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Tinnitus is a debilitating hearing condition that causes the constant misperception of sound, including hissing, ringing and rushing noises that can considerably impact overall health and quality of life. Research shows Pycnogenol® is effective in relieving tinnitus symptoms and improving inner ear blood flow. In a study conducted by the Chieti-Pescara University in Italy and published in Panminerva Medica, 82 patients with mild-to-moderate tinnitus in only one ear, while the other remains unaffected, were studied throughout a four-week period.
Horphag Research supplies Pycnogenol® as a raw material to companies that produce a variety of Pycnogenol®-containing products. Kaneko, Megumi et al., Intrathecally Administered Gabapentin Inhibits Formalin-Evoked Nociception and the Expression of Fos-Like Immunoreactivity in the Spinal Cord of the Rat, J. FIELD OF THE INVENTIONThis invention relates to a method for treating severe tinnitus.BACKGROUND OF THE INVENTIONTinnitus is the perception of ringing, hissing, or other sounds in the ears or head when no external sound is present.
Some important reasons for these circumstances are the stigma of wearing hearing aids, an unsatisfactory solution in contrast to the marketing promises of the prescribed device, the quality of fitting in artificial conditions rather than in real soundscapes, and the price.
The environment of the sound-protected fitting room in which a technician generally fits a hearing aid often is not relevant to actual soundscapes in which the patient experiences communication problems. Programming at the remote location can be accomplished by means of a variety of hardware and software combinations, such as the special hand-held device in Figure 3 or a commercially available personal digital assistant, such as the lornada 680 from Hewlett Packard (Hewlett Packard, Palo Alto, CA, USA).
At the remote location, the patient receives the hearing aids and undergoes a first hearing test, to measure the achieved benefit and to determine whether a fine tuning by telecommunication is required. One advantage of the on-line telecommunication concept is that a highly experienced hearing aid technician is available to remote centers without restrictions of time and location.
Such a system makes possible the initial fitting, setup, fine tuning, and after-care fitting of all types of digitally programmable and digital hearing aids. We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. In recent years, there has been a significant increase in the use of electroencephalography (EEG) and magnetoencephalography (MEG) to investigate changes in oscillatory brain activity associated with tinnitus with many conflicting results.
The precise neural mechanism of subjective tinnitus generation is unknown but it is a symptom of many pathologies.
In human beings, several clinical and psychoacoustic observations suggest that while damage to the auditory periphery can trigger tinnitus, it is not by itself sufficient to sustain it, and that tinnitus has neural correlates in the brain (8). But how can these techniques be best applied to tinnitus research, what are their limitations, and how easy is it to misinterpret the results?
With regard to the animal models of tinnitus, the applicability of results from animal studies to human beings is limited, partly because of the restricted spatial sampling and partly because of the difficulties in assessing the presence of tinnitus and associated distress in laboratory animals. It is not within the remit of the current discussion to review the various putative mechanisms of central tinnitus generation as these have been discussed at length elsewhere (13–15).
Within the structures of central auditory system, different types of abnormal activity have been identified, mainly based on animal studies. The basic theoretical assertion of the various network models is that altered activity in the central auditory pathways is insufficient to give rise to phantom percepts such as pain and tinnitus. MEG and EEG are extremely sensitive to miniscule changes in the magnetic fields and electrical potentials, respectively, which are produced by changes in the electrical activity within the brain.
There are two main types of neuroelectric events associated with the activity of neurons in the brain: the action potential and the postsynaptic potential.
Despite their many similarities, EEG and MEG have certain important differences, which have been discussed extensively elsewhere (37–39). Each pyramidal neuronal column behaves as an electrical dipole; however, not all active brain regions produce detectable scalp fields and potentials. Electroencephalography is more sensitive to signals arising from sub-cortical structures while MEG is most sensitive to the superficial cortical sources (37, 45). Another difference is that MEG is sensitive to mainly tangential sources while EEG can detect both tangential and radial sources. This theoretical insensitivity of MEG to radial sources requires further clarification because this is not strictly true in practice.
The differential sensitivity of MEG and EEG to source orientation has important practical implications that could underlie some of the observed discrepancies between studies, not only in tinnitus but in other areas of brain research.
Modern MEG devices can be equipped with different sensor configurations, which have different sensitivities and noise-cancelation properties. A final common pathway for tinnitus is hypothesized to exist for all patients with tinnitus. Its function is the transition of the sensory to the affect component of the symptom of tinnitus. Single Photo Emission Computerized Tomography (SPECT) with the radio isotope TC99-HMPAO has identifie side to side perfusion asymmetries highlighted by that of the amygdala - hippocampal complex. It is hypothesized that a fundamental function of the amygdala - hippocampal structures is the establishment of a paradoxical auditory memory for tinnitus. A Final Common Pathway (FCP) is hypothesized to exist for all patients with tinnitus, particularly of the severe disabling type (SIT). Historically, this search for understanding how the transition from sensory to affect occurs in the brain is not new.
The concept of William James, the Father of American Psychology is suggested to find application to a FCP for tinnitus. Single Photon Emission Computerized Tomography (SPECT) with the radioi sotope Tc-99 HMPAO is a detection method which provides information of cerebral perfusion in brain.
Based on clinical experience with tinnitus particularly of the severe disabling type and supported by SPECT imaging of the brain, the medial temporal lobe system is speculated to be a key site of action of processing of an aberrant auditory signal resulting in a paradoxical auditory memory; and an accompanying parallel transition in processing of the sensory to the affect component of the symptom of tinnitus. In other words, the eterogeneity of the symptom of tinnitus is reflected in FCP for tinnitus.
The FCP is presented as a hypothesis focusing on a process within the MTLS of a paradoxical auditory memory with speculations as to its clinical applications for both diagnosis and treatment.
It is hypothesized that for all sensory systems the sensory and affect components are linked by memory.2 The experience of the sensation is a perceptual image of the stimulus. Psychology and neuroscience evidence have differentiated between long term and short term memory. The modulator of the sensory component is considered to be the efferent system and the process of masking.3 The modulator of the afferent component is considered to be stress.
In the patient with tinnitus, particularly of the severe disabling type it is hypothesized that both the hippocampus and amygdala of the MTLS are significant for the transition of the sensory to the affect component. In summary, the FCP model for tinnitus involving the medial temporal lobe system is initiated in the MTLS by the process of establishment of a paradoxical memory. Our approach is clinical and attempts to identify not all components of the FCP but rather to focus on one aspect, specifically memory which is considered at present to be clinically most significant; and is explainable by what has been reported for understanding brain function specifically memory.
The activity in the brain that corresponds to memory can be found in the medial temporal lobe system. Crick's comments on the problem of visual awareness I believe can be applied to that of tinnitus - an auditory perceptual phenomenon.6,31 Specifically, investigations for tinnitus are necessary from a psychological and a neuro-science perspective for the issues of attention and very short term memory. The MTLS can be considered an information processing pathway for the integration of sensory and affect components of all sensory inputs. The perception of a auditory image, considered to be "normal", is hypothesized to be determined by a normal masking function. It has become apparent to us from our clinical experience with SPECT since 1989, that the manner in which the brain processes auditory sensory information is radically different with or without the presence of tinnitus.
The consequences of the identification of a FCP for tinnitus and the role of the MTLS are considered significant. The following SPECT images of the brain demonstrate multiple perfusion asymmetries, highlighted by the MTLS (Fig. The FCP for tinnitus provides a rationale and model for understanding the integration, interaction, translation, and transformation of the sensory auditory signal to the affect behavioral response. An initial process, in the MTLS, is hypothesized to be the establishment of a paradoxical auditory memory for tinnitus.
SPECT imaging of brain provides an ability to identify regions of interest in the brain which demonstrate perfusion asymmetries frequently found in patients with tinnitus of the severe disabling type. The processes involved in the establishment of the symptom of tinnitus particularly of the severe disabling type and the problems encountered, relate to the overall problem and question over centuries of what is the relationship of mind and brain and what are the processes involved in such identification.
Horphag Research does not make any claims regarding the use of these finished products and each manufacturer is responsible for ensuring that the claims made for and use of its products comply with the regulatory requirement of the locations in which it markets its products. The method of the present invention comprises implanting a catheter into a patient and administering a drug formulation or fluid comprising a therapeutic agent intrathecally into the patient's cerebrospinal fluid.
The method of claim 1, wherein the solvent comprises an effective amount of NaCl to make the drug formulation isotonic. The method of claim 1, wherein the drug formulation is substantially free of preservatives. The method of claim 1, wherein the at least one therapeutic agent comprises a GABAB agonist.
The method of claim 10, wherein the infusing baclofen comprises a daily dose between 20 and 2000 mcg. The method of claim 10, wherein the infusing baclofen comprises a daily dose between 50 and 1500 mcg.
The method of claim 10, wherein the infusing baclofen comprises a daily dose between 100 and 1000 mcg. The method of claim 1, wherein the at least one therapeutic agent comprises a thyrotropin-releasing hormone. The method of claim 1, wherein the at least one therapeutic agent comprises sodium valproate. The method of claim 1, wherein the at least one therapeutic agent comprises a GABAA agonist. The method of claim 1, wherein the distal end of the catheter is placed in subarachnoid space between fifth thoracic and first cervical vertebrae. The method of claim 1, wherein the distal end of the catheter is placed in subarachnoid space between fifth lumbar and fifth thoracic vertebrae.
The method of claim 26, wherein the gabapentin delivered comprises a daily dose between 1 and 200 mg.
The method of claim 26, wherein the gabapentin delivered comprises a daily dose between 1 and 150 mg. The method of claim 26, wherein the gabapentin delivered comprises a daily dose between 2 and 60 mg.
The method of claim 26, wherein the distal end of the catheter is placed in the subarachnoid space between fifth thoracic and first cervical vertebrae.
The method of claim 26, wherein the distal end of the catheter is placed in the subarachnoid space between fifth lumbar and fifth thoracic vertebrae. The method of claim 35, wherein the solvent comprises an effective amount of NaCl to make the drug formulation isotonic.
The method of claim 39, wherein the distal end of the catheter is placed in the subarachnoid space between fifth thoracic and first cervical vertebrae. The method of claim 39, wherein the distal end of the catheter is placed in the subarachnoid space between fifth lumbar and fifth thoracic vertebrae. The method of claim 42, wherein the solvent comprises an effective amount of NaCl to make the drug formulation isotonic. The method of claim 46, wherein the distal end of the catheter is placed in the subarachnoid space between fifth thoracic and first cervical vertebrae. The method of claim 46, wherein the distal end of the catheter is placed in the subarachnoid space between fifth lumbar and fifth thoracic vertebrae. The method of claim 49, wherein the solvent comprises an effective amount of NaCl to make the drug formulation isotonic. Method for treating tinnitus, the method comprising of: intrathecally administering drug formulation comprising at least one therapeutic agent and a solvent in an amount effective to treat tinnitus. The term telematics, a compound of the words telecommunication and informatics, means (in general) electronic transfer of digital data. Hans-Peter Zenner of Tubingen, Germany (personal communication, 2000), approximately 20% of all Germans complain of a hearing loss, and only 20% of this group could be rehabilitated by an operation.
On-line telecommunication can be used to address these medical, audiological, technical, and financial issues and to integrate the ear, nose, and throat (ENT) doctor in the on-line fitting concept.
This situation can be improved by on-line telecommunication, employing the audiological and technical competence of a highly experienced hearing aid technician in cooperation with an ENT doctor (Fig.
Principal method of on-line telecommunication between a hearing aid technician and an ear, nose, and throat doctor.
In the ensuing days or weeks, further fine adjustments of the hearing aid parameters are made, and a follow-up fitting may be performed on the basis of the feedback obtained on a patient questionnaire and the results of hearing tests.
The hearing aid technician is trained in the latest technical developments and programming procedures. Against a backdrop of limited resources and continuous innovations, telemedicine offers an opportunity to increase the efficiency of audiological methods and decrease expenses simultaneously. This means that you will not need to remember your user name and password in the future and you will be able to login with the account you choose to sync, with the click of a button. This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. Current view of the underlying mechanism of tinnitus is that it results from changes in brain activity in various structures of the brain as a consequence of sensory deprivation. A general conception is that damage to the auditory periphery (mainly the cochlea) results in functional modifications of the central auditory system. Furthermore, neuroimaging studies such as functional magnetic resonance imaging (fMRI) have revealed abnormalities at various stages of the classical auditory pathway, including the inferior colliculus (9) and the auditory cortex (10, 11). What is the advantage of these techniques for tinnitus research compared to animal studies or other neuroimaging techniques such as fMRI?
It is generally believed that deafferentation due to hearing-loss triggers a chain of neural events that lead to hyperactivity and the tinnitus sensation (14). For tinnitus to be consciously perceived, auditory activity requires integration with activity from the global awareness or attentional network (24) involving frontal and parietal areas. Neural activation generates an electric current, which corresponds to the electric potentials in case of EEG, and magnetic fields in case of MEG, measured outside the head with an array of electrodes. Pyramidal cells are elongated structures possessing an apical dendrite while stellate cells are more rounded with dendrites that are equally spread around the cell body. Synchronous sources produce much larger signals than asynchronous sources and optimal signal summation occurs for PSPs with zero time lag (33). The signal measured on the scalp is the spatial average of potentials produced by the underlying neuronal concentration.
EEG is sensitive to dipoles oriented in any direction but is more sensitive to the radially oriented dipole when both radial and tangential dipoles are present (33).
When using a spherically symmetric volume conductor to model the intracranial source of a magnetic field, only the tangential sources are measurable because theoretically, in a perfectly symmetrical volume conductor radially oriented sources do not produce externally measureable magnetic fields (37, 46). MEG measures magnetic fields that arise from the intracellular or extracellular currents depending on the orientation of the measurement coils relative to the head.
MEG detection probability maps of entire brain for one person by Hillebrand and Barnes (47). Potentially, this problem is accentuated for studies of the relatively small auditory cortex, which is often convoluted, with high inter-individual anatomical heterogeneity (49).
Because MEG is sensitive to magnetic fields, participants are required to be free from metal components that perturb the tiny signals from the brain, including belts or dental braces. Adjacent perfusion asymmetries involving the frontal, temporal and parietal lobes suggest a interneuronal network resulting in the transition of the sensory to the affect components of the symptom of tinnitus. Descartes regarded the mind as something immaterial, separate from brain but interacting with it in some manner. Fear and stress in tinnitus patients particularly of the severe disabling type are a result of a paradoxical auditory memory of an aberrant dysynchronous auditory signal. The establishment of a paradoxical auditory memory for tinnitus is hypothesized to be the initial process localized in the medial temporal lobe. Demonstrations of SPECT imaging of rain in patients are presented to support this hypothesis.
The heterogeneity of response both for sensory and affect has been reported by professionals of all disciplines who are involved in tinnitus diagnosis and attempts for its control.
The Papez circuit proposed the anatomical basis of emotion to consist of the cingulate gyrus which connects with the parahippocampal gyrus and peripheral area of the temporal lobe. The anatomical components are best seen by a saggital section of the medial surface of the brain; and ventral views of the base of brain. Non-declarative memory, also called implicit memory, includes all abilities which are unconscious and expressed through performance.16 Such abilities provide for cumulative changes in perceptual and response systems of new skills and habits, priming, simple classical conditioning, and non-associative learning. Its chieffunction is the transition of a aberrant dysynchronous auditory sensory signal to a affective behavioral response (Fig. This conceptualization is a basic tenet of the FCP for tinnitus of the cochleovestibular system. The sensory and affect components are considered to be in a constant state of reciprocal interaction.
For memory, alterations occur in the hippocampal formation with the establishment of a paradoxical memory for an aberrant dysynchronous signal.

I consider the experimental and theoretical work of consciousness as reflected in memory, to be a starting point to explain our SPECT findings to date. Neurobiological theories of tinnitus awareness need to be developed and tested using a combination of molecular, neurobiological and clinical imaging studies.
It is possible that there is a localization in the MTLS for all sensory inputs similar to that which exists in the motor cortex.
Specifically, the anatomic substrate where integration of sensory and affect components occurs for the auditory system, is suggested at this time to be in the MTLS. Interference in masking within brain, initially at brain stem is hypothesized to set in motion a cascade of events wherein the sensory component is overwhelmed by that of the affect due to the establishment of a paradoxical auditory memory. Hinton et al.35 have described such neuronal networking in investigations simulating brain damage. For the first time, here is a model which may differentiate tinnitus between its sensory and affect components both from its clinical and basic science perspectives. Jacobson L, Sapolsky R: The role of the hippocampus in feedback regulation of the hippothalamic - pituitary - adrenal cortex axis.
LeDoux JE: Information flow from sensation to emotion plasticity in the neural computation of stimulus value.
Eggermont, “Effects of salicylate on neural activity in cat primary auditory cortex.” Hearing Research, 1996, pp. We describe an application of telemedicine in the field of audiology: the initial fitting, setup, fine tuning, and follow-up fitting of all kinds of digital programmable and digital signal-processing devices and the fitting of hearing aids in real soundscapes.
Such technologies as telephone, fax, and e-mail already are being used to communicate with hearing-impaired persons, as are more sophisticated forms of telecommunication, such as interactive video and remote-control audiometry. Another advantage is that this concept affords the ENT doctor who is responsible for the rehabilitation of patients with hearing loss an opportunity to understand and address the individual needs of patients in cooperation with the hearing aid technician. According to this thalamo-cortical dysrhythmia (TCD) model, tinnitus is due to a disruption of activity between thalamus and cortex initiated by neural deafferentation, due to hearing loss, which causes inhibition of thalamic neurons.
The model hypothesizes that under normal circumstances hyperactivity in auditory pathways is canceled out at the level of the thalamus by an inhibitory feedback loop (noise-cancelation system) originating in the ventromedial pre-frontal cortex and the nucleus accumbens. Moreover, the neural mechanisms associated with the tinnitus percept are distinct from those responsible for tinnitus-related distress, which requires the activation of the distress network (24).
On the other hand, the postsynaptic potentials (PSPs) have longer time courses lasting for several tens, or even hundreds, of milliseconds with a peak value of ~10 mV (25), which facilitates summation of synchronized activity from adjacent neurons.
Here, I will briefly describe those differences that may become important when interpreting and comparing the results between studies that employ MEG and EEG.
However, because the EEG signal is highly dependent on volume conduction, the signals are smeared as they pass through the surrounding tissue and the poorly conductive skull. If the axis of the coil is perpendicular to the head such that it measures only the radial component of the extracranial magnetic field, the measured magnetic field will be just the intracellular currents. Overall, MEG and EEG provide complementary information with complementary SNR depending on the orientation and depth of the signal of interest and therefore it is beneficial to combine MEG and EEG where possible (45). Importantly for hearing research, participants with cochlear implants cannot be tested and hearing aids must be removed.
A simple magnetometer is a single loop of wire, which detects the magnetic field perpendicular to the surface of the coil, and is sensitive not only to nearby signals but also those from distant sources. Localization of brain action is now possible and is being investigated with both Positron Emission Tomography (PET) and Single Photon Emission Computer Tomography (SPECT) brain imaging. The transition is acknowledged to be complex, involving an integration of multiple neuronal networks within the brain. The underlying mechanism is that of dysynchronization, that is, a lack of synchrony or interference in timing of the discharge rate and phase locking of the auditory signal having a location peripheral, central or both.
To date 48 patients were selected for SPECT imaging of the brain identified with the MATPP to have severe disabling tinnitus of the central type.
The clinical application of this hypothesis for present and future tinnitus diagnosis and treatment is conside d significant.
It includes the subcallosal, cingulate, and parahippocampal gyri, the hippocampal formation, and the dentate gyrus. The temporal lobe connects with the hippocampus (AMMONS horn) via the temporoammonic tract.
The entorhinal cortex is a major source of projections at the hippocampus and in turn receives input from adjacent perirhinal, parahippocampal cortices. Final Common Pathway for Tinnitus - The Medial Temporal Lobe System (Presentation at the Charles Univ. It is hypothesized based on our tinnitus experience that in the normal auditory system a sequence of auditory images, results first in establishment of an auditory memory for a sensory input, both short and long term; and secondarily a positive affective behavioral response.
It is possible that there may be further or additional localization for a particular sensation. Feldmann reported the difference in interaction of signal and masker in patients with and without tinnitus by masking curves.
SPECT findings at this time suggest a common neural pathway and not an abstract algorithmic description.
The FCP is a biological model which is an outgrowth of our ongoing attempts to integrate the basic sciences with our clinical experience for the diagnosis and treatment of all types and subtypes of tinnitus. Presented at the Fourth International Seminar Inner Ear Medicine and Surgery, July 1994, Snowmass, Colorado.
Observations of simultaneous auditory brainstem responses with monaural stimulation in the tinnitus patient. On the Functional State of Central Vestibular Structures in Monaural Symptomatic Tinnitus Patients.
Not only are these results significant for the improvement of inner ear blood micro-circulation and, consequently reduction of tinnitus symptoms, but they also indicate the potentially dose-related effect of Pycnogenol® on the condition.
According to the American Tinnitus Association, over 50 million Americans experience tinnitus to some degree and of these, approximately 12 million people have tinnitus to a distressing degree.Approximately 2 million Americans have tinnitus to the point where they are so seriously debilitated that they cannot function on a “normal” day-to-day basis and some may commit suicide. Against a backdrop oflimited resources and continuous innovations, telemedicine offers the possibility of increasing the efficiency of audiological methods and decreasing expenses at the same time. Of these, however, fewer than 25% have yet received hearing aids, and a number of those who have hearing aids do not use them. In addition, especially over the last 15 years, hearing devices have evolved from behind-the-ear, in-the-ear, inthe- canal, and semi-implantable or implantable hearing systems and their supportive technology through analog to digital devices. The figure shows the principal method of implementing the on-line telecommunication procedure. An additional benefit of this application of on-line telecommunication via the hand-held device shown in Figure 3 is that the wearer can be supported in the fine adjustment of the hearing aid in real soundscapes (Figs. Subsequently, numerous animal studies have provided support for this hypothesis, reporting changes in neural activity within structures of the central auditory system (2–7). This dynamic activity is recorded with millisecond temporal resolution so that precise information about the timing of neural events can be obtained in human beings. Human brain imaging can reflect these neural events at the macroscopic level, and therefore the findings in neuroimaging studies of tinnitus in human beings is commonly interpreted as resulting from hyperactivity, or increased neural synchrony (17). This in turn leads to changes in oscillatory activity at the cortical level and large-scale slow-wave and gamma activity in the neighboring cortical regions. These structures are part of a circuit in the subcallosal ventral striatum, which identify the presence of unwanted neural activity (in this case tinnitus). Bothersome tinnitus is thus continuously associated with aversive emotional states, involving abnormal input from structures of the limbic system, including the amygdala and the insula. Nunez (34) has estimated that in order to obtain amplitude of a scalp EEG signal, the synchronous activity of neurons within a 1 cm2 cortical surface is required.
It thus follows that a reduction in amplitude is a desynchronization of current sources (36), which in theory, occur as a result of either reduction in source magnitude or reduction in the activated surface area (33). The EEG measures the difference in voltage, or potential, between two electrode sites across the scalp one of which is placed at an electrically silent location to act as a reference point. The SNR of deep sources for EEG was larger compared to MEG, whereas for superficial sources, SNR was higher for MEG.
But if the axis of the measurement coil is tilted relative to the head, it measures the tangential component of the magnetic field, which will reflect both the intracellular and the extracellular current flows. Moreover, because recording devises are not attached to the scalp, head movement must be kept to a minimum as this can cause large discrepancies in source localization.
Underlying mechanisms are hypothesized to exist and to be highlighted by a diminution of inhibition mediated by gamma aminobutyric acid (GABA) due to disconnection from excitatory (glutamate) inputs. It is considered to transcend the classica thinking of tinnitus as an auditory signal restricted to the auditory pathway. The limbic system is a term used to include the limbic lobe and associated subcortical nuclei (amygdaloid complex, septal nuclei, hypothalamus, epithalamus and other thalamic nuclei). The frontal, temporal, parietal lobes project to the perirhinal, parahippocampal cortices from unimodal and polymodal areas. A paradoxical memory modulates the transition between the sensory and behavioral component of tinnitus. It is speculated that for tinnitus the amygdala is significant for the alteration in emotional behavior described by the patient. It is speculated that the primary auditory cortex projects to the hippocampus and amygdaloid complex.
The masking curves "can be thought of as contour lines of the neural elements involved in processing signal and masker."34 Tinnitus is believed to produce or reflect a instability or interruption in auditory masking function. The future is to identify neural networks and to create idealized computer simulates of groups of neurons. For auditory perception this includes the inner ear and Organ of Corti; transmission within the ascending auditory system to registration of impulses within the auditory cortex. McGeer, “Age Changes in the Human for Some Enzymes Associated with Metabolism of the Catecholamines, GABA and Acetycholine.” Neurobiology of Aging, 1975, pp. The latter typically have a digital control section, which stores the auditory parameters, and a signal-processing section, which may be analog in the digital programmable hearing aids or digital in the digital signal-processing devices.
In the upper left portion of the figure is depicted the building housing the computer center in which the hearing aid technician is working. However, both MEG and EEG have their limitations and research results can be misinterpreted without appropriate consideration of these limitations. Therefore, fundamental to the concept of subjective tinnitus is the idea that the central nervous system is involved in the perception of the sound and the associated emotional and psychological symptoms. Since then there has been a range of studies using both MEG and electroencephalography (EEG) to investigate oscillatory changes in tinnitus compared to non-tinnitus controls to gain a better understanding of the central mechanism of this disorder [see Adjamian et al.
The unwanted neural activity is fed back to the reticular nucleus of the thalamus, which removes the signal from input to the auditory cortex. Accordingly, this may partly explain why many people with hearing loss and concomitant increase in activity in auditory pathways do not develop tinnitus.
The changes in the resting potential are due to the exchange of ions between the inside and outside of the neuron, which causes current flows both in the extracellular and the intracellular space, through the volume conductor (27). The problem with reference points is that no electrode site is completely electrically silent (37).
Therefore, EEG is more likely to measure activity of sub-cortical structures, however, it should be noted that detecting a signal is not the same as its accurate localization. In practice, the coils are perpendicular to the head and thus measure the intracellular currents, but with the multi-channel systems, many of the channels are tilted relative to the head.
One way to suppress this noise is to use gradiometers (51), which consist of a compensation coil wound in opposite direction to the magnetometer and thus the homogenous part of the field is canceled out. Blockage of GABA mediated inhibition results in Tinnitogenesis, a epileptiform auditory phenomena. The clinical manifestations of the affective behavior of the tinnitus patient can be considered to be components of the FCP for tinnitus. Physiologic evidence suggests functional differences between the various components although most are related to visceral or behavioral activities (Fig. The mamillary body connects with the anterior nucleus of the thalamus via the mamillothalamic tract. Severe memory impairment associated with hippocampal and amygdala lesions were attributed not to the addition of the amygdala to the hippocampal lesion but instead to the addition of cortical regions that lie adjacent to the amygdala and that are necessarily damaged when the amygdala is removed or impaired.
This sequence of events is hypothesized to exist in general for other sensory systems and specifically for the cocheovestibular system. The central efferent system at a cortical and subcortical level at brainstem is speculated to control the masking capability of the auditory system.
Hence, increasingly often the hearing devices are programmed on-line in a sound-protected fitting room using a computer and interface (Fig.
At the next step in the process, the hearing aid technician calculates the auditory parameters of the particular patient's hearing deficiency and programs the hearing aids. In this article, I intend to provide a brief review of these techniques, describe what the recorded signals reflect in terms of the underlying neural activity, and their strengths and limitations. The recorded oscillatory activity conveys neuronal processing that can be used to measure effective and functional connectivity between disparate brain regions to examine network models of tinnitus. Support from this model has come from analysis of structural images of the brain (20–22) but overall the anatomical studies provide scant support for the gating mechanism (23) and functional imaging studies are even less convincing. The extracellular currents (also known as secondary or volume currents) spread through the brain, pass through the tissues, and the skull, producing voltage potentials that vary in amplitude over the scalp and are measurable with EEG electrodes.
On the other hand, pyramidal cells have asymmetrical dendrites in parallel to each other and therefore generate dipole-like potentials, which could be recorded at a distance. Therefore, absolute power and phase of scalp EEG signal in a given frequency band is ambiguous because the results are strongly influenced by the activity at the reference electrode (40). Localization of deep sources with EEG is complicated due to the afore-mentioned uncertainties in the forward solution. Hillebrand and Barnes (47) estimated the detection probability of MEG across the entire brain that is visible to MEG sensors and showed that MEG is not completely insensitive to radially oriented sources. Note that the probability of detecting signal sources decreases with depth [adapted from Hillebrand and Barnes (47)]. As distant sources produce more homogenous fields than nearby sources, for a gradiometer sensitivity to nearby sources is greater (52). In the future, as the clinical experience of multiple disciplines increases for the symptom of tinnitus, it is predicted that additional components will be identified.
The anterior nucleus of the thalamus connects with the cingulate gyrus via the superior thalamic peduncle, thus completing the circuit. The entorhinal cortex was suggested to be the principle route by which information from the neocortex reaches the hippocampus.
Other aberrant sensations experienced by patients include hyperacusis, dysacusis, vertigo, etc. For tinnitus such abilities may reflect cumulative changes in perceptual and response systems and for the development of new skills and habits personified by increasing attention to tinnitus and inability to "cope" with tinnitus.
The reciprocal projections between the entorhinal cortex, hippocampus and amygdala result in an emotional response.
The degree of inhibition regulated by GABA function is hypothesized to be reflected in the degree of development of the paradoxical memory for tinnitus. Kassirer stated it well in discussing a visual image in clinical medicine that "often we are creating mental models of physical models. The patient's hearing aid is remotely connected via a communication medium, in this case a telephone cable. I also discuss some pertinent methodological issues involved in tinnitus-related studies and conclude with suggestions to minimize possible discrepancies between results.
The magnetic field is generated by both the extracellular volume currents and intracellular currents (also known as primary currents) (28, 29).
The surface distribution of currents is also somewhat distorted as the conductivity and the thickness of the skull is non-uniform. They found that only 5% of the whole cortical surface is within 15° of radial sources and that it is source depth, rather than orientation, that compromises the sensitivity of MEG to activity in the brain.
Therefore, the gradiometer behaves like a spatial high-pass filter that measures the gradient of the magnetic field instead of the magnetic field itself, accentuating signals from sources near the detection system, while minimizing the contribution from stronger distant sources. Additional feeding pathways to the circuit were described to include the septal and olfactory regions and amygdala.
Increasing attention and a probable relationship to sleep phenomena also is considered to be a reflection or projection from the amygdala to sleep areas in cortex. The overall message is that while MEG and EEG are extremely useful techniques, the interpretation of results from tinnitus studies requires much caution given the individual variability in oscillatory activity and the limits of these techniques. In general, auditory research with fMRI presents significant challenges as the MR scanner generates an acoustic sound exceeding 100 dBA.
Thus estimating the strength and distribution of the signal at the EEG sensors on the scalp (forward solution) is more complex (41) and the estimation of signal sources (inverse solution) is less precise (42).
Higher order gradiometer devices can be obtained by increasing the number of opposite-wound coils. The reciprocal interconnections between primary and secondary associated auditory cortices and vestibular cortices of the cochleovestibular system reflect multiple neuronal networks which have the capability to adapt to changes reflecting alteration in sensory input and output due to different factors influencing neuronal activity of the cochleovestibular system and other systems at a cortical and subcortical levels.
The set of auditory parameters of the individual patient can be stored in the programmable memory of the hearing aid.

In the light of recent renewed interest in application of these techniques in tinnitus research, it is important to be aware of how these techniques reflect brain function and malfunction. Therefore, both spatial and temporal summation of their activity is possible when sufficient synapses are active in relative synchrony (32). EEG potentials cannot be considered a true reflection of the brain’s electrical events, contributing an estimated 5% to the extracranial measured magnetic field only (43). The axial gradiometer configuration consists of coils along the same radial axis, while planar gradiometers consist of coils that are in the same plane, providing different spatial derivatives of the magnetic field.
Young (1991) considered for depression that the location of cortisol control to be not in the hypothalamus but rather in the hippocampus.26 It is proposed for tinnitus that a cycle can be established wherein reciprocal projections between hippocampus, amygdala, entorhinal cortex and hypothalamus vary in the degree of control of cortisol levels resulting in further strengthening of an already established paradoxical memory with resultant additional negative affect behavioral manifestations of emotion, fear, anxiety, depression, etc. In this case, a modem and a personal computer with interfaces are on both sides of the communication media at the remote location. The magnetic fields recorded by MEG, however, are significantly less distorted by the surrounding tissue, particularly within a spherically homogenous head model whereby the secondary volume currents diminish rapidly. Neuronal networks are hypothesized to exist which in the past were identified as primary and secondary areas.
Thus the magnetic field recorded outside the head reflects the intracellular primary currents and are essentially the same as what would be recorded if the brain surface were exposed (29). It is this severely affected population, which is only poorly managed with therapies available today, that may benefit from intrathecal pharmacotherapy proposed in the current investigation.In terms of population percentages, approximately 17% of the general population, and 33% of the elderly population suffer from tinnitus. A simple magnetometer measures the absolute magnitude of the magnetic field without the need for a reference point.
Because of this, the forward solution is far easier to obtain with MEG than with EEG, and hence signal source reconstruction (inverse solution) tends to be more accurate with MEG (39, 44). It is conceived that the excitatory action of the amino acid glutamate may result in more than one physiological function. It is speculated that the GABAergic inhibition and resultant glutamate excess produces a disruption in calcium homeostasis. Most of the therapies that are presently available attempt to minimize the patients' awareness of the tinnitus symptoms or reduce their emotional reaction to their condition.Rational treatment for the small proportion of patients with a reversible cause for their tinnitus involves correcting the underlying condition.
In its simplest form, masking consists of self-exposure to background noise such as, radio, television, or recorded music. People with normal hearing and severe tinnitus can wear a small hearing-aid-like device that produces background (masking) noise in the affected ear. Patients with concomitant impaired hearing and tinnitus sometimes benefit (both their hearing and tinnitus) from use of a conventional hearing aid.PsychotherapyLimbic structures of the brain may be involved in the neural plastic changes associated with tinnitus.
Supportive of this notion is the observation that the perceived amplitude of the tinnitus often does not correspond to the overall severity of the condition. For example, some patients with tinnitus of a relatively low volume are extremely disturbed, whereas others with high volume tinnitus are relatively unaffected by it. Habituation is a psychological technique that trains patients to ignore or minimize their emotional reaction to tinnitus. Habituation is traditionally defined as the disappearance of reactions to sensory stimuli because of repetitive exposure and the lack of positive or negative reinforcement. The most popular version of this therapy, tinnitus retraining therapy, has been developed and popularized by Dr.
Treatments tend to be more successful for mild and moderate forms of tinnitus and for cases of shorter duration.Psychoactive DrugsThe drugs most commonly used to manage tinnitus are antidepressants (especially tricyclics) and anxiolytics (valium, alprazolam, buspirone), although they have limited efficacy. Anxiolytics and antidepressants affect the secondary psychological sequelae of tinnitus, rather than the perception of the noise itself. The neural plasticity associated with tinnitus may involve the formation of new neural connections between the auditory and limbic systems of the brain. Most agents have been administered orally, although several clinical trials attempting to directly administer agents into the ear have also failed to show efficacy. Unlike other commonly prescribed oral medications that tend to manage only the emotional symptoms associated with tinnitus, lidocaine actually reduces or eliminates the noise.
Lidocaine ameliorates tinnitus in approximately 60-80% of sufferers, a result that has been replicated in numerous well-controlled clinical trials. The efficacy of IV lidocaine is greater than the efficacy produced by auditory nerve transection (approximately 50%), suggestive of a central mechanism of lidocaine action.
However, locally administered lidocaine (to the ear or cochlea) has been relatively ineffective. In addition, locally administered lidocaine to the ear has been associated with significant vestibular side effects such as vertigo and nausea. Tinnitus patients effectively treated with IV lidocaine in the short term, usually experience a return of their symptoms shortly after the medication has been stopped.
Intravenous lidocaine (bolus administration) has a short duration of action (10-20 minutes) and is metabolized rapidly by the liver (terminal half life of 1.5 to 2 hours in humans). Lidocaine used in the treatment of cardiac arrhythmias is typically diluted with saline, and administered as a precisely-metered IV infusion. Unfortunately in tinnitus patients with healthy heart rhythms, IV lidocaine can induce potentially life-threatening cardiac arrhythmias. If administered orally, lidocaine is ineffective due to a major first pass effect.BaclofenTinnitus is associated with abnormal spontaneous neural activity at multiple levels within the central auditory pathways.
Gamma-amino-butyric acid (GABA) is the main inhibitory neurotransmitter of the mammalian CNS. An example of a GABAB-receptor agonist is baclofen, which mimics in part the effects of GABA.Several studies have correlated age-related changes in the concentrations of GABA and GABAB-binding sites in the Inferior Colliculus (“IC”), the major auditory midbrain structure. Age-related decreases in the enzyme responsible for GABA synthesis (glutamic acid decarboxylase) have been reported in the IC of both rats and humans. Age changes in the human for some enzymes associated with metabolism of the catecholamines, GABA and acetycholine. In rats, age-related decreases in the levels of GABA and the number of GABAB-binding sites within the IC have also been reported. These biochemical findings may explain why tinnitus is more prevalent among the elderly.In addition to age-related biochemical changes, the inferior colliculus also shows changes in function (increased spontaneous activity) in response to noise exposure or injury to the peripheral auditory system, results commonly associated with tinnitus in humans.
In rats, IV baclofen inhibited noise-induced electrical potentials recorded directly from IC neurons. An additional observation suggestive of the inhibitory role of GABA in the normal auditory system comes from clinical reports of auditory hallucinations that are sometimes experienced with baclofen withdrawal in humans. The authors conducted a randomized, double-blinded study after anecdotal reports described patients who experienced beneficial subjective reduction in tinnitus while taking oral baclofen. Not all of the patients had severe tinnitus, and for some, tinnitus was not their primary complaint.
Oral baclofen therapy was associated with significant side effects that included sedation, confusion, dizziness, GI upset, and weakness, the combination of which caused 25% of the enrolled patients to drop out of the trial.These side effects are also associated with oral baclofen used to treat spasticity but are typically not a problem when baclofen is administered intrathecally to treat spasiticity. By acting at GABAA receptors, benzodiazepines act to inhibit neuronal activity and have proven to be useful in decreasing neuronal hyperactivity associated with epilepsy and anxiety.Benzodiazepines are also commonly used in anesthesiology as tranquilizers.
In addition to quelling the hyperactive neurons associated with tinnitus, these agents may offer the added benefit of decreasing anxiety, a common comorbidity associated with severe tinnitus. Two drugs in the benzodiazepine family are midazolam and alprazolam, both of which may be useful in the management of tinnitus.GabapentinGabapentin is a GABA-agonist-like drug. Because it does not bind directly to GABA receptors, it is not a true pharmacologic GABA agonist.
On the other hand, it is known that gabapentin produces inhibitory effects like GABA on selective neuronal populations and thus has been useful in treating several diseases characterized by hyperactivity of central neurons including epilepsy and neuropathic pain.
Since the pathophysiology of chronic severe tinnitus appears to be similar to neuropathic pain (plastic neural changes leading to central facilitation of synaptic transmission), many drugs that are effective for neuropathic pain may be effective for tinnitus. Indeed, reports both in animal models and humans suggest that oral gabapentin may be useful in reducing tinnitus. Because gabapentin does not readily penetrate the blood-brain barrier, intrathecal delivery should produce higher more effective concentrations of gabapentin in the CNS.Thyrotropin-releasing hormone (TRH)TRH, a peptide neurotransmitter in the CNS, has been suggested as a useful agent for treating both mood disorders and epilepsy by acting primarily to inhibit the activity of glutamine-containing neurons. Glutamine is the major excitatory neurotransmitter of the CNS and may be associated with increased activity of the central auditory neurons involved in tinnitus. The loss of GABA-containing neurons with aging, results in an increased activity of glutamine-containing neurons that may be controlled by supplying exogenous TRH.Sodium ValproateSodium valproate is another agent that is used to treat central diseases of the nervous system associated with increased neuronal activity. Clinically it is used to treat both epilepsy and as a mood stabilizer to treat bipolar disorder.
5,676,655 discloses a method for implanting a neural prosthetic drug delivery apparatus into a target zone of a patient's brain for reducing or eliminating the effects of tinnitus.
The apparatus includes a catheter that is inserted into the patient's auditory cortex or thalamus. The catheter microinfuses drugs that suppress or eliminate abnormal neural activity into geometrically separate locations of the patient's cortex or thalamus, thereby reducing or eliminating the effects of tinnitus. The patent, however, deals with drug delivery directly into brain tissue or into specific anatomical structures, i.e. There are a number of disadvantages to intraparenchymal drug delivery to treat severe tinnitus. For example, intraparenchymal drug delivery is relatively invasive and requires a highly trained neurosurgeon to implant the catheter into the brain tissue or specific anatomical structure.SUMMARY OF THE INVENTIONOne or more of the above-mentioned deficiencies in the art are satisfied by the method of the present invention of intrathecal drug delivery for the treatment of severe tinnitus. One embodiment of the invention involves the use of a drug formulation infused intrathecally to treat tinnitus.
For example, a catheter is implanted into a patient, the catheter having a proximal end and a distal end.
The distal end of the catheter is adapted to infuse the drug formulation intrathecally into a patient's cerebrospinal fluid. The drug formulation may comprise a solvent and at least one therapeutic agent such as baclofen, gabapentin, sodium valproate, a benzodiazepine such as midazolam or alprazolam, or a thyrotropin-releasing hormone.In one embodiment of the invention, the proximal end of the catheter is coupled to an implantable pump and the distal end of the catheter is inserted into the subarachnoid space of a patient's spinal column.
The implantable pump is operated to deliver a fluid that may comprise a therapeutic agent such as gabapentin, sodium valproate, or a thyrotropin-releasing hormone. 2 is a diagrammatic illustration of the location of a patient's inferior colliculus and the flow of cerebrospinal fluid in the subarachnoid space.FIG. 3 is diagrammatic illustration of a catheter implanted in a patient according to an embodiment of the present invention.FIG. 4 is a diagrammatic illustration of an implanted catheter and pump in accordance with an embodiment of the present invention.FIG. 5 is a diagrammatic illustration of a catheter implanted in a patient's subarachnoid space for the delivery of a therapeutic agent or agents into the cerebrospinal fluid.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTSAs illustrated in FIG. 1, the central auditory pathways comprise, the inferior colliculus 1, the auditory cortex 2, the dorsal acoustic stria 102, the cochlear nuclei 104, the geniculate nucleus 106, the nucleus of the lateral lemniscus 108, the superior olivary nuclei 110, and the intermediate acoustic stria 112.
Experimental evidence suggests that the dorsal cochlear nuclei 104, the inferior colliculus 1, and the auditory cortex 2, as shown in FIGS. These major auditory structures are relatively shallow brain structures that lie in close proximity to the subarachnoid space 3 as shown in FIG. 2.The inferior colliculus 1 lies on the dorsal surface of the midbrain 4 and rostral (cephalad) to the fourth ventricle 5 and dorsal to the cerebral aqueduct of Sylvius 8. The superficial surface of the inferior colliculus 1 is bathed in cerebrospinal fluid (CSF) 6 that exits the foramina of Magendie and Luschka to flow around the brainstem and cerebellum. 2 indicate cerebrospinal fluid 6 flow.The subarachnoid space 3 is a compartment within the central nervous system that contains cerebrospinal fluid 6.
The cerebrospinal fluid 6 is produced in the ventricular system of the brain and communicates freely with the subarachnoid space 3 via the foramina of Magendie and Luschka.As previously discussed in the background of the invention, available evidence suggests that tinnitus arises within the central auditory structures of the brain, and that those structures represent an important target for therapeutic agents. Given the limited efficacy of other treatments, intrathecal delivery of therapeutics into the cerebrospinal fluid 6 in accordance with the present invention offers the potential to reduce the perception of tinnitus in a large portion of severely affected patients who currently have very limited options.The therapeutic agent or agents may include baclofen, gabapentin, sodium valproate, a benzodiazepine such as midazolam or alprazolam, or a thyrotropin-releasing hormone. Each of the agents may be combined with a solvent to form a drug formulation that may be administered intrathecally to a patient. In addition, the drug formulation may comprise an effective amount of NaCl to make the drug formulation isotonic. The drug formulation may have a pH between 4 and 9 and more preferably a pH between 5 and 7. Also, the drug formulation may be substantially free of preservatives and may contain cyclodextrin acting as an excipient to increase solubility.Intrathecal delivery of therapeutics into the cerebrospinal fluid is less invasive than intraparenchymal (direct tissue) delivery of therapeutics.
In addition, intrathecal delivery of therapeutics may not require the need for a neurosurgeon as the delivery of the therapeutics does not require delivery to a direct brain target. Numerous other physicians may be qualified to insert a catheter into the lumbar subarachnoid space of the spinal column in order to initiate intrathecal therapeutic delivery.Referring to FIG. The device 30 has a port 34 into which a hypodermic needle can be inserted through the skin to inject a quantity of therapeutic agent. The therapeutic agent is delivered from device 30 through a catheter port 37 into a catheter 38.
Catheter 38 is positioned so that the distal tip 39 of catheter 38 is positioned in the subarachnoid space 3 between the fourth cervical vertebrae (C4) 52 and the seventh cervical vertebrae (C7) 54, as shown in FIG. The distal tip 39 can be placed in a multitude of locations to deliver a therapeutic agent into the cerebrospinal fluid of the patient.
In one embodiment, the distal tip 39 of catheter 38 is inserted in the subarachnoid space 3 between the fourth cervical vertebrae (C4) 52, and the seventh cervical vertebrae (C7) 54, to allow for relatively high therapeutic dose infusion concentrations in the intracranial CSF compartment near the inferior colliculus 1 while minimizing spinal exposure. In other embodiments, the distal tip 39 of the catheter 38 is inserted in the subarachnoid space 3 between the fifth thoracic (T5) 49 (FIG. 4) and the first cervical vertebrae (C1) 56, or in the subarachnoid space 3 between the fifth lumbar (L5) 48 (FIG. 3, delivery of a therapeutic agent into the CSF to treat severe tinnitus can be accomplished by simply injecting the therapeutic agent via port 34 to catheter 38.A higher concentration of baclofen delivered intrathecally into the CSF in accordance with the present invention can provide improved reduction of the perception of tinnitus in a large proportion of severely effected patients. Baclofen is a zwitterionic, hydrophilic molecule that does not readily penetrate the blood-brain barrier. The enhanced efficacy and reduced side effects associated with baclofen delivered intrathecally provides higher concentrations of baclofen in CSF than baclofen delivered orally.
For example, pharmacokinetic data shows that baclofen levels in the cisternal CSF, at the base of the brain, after lumbar intrathecal administration are approximately 20-30 times higher in the CSF than levels after oral administration to treat spasticity.
The higher concentration reduces the amount of time between pump reservoir refills whereas the lower concentrations may allow for a greater amount of volume to be delivered intrathecally. In addition, the daily dosage of baclofen to be administered may depend upon the particular treatment protocol to be administered. Unlike baclofen, which is a selective GABAB agonist, muscimol is a selective GABAA agonist that inhibits neuronal activity by activating chloride channels leading to neuronal hyperpolarization.In addition, a GABAA agonist family of therapeutics, benzodiazepines, may also be intrathecally delivered into the CSF as a therapeutic agent alone or in combination with other therapeutic agents. The benzodiazepines may be comprised of the therapeutics midazolam or alprazolam.A GABA-agonist-like drug, gabapentin, may also be administered intrathecally in the treatment of tinnitus. In addition, the daily dosage of gabapentin to be administered may depend upon the particular treatment protocol. 4, an implantable medical device known as an implantable therapeutic pump 40 is implanted into a patient.
The location of pump implantation is one in which the implantation interferes as little as practicable with patient activity, such as subcutaneous in the lower abdomen.
The proximal end 35 of a catheter 38 is connected to the implantable therapeutic pump outlet.
The catheter 38 is a flexible tube with a lumen typically running the length of the catheter 38. The distal end 33 of catheter 38 is positioned to infuse a fluid into the target area of CSF of the patient. The pumped fluid may comprise a therapeutic agent such as gabapentin, sodium valproate, or a thyrotropin-releasing hormone. In addition, the pumped fluid may comprise an effective amount of NaCl to make the drug formulation isotonic.The target area of CSF of the patient may be the subarachnoid space 3 between the fourth cervical vertebrae (C4) 52 and seventh cervical vertebrae (C7) 54, as shown in FIG. In addition, other target areas of the CSF of the patient may include the subarachnoid space 3 between the fifth thoracic (T5) 49 (FIG. 4) and the first cervical vertebrae (C1) 56, or the subarachnoid space 3 between the fifth lumbar (L5) 48 (FIG.
The implantable therapeutic pump 40 is operated to discharge a predetermined dosage of the pumped fluid into the CSF of the patient.The implantable therapeutic pump 40 contains a microprocessor 42 or similar device that can be programmed to control the amount of fluid delivery.
A controlled amount of fluid comprising therapeutics may be delivered over a specified time period.
With the use of the implantable therapeutic pump 40, different dosage regimens may be programmed for a particular patient. Additionally, different therapeutic dosages can be programmed for different combinations of fluid comprising therapeutics. Those skilled in the art will recognize that a programmed implantable therapeutic pump 40 allows for starting conservatively with lower doses and adjusting to a more aggressive dosing scheme, if warranted, based on safety and efficacy factors.The embodiments of the invention, and the invention itself, are now described in such full, clear, concise and exact terms to enable a person of ordinary skill in the art to make and use the invention. To particularly point out and distinctly claim the subject matters regarded as invention, the following claims conclude this specification. To the extent variations from the preferred embodiments fall within the limits of the claims, they are considered to be part of the invention, and claimed.

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