location of the brain to enhance or induce a predicted neural activity that causes the desired neural functions to occur. Additional therapies can also be applied in combination with the electrical stimulation methods described above. Several specific applications in which embodiments of electrical stimulation methods are used alone or with complementary therapies will now be described although it will be seen that the methods can be used in many other applications.

to. General applications

The embodiments of the electrical stimulation methods described above are expected to be particularly useful in rehabilitating a loss of mental functions, motor functions and / or sensory functions caused by damage to the brain. In a typical application, the brain has suffered damage due to stroke or trauma

ES 2 274 014 T3 (eg car accident). The extent of the particular brain damage can be assessed using functional MRI or other suitable imaging technique as explained above in connection with Figure 3. A zone of stimulation can then be identified: (a) by peripherally stimulating a body part affected by brain damage to induce the predicted neural activity and determining the zone in which responsive neural activity occurs; (b) determine where neural activity has changed as the patient increasingly regains use of the affected body part; and / or (c) calculating the location at which the brain can recruit neurons to perform neural activity previously performed by the damaged part of the brain. Electrical stimulation therapy can then be applied to the chosen stimulation zone by positioning the first and second electrodes relative to the stimulation zone to apply an electrical current to that part of the brain. As detailed below, the application of an electrical current to the part of the brain that has been recruited to perform neural activity related to the affected body part is expected to produce a lasting neurological effect to rehabilitate the affected body part.

Various specific applications are expected to have a stimulation zone in the cortex since neural activity in this part of the brain is responsible for motor and / or sensory functions that are often affected by stroke or trauma. In these applications, electrical stimulation can be applied directly to the surface of the pia mater of the brain or at least near the surface of the pia mater (eg. the dura, the fluid that surrounds the cortex, or neurons within the cortex). Devices suitable for applying electrical stimulation to the cortex are now described in detail with reference to Figures 6-40.

Electrical stimulation methods can also be used with accessory therapies to rehabilitate damaged parts of the brain. In one embodiment, the electrical stimulation methods can be combined with physical therapy and / or drug therapies to rehabilitate impaired neural function. For example, if a stroke patient has lost the use of a limb, it can be treated by applying electrical therapy to a stimulation zone in which the anticipated neural activity is present while the affected limb also undergoes physical therapy. An alternative embodiment may consist of applying electrical therapy to the stimulation site and chemical treatment of the patient using amphetamines or other suitable drugs.

The embodiments of the electrical stimulation methods described above may also be useful, it is hoped, in the treatment of brain pathologies such as Alzheimer's disease, Parkinson's as well as other brain pathologies. In this application, the area of ​​stimulation can be identified by monitoring and tracking neural activity using functional MRI or other appropriate imaging techniques over a period of time to determine where the brain is recruiting material to perform the activity. neural that has been affected by the pathology. It may also be possible to identify the stimulation zone by having the patient attempt an act that has been affected by the particular pathology, and by monitoring and monitoring the brain to determine if any responsive neural activity appears in the brain. After identifying where the brain is recruiting additional material, electrical stimulation can be applied to this part of the brain. It is hoped that electrical stimulation of the brain regions that have been recruited to perform the neural activity that was affected by the pathology will help the brain to compensate for the damage caused by the disease.

The embodiments of the electrical stimulation methods described above may be expected to be useful for the treatment of neurological disorders such as depression, passive-aggressive behavior, weight control, and other disorders. In these applications, the electrical stimulation can be applied to a stimulation zone of the cortex or to another suitable part of the brain where there is neural activity related to the particular disorder. Embodiments of electrical stimulation methods for performing the particular therapy can be tailored to increase or decrease particular neural activity so as to produce the desired results. For example, a person who has had a limb amputated may experience phantom sensations associated with the amputated limb. This phenomenon can be treated by applying an electrical impulse that reduces phantom sensation. Electrical therapy can be applied in a way that modulates the ability of neurons in that part of the brain to perform sensory functions.

b. Forms and potentials of impulse

Electrical stimulation methods can use several different forms of impulse to achieve the desired neuroplasticity. The impulses can be a biphasic or monophasic stimulus applied to achieve a desired potential in a sufficient percentage of the neuron population in the stimulation zone. In one embodiment, the pulse shape has a frequency of about 2-1000 Hz although the frequency can be particularly useful between about 40 and 200 Hz. For example, initial clinical trials are expected to use a frequency of about 50-100 Hz. The pulses can also have widths of about 10 ps-100 ms or more specifically the pulse width can be about 20-200 // s. . For example, a pulse width of 50-1001 μs can produce beneficial results.

A particularly useful application of the invention is expected to comprise the enhancement or induction of neuroplasticity by increasing the resting membrane potential of neurons to bring the neurons closer to the threshold level to produce an action potential. As stimulation increases the membrane resting potential of neurons, it is expected that these neurons are more likely to "elicit" an action potential in response to a lower level excitation input.

ES 2 274 014 T3

Figure 5C is a graph illustrating the application of a subliminal potential to neurons N1-N3 of Figure 1A. At the moment you and you₂, excitation / inhibition inputs from other neurons "do not bridge" between the resting potential at -X mV and the threshold potential. At the time t₃, electrical stimulation is applied to the brain to increase the resting potential of neurons in the stimulated population so that the resting potential is at -Y mV. At the time t₄ When neurons receive other excitation input, even a small impulse is greater than the difference between the increased resting potential -Y mV and the threshold potential for inducing action potentials in these neurons. For example, if the resting potential is approximately -70 mV and the threshold potential is approximately -50 mV, then electrical stimulation can be applied to increase the resting potential of a sufficient number of neurons to approximately -52 to -60 mV.

The actual electrical potential applied to the electrodes implanted in the brain to achieve threshold potential stimulation will vary depending on the individual patient, type of therapy, type of electrodes, and other factors. In general, the pulse shape of electrical stimulation (eg. frequency, pulse width, waveform and voltage potential) re-chooses to increase the resting potential in a sufficient number of neurons in the stimulation zone to a level below a threshold potential for a statistical part of neurons in the population. The shape of the impulse, for example, can be chosen so that the applied voltage of the stimulus achieves a change in the resting potential of approximately 10% -95% and more specifically of 60% -80% of the difference between the potential of unstimulated rest and threshold potential.

In a specific example of a subliminal application for treating a patient's hand, electrical stimulation is not initially applied to the stimulation site. Although physical therapy related to the patient's hand may cause some activation of a particular population of neurons known to be involved in "hand function," only a reduced level of activation can occur because physical therapy only produces a low level of generation of action potential in said population of neurons. However, if subliminal electrical stimulation is applied, the resting membrane potentials of neurons in the stimulated population are high. These neurons are now much closer to the threshold for the formation of action potentials so that when the same type of physical therapy is given, this population of cells has a greater power of activation since these cells are more likely to elicit potentials of action.

Subliminal stimulation can produce better results than simply stimulating neurons with energy levels sufficient to exceed the threshold for action potential formation. One aspect of subliminal stimulation is increasing the likelihood that action potentials will be produced in response to ordinary triggers, such as physical therapy. This will allow neurons, in this functional network, to train together or "learn" to associate with these types of activities. If neurons are given so much electricity that they continually elicit action potentials without additional excitation inputs (supraliminal stimulation), this will create "noise" and disorganization that is unlikely to produce any improvement in function. In fact, "overexcited" neurons soon deplete their neurotransmitters and become effectively silent.

The application of subliminal stimulation is very different from supraliminal stimulation. Subliminal stimulation according to various embodiments of the invention, for example, is not intended to directly elicit action potentials from neurons with electrical stimulation in a significant population of neurons in the stimulation zone. On the contrary, what is intended with subliminal stimulation is to reduce the "activation energy" necessary to activate a large part of the neurons in the stimulation zone. Subliminal stimulation, therefore, according to certain embodiments of the invention, should appear to increase the likelihood that neurons are excited in response to the usual intrinsic triggers such as attempting to move a limb, physical therapy, or simply thinking about movement of a limb. member, etc. Furthermore, coincident stimulation associated with physical therapy is expected to increase the likelihood that action potentials that occur with a higher probability due to subliminal stimulation are related to significant triggers and not simply "noise."

Stimulus parameters listed above, such as selecting a frequency of approximately 50-100 Hz and an amplitude sufficient to achieve a 60% to 80% increase in the difference between the resting potential and the threshold potential, they are specifically chosen so that they increase the resting potential of the membrane of neurons, thus increasing the probability that they elicit action potentials, without directly causing action potentials in the majority of the neuron population. In addition, and as explained in more detail below with respect to Figures 6-40, various embodiments of stimulation devices have been designed to precisely deliver a pulse shape that produces subliminal stimulation by selectively stimulating regions of the cerebral cortex about 1-2 cm (the estimated size of a “functional unit” of cortex), directly contacting the surface of the pia madre with the electrodes to consistently create the same alterations in the membrane resting potential and / or bypassing the electrodes towards the pia madre surface to obtain a positive connection between the electrodes and the cortex.

B. Devices for electrical stimulation of brain regions

Figures 6-40 illustrate stimulation devices for electrically stimulating brain regions according to one or more of the methods described above. The devices illustrated in Figures 6-40 are commonly used to stimulate a region of the cortex near the surface of the pia mater of the brain (eg the dura, pia mater,

ES 2 274 014 T3 the fluid between the dura mater and the pia mater and a depth in the cortex outside the white matter of the brain). The devices can also be applied to stimulate other parts of the brain in other embodiments.

1. Implantable stimulation device with integrated pulse systems

Figure 6 is an isometric view and Figure 7 a sectional view of a stimulation device 600 for stimulating a region of the cortex near the surface of the pia mater. In one embodiment, stimulation device 600 comprises a support member 610, an integrated pulse system 630 (shown schematically) that rests on support member 610, and first and second electrodes 660 (individually identified by reference numerals 660a and 660b). The first and second electrodes 660 are electrically coupled to pulse system 630. Support element 610 can be configured to implant in the skull or other intracranial region of a patient. In one embodiment, for example, support member 610 comprises a housing 612 and a fastener 614 connected to housing 612. Housing 612 may be a molded liner formed from a biocompatible material that has an interior cavity to carry the pulse system 630. The housing may alternatively be a biocompatible metal or other suitable material. Housing 612 can have a diameter of approximately 1-4 cm and, in many applications, housing 612 can have a diameter of 1.5-2.5 cm. Housing 612 may also have other shapes (eg, rectilinear, oval, elliptical) and other surface dimensions. The stimulation device 600 weighs 35 g or less and / or occupies a volume of 20 cm³ or less. The fixation element 614 may be a flexible cover, a rigid plate, a contoured cap, or other suitable element to carry the support element 610 relative to the skull and another part of the patient's body. In one embodiment, the fastener 614 is a mesh, such as a biocompatible polymer mesh, a metal mesh, or other suitable woven material. The fastener 614 can also be a flexible sheet of Mylar, a polyester, or other suitable material.

Figure 7, more specifically, is a sectional view of the stimulation device 600 after it has been implanted in a patient. Stimulation device 600 is implanted into the patient by forming an opening in the scalp 702 and making a hole 704 through the scalp 700 and dura 706. The hole 704 should be sized to receive the housing 612 of the support element 610 and in most applications, the hole 704 should be smaller than the fixation element 614. A physician inserts the support element 610 into the hole 704 and then secures the fixation element 604 to the skull 700. The fixation element 614 can be secured to the skull using a plurality of fixation devices 618 (eg, screws, nails, etc.) or an adhesive. In an alternative embodiment, a plurality of downward nails that form one piece with fastener 614 may be used to define anchors that can be driven into the skull.

The embodiment of the stimulation device 600 shown in FIG. 7 is configured to be implanted in a patient such that the electrodes 660 are in contact with a desired part of the brain in the stimulation zone. Housing 612 and electrodes 660 may protrude from fixture 614 a distance "D" so that electrodes 660 are positioned at least close to mother pia 708 surrounding cortex 709. Electrodes 660 may protrude from a housing 612 as shown in Figure 7, or electrodes 660 may be flush with the interior surface of housing 612. In the particular embodiment shown in Figure 7, housing 612 has a thickness "T" and the electrodes 660 protrude from the housing 612 a distance "T" so that the electrodes 660 compress the surface of the stem 708. The thickness of housing 612 can be approximately 0.5-4 cm and generally 1-2 cm. The configuration of the stimulation device 600 is not limited to the embodiment shown in Figures 6 and 7 but rather the housing 612, fixture 614, and electrodes 660 can be configured to position the electrodes in several different regions of the brain. For example, in an alternative embodiment, housing 612 and electrodes 660 may be configured to position the electrodes deep within the cortex 709, and / or in a deep region of the brain 710. In general, the electrodes may be at the same level as the housing or extend 0.1 mm to 5 cm protruding from the housing. More specific embodiments of pulse system electrode configurations for the stimulation device will now be described.

Various embodiments of stimulation device 600 are expected to be more effective than existing transcranial magnetic stimulation devices and transcranial electrical stimulation devices. It will be appreciated that much of the energy required for transcranial therapies is dissipated in the scalp and skull before reaching the brain. Contrary to conventional transcranial stimulation devices, stimulation device 600 is implanted so that the electrodes are at least close to the surface of the pia mater of the brain 708. Various embodiments of the methods described herein may utilize stimulation device 600 to deliver electrical therapy directly to pia mater 708, dura 706, and / or other part of cortex 709 at significantly lower power levels than therapies. existing transcranial. For example, a potential of about 1 mV to 10 V can be applied to electrodes 660; in many cases from 100 mV to 5 V to the 660 electrodes for certain applications. It will also be appreciated that other potentials can be applied to the electrodes 660 of the stimulation device 600 according to other methods described herein.

Certain certain embodiments of stimulation device 600 can also apply stimulation to a precise area of ​​stimulation. Also in this case, because the stimulation device 600 positions the electrodes 660 at least close to the surface of the pia mater 708, precise levels of stimulation with good fidelity will be accurately transmitted to the stimulation zone of the brain. form of impulse. It will be appreciated that transcranial therapies may not be able to apply stimulation to a precise area of ​​stimulation.

ES 2 274 014 T3 because the magnetic and electrical properties of the scalp and skull can vary from one patient to another so that an identical stimulation using the transcranial device can produce a different level of stimulation in the neurons in each patient. Furthermore, the ability to focus the stimulation in a precise area is impeded by the transmission of the stimulation through the skull because the scalp, the skull and the dura diffuse the energy from a transcranial device. Various embodiments of stimulation device 600 overcome this drawback in that electrodes 660 are positioned under skull 700 so that impulses generated by stimulation device 600 do not diffuse through scalp 702 and skull 700.

2. Integrated Impulse Systems for Implantable Stimulation Devices

The pulse system 630 shown in Figures 6 and 7 generates and / or transmits electrical impulses to electrodes 660 to create an electric field in a stimulation zone of a brain region. The particular embodiment of the pulse system 630 shown in Figure 7 is an "integrated" unit that rests on the support element 610. Pulse system 630, for example, can be housed within housing 612 so that electrodes 660 can be connected directly to pulse system 630 without conductors within stimulation device 600. The distance between electrodes 660 and pulse system 630 can be less than 4 cm and is generally 0.10 to 2.0 cm. Stimulation device 600 can therefore provide electrical impulses to the stimulation site without having to surgically create tunnels through the patient to connect electrodes 660 to a pulse generator implanted remote from stimulation device 600. It will be appreciated, however, that alternative embodiments of the stimulation device may include an implanted pulse system separate from the stimulation device 600 in the skull or in an external pulse system. Several particular pulse system embodiments that can be used with stimulation device 600 will now be described in more detail.

Figures 8 and 9 schematically illustrate an integrated pulse system 800 for implantation in the skull within stimulation device 600. Referring to Figure 8, pulse system 800 may include a power supply 810, an integrated controller 820, a pulse generator 830 and a pulse transmitter 840. Power source 810 may be a primary battery, such as a rechargeable battery or other suitable device for storing electrical energy. In alternative embodiments, the power source 810 may be an RF transducer or a magnetic transducer that receives energy emitted from an external power source and converts the emitted energy into power for the electrical components of the pulse system 800. The integrated controller 820 can be a wireless device that responds to command signals sent by an external controller 850. The integrated controller 820, for example, can communicate with the external controller 850 by RF or magnetic links 860. The integrated controller 820 provides control signals to the pulse generator 830 in response to command signals sent by the external controller 850. The Pulse generator 830 may have a plurality of channels that send suitable electrical pulses to pulse transmitter 840, which is coupled with electrodes 660. It is well known to any person skilled in the art of implantable medical devices which components are suitable for the power supply 810, the integrated controller 820, the pulse generator 830, and the pulse transmitter 840.

Referring to FIG. 9, pulse system 800 may rest on support member 610 of stimulation device 600 in the manner previously described with reference to FIGS. 6 and 7. External controller 850 may be located externally with respect to FIGS. patient 500 so that external controller 850 can be used to control pulse system 800. In one embodiment, multiple patients in need of a common treatment can be treated simultaneously using a single external controller 850, placing the patients within the working environment of the controller 850. In an alternative embodiment, the external controller 850 may contain a plurality of codes. The embedded controller 824 for a particular patient may have an individual operational code. A single controller 850 can therefore be used to treat a plurality of different patients by entering the appropriate opcode in the controller 850 corresponding to the particular opcodes of the integrated controllers 820 for the patients.

Figure 10 is a schematic view illustrating a pulse system 1000 and an external controller 1010 that is used with the stimulation device 600. The external controller 1010 comprises a power supply 1020, a controller 1022 coupled to the power supply 1020 and a user interface 1024 coupled to the controller 1022. The external controller 1010 may also comprise a pulse generator 1030 coupled with the power supply 1020, a pulse transmitter 1040 coupled with the pulse generator 1030, and an antenna 1042 coupled with the pulse transmitter 1040. The external controller 1010 generates the signal. power and pulse signal and antenna 1042 transmits a pulse signal 1044 to pulse system 1000 in stimulation device 600. Pulse system 1000 receives pulse signal 1044 and sends an electrical pulse to the electrodes. Pulse system 1000 therefore does not necessarily comprise an integrated power supply, controller, and pulse generator within housing 610 as the components are located in external controller 1010.

FIG. 11 is a schematic view illustrating an embodiment of pulse system 1000 in more detail. In this embodiment, the pulse system 1001 rests on the support member 610 of the stimulation device 600. The pulse system 1000 may include an antenna 1060 and a pulse emitting system 10 coupled to the antenna 1060. The antenna 1060 receives the pulse signal 1044 from the external controller 1010 and is sent by the pulse emission system 1070, which transforms the pulse signal 1044 into electrical pulses. By getting14

ES 2 274 014 T3 te, the electrodes 660 may be coupled with the pulse emitter system 1070. The pulse emitter system 1070 may include a filter to remove noise from the pulse signal 1044 and a pulse shaper that creates an electrical pulse from pulse signal 1044. The pulse shaper may be powered by the energy of the pulse signal 1044 or, in an alternative embodiment, the pulse system 1000 may also include an integrated power supply to drive the pulse shaper.

Figure 12 is a schematic view illustrating one embodiment of pulse system 1200 that is used in one embodiment of stimulation device 600, and an external controller 1210 to control pulse system 1200 away from the patient using RF energy. In this embodiment, the external controller 1210 includes a power supply 1220, a controller 1222 coupled with the power supply 1220, and a pulse generator 1230 coupled with the controller 1222. The external controller 1210 may also include a modulator 1232 coupled with the pulse generator 1230 and an RF generator 1234 coupled with the modulator 1232. When operating, the external controller 1210 outputs pulses of RF energy through an antenna 1242.

Impulse system 1200 can be housed within stimulation device 600 (not shown). In one embodiment, pulse system 1200 includes an antenna 1260 and a pulse emission system 1270. Antenna 1260 incorporates a diode (not shown), which rectifies the RF energy emitted from antenna 1242. The pulse emission system 1270 may include a filter 1272 and a pulse shaper 1274 that shapes the electrical pulses that correspond to the RF energy emitted from the antenna 1242. The pulse system 1200 therefore receives the RF energy in the signal. pulse system from external controller 1210 so pulse system 1200 does not need a separate power supply in pacing device 600.

Figure 13 is a sectional view of a pulse system 1300 that is used in another embodiment of implantable stimulation device 600 in conjunction with an external controller 1310 to remotely control pulse system 1300 from outside the patient using magnetic energy. In this embodiment, the external controller 1310 includes a power supply 1320 includes a power supply 1320, a controller 1322, coupled to the power supply 1320, and a user interface 1324 coupled to the controller 1322. External controller 1310 may also include a pulse generator 1350 coupled to controller 1332, a pulse transmitter 1340 coupled to pulse generator 1330, and a magnetic coupler 1350 coupled to pulse transmitter 1340. Magnetic coupler 1350 may include a ferrite core 1352 and a coil 1354 wound around the ferrite core 1352. Coil 1354 may also be electrically connected to pulse transmitter 1340 so that electrical pulses applied to coil 1354 generate changes in a corresponding magnetic field. The magnetic coupler 1350 may also include a flexible cap 1356 to position the magnetic coupler 1350 over the implanted stimulation device 600.

The pulse system 1300 may include a ferrite core 1360 and a coil 1362 wound around a portion of the ferrite core 1360. The pulse system 1310 may also include a pulse emitter system 1370 comprising a rectifier and a coil former. impulses. When the ferrite core 1360 and coil 1362 are operating they convert the changes in the magnetic field generated by the magnetic coupler 1350 into electrical pulses that are sent to the pulsing system 1370. Electrodes 660 are coupled with pulse delivery system 1370 so that electrical pulses corresponding to electrical pulses generated by pulse generator 1330 in external controller 1310 are delivered to the stimulation zone on the patient.

3. Electrode configurations

Figures 14-24 illustrate electrodes that can be used with the stimulation device described herein. Figures 14-22 illustrate embodiments of electrodes configured to apply an electrical current to a stimulation zone at least close to the surface of the pia mater of the cortex, and Figures 23 and 24 illustrate embodiments of electrodes configured to apply a current. electrical inside or below the crust. Clearly, other electrode configurations can be used with other implantable stimulation devices.

Figure 14 is a bottom plan view and Figure 15 a sectional view of a stimulation device 1400. The stimulation device 1400 includes a first electrode 1410 and a second electrode 1420 that concentrically surrounds the first electrode 1410. The first Electrode 1410 may be coupled to the positive terminal of a pulse generator 1430, and the second electrode 1420 may be coupled to the negative terminal of a pulse generator 1430. Referring to FIG. 15, the first and second electrodes 1410 and 1420 generate a toroidal electric field 1440.

Figure 16 is a bottom plan view and Figure 17 a sectional view of a stimulation device 1600. The stimulation device 1600 includes a first electrode 1610, a second electrode 1620 surrounding the first electrode 1610, and a third electrode. 1630 surrounding the second electrode 1620. The first electrode 1610 may be coupled to the negative terminals of a first pulse generator 1640 and a second pulse generator 1642; the second electrode 1620 may be coupled to the positive terminal of the first pulse generator 1640; and the third electrode 1630 may be coupled to the positive terminal of the second pulse generator 1642. During operation, the first electrode 1610 and the third electrode 1630 generate a first toroidal electric field 1650, and the first electrode 1610 and the second electrode 1620 generate a second field.

ES 2 274 014 T3 toroidal electrical field 1660. The second toroidal electrical field 1660 can be manipulated to vary the depth that the first toroidal electrical field 1650 projects from the base of the stimulation device 1600.

Figure 18 is a bottom plan view and Figure 19 a sectional view of a stimulation device 1800. The stimulation device 1800 includes a first electrode 1810 and a second electrode 1820 separate from the first electrode 1810. The first and the second electrodes 1810 and 1820 are linear electrodes that are coupled to opposite terminals of a pulse generator 1830. With reference to Figure 19, the first and second electrodes 1810 and 1820 can generate a more or less linear electric field.

Figure 20 is a bottom plan view of a stimulation device 2000. The stimulation device 2000 includes a first electrode 2010, a second electrode 2020, a third electrode 2030, and a fourth electrode 2040. The first and second electrodes 2010 and 2020 are coupled with a first pulse generator 2050, and the third and fourth electrodes 2030 and 2040 are coupled with a second pulse generator 2060. More specifically, the first electrode 2010 is coupled with the positive terminal and the second electrode 2020 is coupled with the negative terminal of the first pulse generator 2050, and the third electrode 2030 is coupled with the positive terminal and the fourth electrode 2040 is coupled with the negative termination of the second pulse generator 2060. The first and second electrodes 2010 and 2020 are expected to generate a first electric field 2070 and the third and fourth electrodes 2030 and 2040 generate a second electric field 2072. It can be seen that the ions will have relative freedom to move around the brain so that a certain number of ions will pass between the first and second electric fields 2070 and 2072, as shown by arrows 2074. This embodiment provides the control of electric field gradients in the stimulation zones.

Figure 21 is a bottom plan view of another embodiment of the stimulation device 2000. In this embodiment, the first electrode 2010 is coupled to the positive terminal and the second electrode 2020 is coupled to the negative terminal of the first pulse generator 2050. In In contrast to the embodiment shown in FIG. 20, the third electrode 2030 is coupled to the negative terminal and the fourth 2040 to the positive terminal of the second pulse generator 2070. This arrangement of electrodes is expected to result in a plurality of electric fields between the electrodes. This allows the direction or orientation of the electric field to be controlled.

Figure 22 is a bottom plan view schematically illustrating a stimulation device 2200. The stimulation device 2200 includes a first electrode 2210, a second electrode 2220, a third electrode 2230, and a fourth electrode 2240. The electrodes are coupled to a pulse generator 2242 via a switching circuit 2250. The switching circuit 2250 may include a first switch 2252 coupled with the first electrode 2210, a second switch 2254 coupled with the second electrode 2220, a third switch 2256 coupled with the third electrode 2230, and a fourth switch 2258 coupled with the fourth electrode 2240 During operation, switches 2252-2258 can be open and closed to establish various electric fields between electrodes 2210-2240. For example, first switch 2252 and fourth switch 2258 may be closed in coordination with a pulse from pulse generator 2242 to generate a first electric field 2260 and / or second switch 2254 and third switch 2256 may be closed in coordination. with another pulse from pulse generator 2242, to generate a second electric field 2270. The first and second electric fields 2260 and 2270 can be generated in the same pulse to produce simultaneous fields or alternate pulses to produce alternate or rotating fields.

Figure 23 is a bottom plan view and Figure 24 is a side view of a stimulation device 2300. The stimulation device 2300 has a first electrode 2310, a second electrode 2320, a third electrode 2330, and a fourth electrode 2340. Electrodes 2310-2340 may be configured in any of the arrangements described above with reference to Figures 14-22. Electrodes 2310-2340 also include electrically conductive pins 2350 and / or 2360. Pins 2350 and 2360 may be configured to pass below the surface of the cortex pia mater. For example, because the length of pin 2350 is less than the thickness of cortex 709, the tip of pin 2350 will therefore conduct electrical impulses to a stimulation zone within cortex 709 below the surface of the skin. pious mother. The length of the pin 2360 is greater than the thickness of the cortex 709 to conduct the electrical impulses to a part of the brain below the cortex 709 as a deep region of the brain 710. The lengths of the pins are chosen to conduct the electrical impulses to stimulation zones below the pia mater 709. The lengths of pins 2350 and 2360 may be the same for each electrode or different for individual electrodes. Furthermore, only a certain part of the electrodes and pins can have an uncovered conductive zone. For example, electrodes 2310-2340 and a portion of pins 2350 and 2360 can be covered with a dielectric material so that the only exposed conductive material is at the tips of the pins. It will also be appreciated that the electrode configurations set forth in Figures 14-22 can be adapted to apply electrical current to areas of stimulation below the pia mater using pin-type electrodes similar to the electrodes shown in Figures 23 and 24.

Various embodiments of the stimulation device described above with reference to Figures 6-24 are expected to be more effective than existing transcranial or subcranial stimulation devices. In addition to placing the electrodes below the skull, many embodiments of the stimulation device described above also accurately focus electrical energy in the desired shape relative to the pia mater 708, dura 706, and / or cortex 709. It will be seen that transcranial devices may not accurately focus energy because the electrodes or other types of energy emitters are placed relatively far from the

ES 2 274 014 T3 stimulation areas and the skull diffuses part of the energy. Likewise, existing subcranial devices often simply place the electrodes near a specific nerve, but do not provide electrode configurations that generate an electric field according to a model designed for the area of ​​stimulation. Several of the embodiments of the stimulation device described above with reference to Figures 6-24 overcome this drawback as the electrodes can be positioned against neurons in the desired stimulation zone. In addition, the electrode configurations of the stimulation device can be configured to provide a desired electrical field not diffused through the skull 700. Therefore, various embodiments of the stimulation device according to the invention are expected to be more efficient as they precisely focus the energy in the stimulation zone.

Four. Implantable stimulation device with deflection elements

Figures 25-30 illustrate various stimulation device embodiments having a biasing element. The stimulation device shown in Figures 25-30 may be similar to those described above with reference to Figures 6-24. Accordingly, the embodiments of the stimulation device shown in the 2530 may have the same pulse systems, support elements, and electrode configurations described above with reference to Figures 6-24.

Figure 25 is an isometric view and Figure 26 a sectional view of a stimulation device 2500. The stimulation device 2500 includes a support member 2510, a pulse system 2530 that rests on the support member 2510 and a first and a second electrode 2650 coupled to pulse system 2530. Support member 2510 may be identical or similar to support member 610 described above with reference to Figures 6 and 10. Support element 2510 may therefore include a housing 2512 configured to be implanted in skull 700 and a fixation element 2514 configured to connect to skull 700 via fasteners 2518 (Figure 2), an adhesive, and / or an anchor. . The pulse system 2530 can be identical or similar to any of the pulse systems described above with reference to Figures 6-13 and the first and second electrodes 2560 can have any of the electrode configurations discussed above, with reference to the above. Figures 14-24. However, unlike the stimulation device described above, stimulation device 2500 includes a deflection element 2500 coupled to electrodes 2560 to mechanically deflect electrodes 2560 from support element 2510. In an alternative embodiment, deflection element 2550 can be positioned between housing 2512 and fixture 2514 and electrodes 2560 can be attached directly to housing 2512. As explained in more detail below, the deflection element 2550 may be a compressible element, a fluid-filled chamber, a spring, or any other suitable element that flexibly and / or elastically separates the electrodes 2560 from the support element. 2512.

Figure 26 illustrates an embodiment of stimulation device 2500 that has been implanted in the skull 700 of a patient. If the fasteners 2518 have been attached to the skull 700, the deflection member 2550 should be slightly compressed so that the electrodes 2560 are in contact with the stimulation site. In the embodiment shown in FIG. 26, the compressed biasing element 2550 gently compresses the electrodes 2560 against the surface of the stem 708. The deflection element 2550 is expected to provide uniform and consistent contact between the electrodes 2560 and the pia mater surface of the cortex 709. The stimulation device 2500 is expected to be particularly useful when the implantable device is secured to the skull and the zone of stimulation is in the pia mater 708 or the dura mater 706. It can be difficult to position the contacts against the pia mother 708 as the distance between the skull 700, the dura 706 and the pia mother 708 varies within the skull as the brain moves relative to the skull and also because the depth varies from patient to patient. other. The stimulation device 2500 with the deflection element 2550 compensates for the different distances between the skull 700 and the pia mater 708 so that a single type of device can accommodate several different patients. In addition, stimulation device 2500 with deflection element 2550 adapts to changes as the brain moves within the skull. In contrast to stimulation device 2500 with deflection element 2550, an implantable device that does not have a deflection element 2550 may not be tailored to a particular patient or consistently provide electrical contact with the pia mater.

Figures 27 and 28 are sectional views of the stimulation device where the deflection elements are compressible elements. Figure 27, more specifically, illustrates a stimulation device 2700 having a deflection element 2750. The stimulation device 2700 may have an integrated pulse system 2530 and electrodes 2560 coupled to the pulse system 2530 in a manner similar to the device. stimulation 2500. Diverter element 2750 in this embodiment is a compressible foam, such as a closed or open cell biocompatible foam. As best seen in FIG. 27, the deflection element 2750 is compressed when the stimulation device 22700 is secured to the skull. Figure 28 illustrates a stimulation device 2800 having a deflection element 2850. Diverter element 2850 can be a compressible solid such as silicone rubber or other suitable compressible materials. Electrodes 2560 are attached to deflection element 2850.

Figure 29 is a sectional view of a stimulation device 2900 having a deflection element 2950. The stimulation device 2900 may have a support element 2910 comprising an inner lumen 2912 and a diaphragm 2914. The deflection element 2950 It may include a flexible chamber 2952 attached to support member 2910 and electrodes 2560 may be attached to flexible chamber 2952. During operation, flexible chamber 2952 is filled with fluid 2954 until electrodes 2560 compress the stimulation zone. In a

In an embodiment, the flexible chamber 2952 is filled by inserting the needle of a syringe 2956 through the diaphragm 2914 and injecting the fluid 2954 into the lumen 2912 and the flexible chamber.

Figure 30 is a sectional view of a stimulation device 3000 having a biasing element 3050 is a spring and the electrodes 2560 are attached to the spring. Biasing element 3050 can be a wave spring, flexible leaf spring, or any other suitable spring that can mechanically bias electrodes 2560 against the stimulation zone.

Although various embodiments of the stimulation device shown in Figures 25-30 may have a deflection element and some of the pulse systems described above with respect to Figures 6-13, it is not necessary to have a pulse system contained within the element. of support. Accordingly, some implantable stimulation device embodiments may have a pulse system and / or a biasing element in any combination of the embodiments described above with respect to Figures 6-30.

5. Implantable stimulation device with external impulse systems

Figures 31-35 are schematic sectional views of various embodiments of implantable stimulation device with external pulse system. Figure 31, more specifically, illustrates an embodiment of a stimulation device 3100 having a deflection element 3150 in which a plurality of electrodes 3160 have been attached in a manner similar to the stimulation device described above with reference to Figures 25- 30. It will be seen that the stimulation device 3100 may not include the deflection element 3150. The stimulation device 3100 may also include an external receptacle 3120 having an electrical plug 3122 and an implanted lead line 3124 coupled with the electrodes 3160 and contacts. (not shown) in plug 3122. Lead line 3124 may be implanted in a subcutaneous tunnel in another passageway in a manner known to one of ordinary skill in the art.

The stimulation device 3100 does not, however, have an internal pulse system that rests on the part of the device implanted in the skull 700 of the patient 500. The stimulation device 3100 receives electrical impulses from an external pulse system 3130. The pulse system External 3130 may have an electrical connector 3132 with a plurality of contacts 3134 configured to insert the contacts into receptacle 3120. The external pulse system 3130 may have a power source, controller, pulse generator, and pulse transmitter to generate the electrical pulses. During operation, external pulse system 3130 sends electrical pulses to stimulation device 3100 through connector 3132, receptacle 3120, and lead line 3124.

Figures 32 and 33 illustrate an embodiment of a stimulation device 3200 that is used with an external pulse system. Referring to FIG. 33, stimulation device 3200 may include a support structure 3210 having a socket 3212, a plurality of contacts 3214 disposed on socket 3212, and a diaphragm 3216 covering socket 3212. Stimulation device 3200 may also include a deflection element 3250 and a plurality of electrodes 3260 attached to deflection element 3250. Each electrode 3260 is directly coupled to one of the contacts 3214 within the support structure 3210. It will be seen that An alternate embodiment of stimulation device 3200 does not include deflection element 3250.

Referring to Figures 32 and 33 together, stimulation device 3200 receives electrical pulses from an external pulse system 3230 that has a power source, a controller, a pulse generator, and a pulse transmitter. The external pulse system 3230 may also comprise a plug 3232 having a needle 3233 (Figure 33) and a plurality of contacts 3234 (Figure 33) disposed on the needle 3233 to contact the internal contacts 3214 of the socket 3212. During In operation, needle 3233 is inserted into socket 3212 to mate contacts 3234 with contacts 3214 and then pulse system 3230 is activated to transmit electrical pulses to electrodes 3260.

Figures 34 and 35 illustrate additional embodiments of stimulation devices that are used with external pulse systems. Figure 34 illustrates one embodiment of a stimulation device 3400 having electrodes 3410 coupled to a connection line 3420 that extends below the skull 702 of patient 500. The connection line 3420 is coupled to an external pulse system 3450. Figure 35 illustrates an embodiment of a stimulation device 3500 having a support member 3510, electrodes 3512 engaged with support member 3510, and an outer socket 3520 mounted on skull 702. The outer socket 3520 may also be connected to the support member 3510. The outer receptacle 3520 may have a socket 3522 that comes into electrical contact (not shown) with the electrodes 3512. The stimulation device 3500 can be used with the external pulse system 3130 described above with reference to Figure 31 by inserting the plug 3132 into the socket 3522 until the contacts 3134 of the plug 3132 engage the contacts within the socket. socket 3522.

6. Alternative implantable stimulation device embodiments

Figure 36 is a schematic sectional view of an implantable stimulation device 3600 in accordance with one embodiment of the invention. In one embodiment, stimulation device 3600 has a support structure 3610 and a plurality of electrodes 3620 coupled to support structure 3610. Support structure 3610

ES 2 274 014 T3 can be configured to implant beneath the skull 700 between an inner surface 701 of the skull 700 and the pia mater surface of the brain. Support structure 3610 can be a flexible or compressible body such that electrodes 3620 contact the pia mater 708 when stimulation device 3600 is implanted under skull 700. In other embodiments, the support structure 3610 may position the electrodes 3620 so that they are close to the stem 708 without touching it.

In one embodiment, the stimulation device 3610 may receive electrical impulses from an external controller 3630. For example, the external controller 3630 may be electrically coupled to the stimulation device 3600 via a connecting line 3632 that passes through a hole 711. in the skull 700. In an alternative embodiment, stimulation device 3600 may include an integrated pulse system similar to the pulse systems described above with reference to Figures 6-13. This embodiment of the stimulation device 3600 can therefore utilize a wireless external control unit. It can be appreciated that the electrodes 3620 of the stimulation device 3600 may have several of the electrode configurations previously described with reference to Figures 14-24.

Figures 37 and 38 illustrate one embodiment of implantable stimulation device 3600. Referring to Figure 37, support structure 3610 may be a flexible substrate and electrodes 3620 may be conductive events printed on the flexible substrate. The stimulation device 3600, for example, can be manufactured to be similar to flexible printed circuitry used in electrical components. Stimulation device 3600 can be implanted under skull 700 using insertion tool 3700. In one embodiment, insertion tool 3700 has handle 3702 and shaft 3704 protruding from handle 3702. Shaft 3704 can have slot 3706 configured to receive a flat portion of support member 3610. Referring to Figure 38, support member 3610 is wrapped around shaft 3704 and then stimulation device 3600 is brought into tube 3720 disposed in hole 711 through scalp 700 and dura 706. Once the Stimulation device 3600 has passed through tube 3720, it is deployed to place electrodes 3620 at least close to the pia mater 708. The 3620 electrodes can be coupled to an external controller using the 3632 connection lines.

Figure 39 illustrates another embodiment of an implantable stimulation device 3900, also configured to be positioned between the skull 700 and the pia mater 708. In one embodiment, the stimulation device 3900 may include a support member 3910 and a plurality of electrodes 3920. coupled to support member 3910. Electrodes 3920 can be coupled to individual connection lines 3922 to connect electrodes 3920 with an external pulse system. In an alternative embodiment, the integrated pulse system 3930 can be rested on the support member 3910 so that the electrodes 3920 can be directly coupled to the integrated pulse system 3930 without the need for external connection lines 3922. The support member 3910 can be an elastically compressible element, an inflatable device such as a balloon or an incompressible, practically solid body. In the particular embodiment shown in Figure 39, the support element 3910 is an inflatable device in the shape of a balloon that carries the electrodes 3920. During operation, the stimulation device 3900 is implanted by passing the distal end of the support element 3910 through hole 711 in skull 700 until electrodes 3920 are positioned in a desired stimulation zone.

Figure 40 is a schematic illustration of a stimulation device 4000 in conjunction with an internal pulse system 4030 in accordance with another embodiment of the invention. Stimulation device 4000 may include a support member 4010, a bias member 4015 that rests on support member 4010, and a plurality of electrodes 4020 carried by bias member 4015. The internal pulse system 4030 may be similar to any of the integrated pulse systems described above with reference to Figures 6-13, although the internal pulse system 4030 is not an integrated pulse system as it is not carried by the housing 4010. The internal pulse system 4030 can be coupled with the electrodes 4020 via a cable 4034. In a typical application, lead 4034 is implanted subcutaneously in a tunnel from a subclavicular region, along the back of the neck, and around the skull. Stimulation device 4000 may also include any of the electrode configurations described above with reference to Figures 14-24.

The foregoing makes it possible to see that specific embodiments of the invention have been described for purposes of illustration, although various modifications can be made without departing from the scope of the invention. Therefore, the invention is limited only by the appended claims.