ULTRASOUND NEUROMODULATION FOR CLINICAL EFFECTS

Disclosed are methods and systems and methods for non-invasive neuromodulation using ultrasound to treat Traumatic Brain Injury including Concussion, Compulsive Sexual Behavior (sometimes called Compulsive Sexual Disorder), meningitis, and also provide for the elicitation of emotional catharsis. The neuromodulation can produce acute or long-term effects. The latter occur through Long-Term Depression (LTD) and Long-Term Potentiation (LTP) via training Included is control of direction of the energy emission, intensity, frequency, pulse duration, pulse pattern, and phase/intensity relationships to targeting and accomplishing up regulation and/or down regulation. Use of ultrasound neuromodulation in sessions can enhance the effects.

DETAILED DESCRIPTION OF THE INVENTION

It is the purpose of this invention to provide methods and systems and methods for neuromodulation of deep-brain targets using ultrasound to treat Traumatic Brain Injury including concussion, Compulsive Sexual Behavior (sometimes called Compulsive Sexual Disorder), and also provide for the elicitation of emotional catharsis. In addition, effectiveness of the treatment can be enhanced by the application of the ultrasound neuromodulation in sessions and also the use of stimulation patterns. Most applications will not be amenable to continuous neuromodulation.

With respect to delivery of ultrasound neuromodulation in sessions, examples of session types include periodic sessions over extended time typically means a single session of length on the order of 15 to 60 minutes repeated daily or five days per week over one to six weeks. Other lengths of session or number of weeks of neuromodulation are applicable, such as session lengths up to 2.5 hours and number of weeks ranging from one to eight. Period sessions over compressed time typically means a single session of length on the order of 30 to 60 minutes repeated during awake hours with inter-session times of 15 minutes to 60 minutes over one to three days. Other inter-session times such as 15 minutes to three hours and days of compressed therapy such as one to five days are applicable. Maintenance consists of periodic sessions at fixed intervals or on as-needed maintenance tune-ups. Maintenance categories are maintenance post-completion of original treatment at fixed intervals and maintenance post-completion of original treatment with as-needed maintenance tune-ups. An example of the former are with one or more 50-minutes sessions during week 2 of months four and eight, and of the latter is one or more 50-minute sessions during week 7 because a tune up is needed at that time as indicated by return of symptoms. Use of sessions is important for the retraining of neural pathways for change of function, maintenance of function, or restoration of function. Retraining over time, with its ongoing reinforcement, can allow more effectively achievement of desired impacts. Another consideration is the desirability for practical reasons to limit tying up the time of the patient depending on the individual situation. Such neuromodulation systems can produce applicable acute or long-term effects. The latter occur through Long-Term Depression (LTD) or Long-Term Potentiation (LTP) via training Included is control of direction of the energy emission, intensity, frequency (carrier frequency and/or neuromodulation frequency), pulse duration, pulse pattern, and phase/intensity relationships to targeting and accomplishing up-regulation and/or down-regulation.

The stimulation frequency for inhibition is lower than 500 Hz (depending on condition and patient). The stimulation frequency for excitation is in the range of 500 Hz to 5 MHz. In this invention, the ultrasound acoustic frequency is in range of 0.3 MHz to 0.8 MHz with power generally applied less than 60 mW/cm2but also at higher target- or patient-specific levels at which no tissue damage is caused. The acoustic frequency is modulated at the lower rate to impact the neuronal structures as desired (e.g., say typically 300 Hz for inhibition (down-regulation) or 1 kHz for excitation (up-regulation). The modulation frequency (superimposed on the carrier frequency of say 0.5 MHz or similar) may be divided into pulses 0.1 to 20 msec. repeated at frequencies of 2 Hz or lower for down regulation and higher than 2 Hz for up regulation although this will be both patient and condition specific. Ultrasound therapy can be combined with therapy using other devices (e.g., Transcranial Magnetic Stimulation (TMS)).

The lower bound of the size of the spot at the point of focus will depend on the ultrasonic frequency, the higher the frequency, the smaller the spot. Ultrasound-based neuromodulation operates preferentially at low frequencies relative to say imaging applications so there is less resolution. Keramos-Etalon can supply a 1-inch diameter ultrasound transducer and a focal length of 2 inches that with 0.4 Mhz excitation will deliver a focused spot with a diameter (6 dB) of 0.29 inches. Typically, the spot size will be in the range of 0.1 inch to 0.6 inch depending on the specific indication and patient. A larger spot can be obtained with a 1-inch diameter ultrasound transducer with a focal length of 3.5″ which at 0.4 MHz excitation will deliver a focused spot with a diameter (6 dB) of 0.51.″ Even though the target is relatively superficial, the transducer can be moved back in the holder to allow a longer focal length. Other embodiments are applicable as well, including different transducer diameters, different frequencies, and different focal lengths. Other ultrasound transducer manufacturers are Blatek and Imasonic. In an alternative embodiment, focus can be deemphasized or eliminated with a smaller ultrasound transducer diameter with a shorter longitudinal dimension, if desired, as well. Ultrasound conduction medium will be required to fill the space.

FIG. 1shows a diagram of exemplar session types for both initial treatment and maintenance sessions.FIG. 1Aillustrates example100, Periodic Over Extended Time with 4 weeks of treatment where time divisions are weeks102divided into days104with 50-minute sessions on indicated days106. For all of these examples, the session length could be longer or shorter than 50 minutes.FIG. 1Billustrates example110, Periodic Over Extended Time with 6 weeks of treatment where time divisions are weeks112divided into days114with 50-minute sessions on indicated days116.FIG. 1Cillustrates example120, Periodic Over Compressed Time with 3 days of treatment where time divisions are weeks122divided into days124with 50-minute sessions on indicated days166.FIG. 1Dillustrates example130, Maintenance Post Completion of Original Treatment at Fixed Intervals where time divisions are months132divided into weeks134with 50-minute sessions during indicated weeks136.FIG. 1Eillustrates example140, Maintenance Post Completion of Original Treatment with As-Needed Maintenance Tune-Ups where time divisions are months142divided into weeks144with 50-minute sessions during indicated week146.

FIG. 2shows an embodiment of a control circuit. The positioning and emission characteristics of transducer array270are controlled by control system210with control input with neuromodulation characteristics determined by settings of intensity220, frequency230, pulse duration240, firing pattern250, and phase/intensity relationships260for beam steering and focusing on neural targets.

FIG. 3shows a set of ultrasound transducers targeting to treat Traumatic Brain Injury. Head300contains two targets, Orbital-Frontal Cortex (OFC)320and Occipital Lobe350, both of which are to be up regulated. The Orbito-Frontal Cortex in this context represents itself and other regions of the Frontal Lobe. While two targets are involved here, others might work as well, or an addition or substitution of other targets. The targets shown are hit by ultrasound from transducers325(in carrier330) and355(in carrier360) fixed to track305. Ultrasound transducer325with its beam335is shown targeting Orbito-Frontal Cortex (OFC)320and transducer355with its beam365is shown targeting Occipital Lobe350. For ultrasound to be effectively transmitted to and through the skull and to brain targets, coupling must be put into place. Ultrasound transmission (for example Dermasol from California Medical Innovations) medium310is interposed with one mechanical interface to the frame305and ultrasound transducers325and355(completed by a layers of ultrasound transmission gel layers340and370respectively) and the other mechanical interface to the head300(completed by a layers of ultrasound transmission gel345and375respectively). In another embodiment the ultrasound transmission gel is placed around the entire frame and entire head. In another embodiment, multiple ultrasound transducers whose beams intersect at that target replace an individual ultrasound transducer for that target. In still another embodiment, mechanical perturbations are applied radially or axially to move the ultrasound transducers.

FIG. 4shows a set of ultrasound transducers targeting to treat concussion. Head400contains five targets, Orbital-Frontal Cortex (OFC)420, Temporal Lobe430, Fornix440, Thalamus450, and Hypothalamus460, all of which are to be up regulated. The Orbito-Frontal Cortex in this context represents itself and other regions of the Frontal Lobe. While five targets are involved here, others might work as well, or an addition or substitution of other targets (e.g., midbrain, Reticular Activating System, brainstem, and corpus callosum) identified currently or in the future. The targets shown are hit by ultrasound from transducers422,432,442,452, and462fixed to track405. Ultrasound transducer422with its beam424is shown targeting Orbito-Frontal Cortex (OFC)420, transducer432with its beam434is shown targeting Temporal Lobe430, transducer442with its beam444is shown targeting Fornix440, transducer452with its beam454is shown targeting Thalamus450, and transducer462with its beam462is shown targeting Hypothalamus460. For ultrasound to be effectively transmitted to and through the skull and to brain targets, coupling must be put into place. Ultrasound transmission (for example Dermasol from California Medical Innovations) medium408is interposed with one mechanical interface to the frame205and ultrasound transducers422,432,442,452and462(completed by a layer of ultrasound transmission gel layer410) and the other mechanical interface to the head400(completed by a layer of ultrasound transmission gel412). In another embodiment the ultrasound transmission gel is only placed at the particular places where the ultrasonic beams from the transducers are located rather than around the entire frame and entire head. In another embodiment, multiple ultrasound transducers whose beams intersect at that target replace an individual ultrasound transducer for that target. In still another embodiment, mechanical perturbations are applied radially or axially to move the ultrasound transducers.

Transducer array assemblies of this type may be supplied to custom specifications by Imasonic in France (e.g., large 2D High Intensity Focused Ultrasound (HIFU) hemispheric array transducer) (Fleury G., Berriet, R., Le Baron, O., and B. Huguenin, “New piezocomposite transducers for therapeutic ultrasound,” 2ndInternational Symposium on Therapeutic Ultrasound—Seattle—Jul. 31-Aug. 2, 2002), typically with numbers of ultrasound transducers of 300 or more. Keramos-Etalon in the U.S. is another custom-transducer supplier. The power applied will determine whether the ultrasound is high intensity or low intensity (or medium intensity) and because the ultrasound transducers are custom, any mechanical or electrical changes can be made, if and as required. At least one configuration available from Imasonic (the HIFU linear phased array transducer) has a center hole for the positioning of an imaging probe. Keramos-Etalon also supplies such configurations.

FIG. 5shows ultrasonic-transducer targeting of the Medial Prefrontal Cortex, Nucleus Accumbens, Hypothalamus, and Ventral Tegmental Area for the treatment of Compulsive Sexual Behavior. A potential additional target is the Amygdala (not shown). Head100contains four targets, Medial Prefrontal Cortex520, Hypothalamus530, VTA (Ventral Tegmental Area)540, and Nucleus Accumbens550, all of which are to be down regulated. While four targets are involved here, others (e.g., Amygdala) might work as well, or an addition or substitution for other targets. The targets shown are hit by ultrasound from transducers525,535,545, and555fixed to track505. Ultrasound transducer525with its ultrasound beam527is shown targeting Medial Prefrontal Cortex520, ultrasound transducer535with its beam537is shown targeting Hypothalamus530, ultrasound transducer545with its beam547is shown targeting VTA540, and transducer555with its beam557is shown targeting Nucleus Accumbens550. For ultrasound to be effectively transmitted to and through the skull and to brain targets, coupling must be put into place. Ultrasound transmission (for example Dermasol from California Medical Innovations) medium508is interposed with one mechanical interface to the frame505and ultrasound transducers525,535,545, and555(completed by a layers of ultrasound transmission gel layers528,538,548,558respectively) and the other mechanical interface to the head500(completed by a layers of ultrasound transmission gel529,539,549, and559respectively). In another embodiment the ultrasound transmission gel is placed around the entire frame and entire head. In another embodiment, multiple ultrasound transducers whose beams intersect at that target replace an individual ultrasound transducer for that target. In still another embodiment, mechanical perturbations are applied radially or axially to move the ultrasound transducers.

FIG. 6shows a set of ultrasound transducers targeting to generate an emotional catharsis. Head600contains two targets, Hippocampus620, and Amygdala640. Both are typically up regulated. Note that while these two targets are covered here, one might work as well, or an addition or substitution of other targets (e.g., thalamus, sub-thalamic nuclei, and basal ganglia) identified currently or in the future. These targets are hit by ultrasound from transducers627and647fixed to track605. Ultrasound transducer627with its beam629is shown targeting hippocampus620, and transducer647with its beam649is shown targeting amygdala640. Bilateral stimulation of one of a plurality of these targets is another embodiment. The Pre-Frontal Cortex (PFC) is potentially another target.

In another embodiment, a feedback mechanism is applied such as functional Magnetic Resonance Imaging (fMRI), Positive Emission Tomography (PET) imaging, video-electroencephalogram (V-EEG), acoustic monitoring, thermal monitoring, and patient feedback.

In still other embodiments, other energy sources are used in combination with or substituted for ultrasound transducers that are selected from the group consisting of Transcranial Magnetic Stimulation (TMS), deep-brain stimulation (DBS), optogenetics application, radiosurgery, Radio-Frequency (RF) therapy, behavioral therapy, and medications.

The invention allows stimulation adjustments in variables such as, but not limited to, direction of the energy emission, intensity, frequency (carrier frequency and/or neuromodulation frequency), pulse duration, pulse pattern, and phase/intensity relationships to targeting and accomplishing up-regulation and/or down-regulation, dynamic sweeps, and position.

The various embodiments described above are provided by way of illustration only and should not be construed to limit the invention. Based on the above discussion and illustrations, those skilled in the art will readily recognize that various modifications and changes may be made to the present invention without strictly following the exemplary embodiments and applications illustrated and described herein. Such modifications and changes do not depart from the true spirit and scope of the present invention.