This patent application is assigned to
The following quote was obtained by the news editors from the background information supplied by the inventors: "Deep Brain Stimulation (DBS) is a surgical procedure used to treat a variety of disabling neurological symptoms--most commonly the debilitating symptoms of Parkinson's disease (PD), such as tremor, rigidity, stiffness, slowed movement, and walking problems. The procedure is also used to treat other conditions such as dystonia, chronic pain and depression. DBS uses a surgically implanted, battery-operated neurostimulator to deliver electrical stimulation to targeted areas in the brain. In PD patients, this stimulation to targeted areas in the brain that control movement and blocks the abnormal nerve signals that cause tremor and PD symptoms. Generally, these targets are the thalamus, subthalamic nucleus, and globus pallidus.
"The DBS system consists of three components: the lead, the extension, and the neurostimulator. The lead (or electrode)--a thin, insulated wire--is inserted through a small opening in the skull and implanted in the brain. The tip of the electrode is positioned within the targeted brain area. The extension is an insulated wire that is passed under the skin of the head, neck, and shoulder, connecting the lead to the neurostimulator. The neurostimulator (the 'battery pack') is the third component and is usually implanted under the skin near the collarbone or lower in the chest or under the skin over the abdomen. Once the system is in place, electrical impulses are sent from the neurostimulator along the extension wire and the lead and into the brain.
"Physiological studies in humans have demonstrated that the PAG, subthalamic nucleus (STN) and pedunculopontine nucleus (PPN) can modulate parameters recognised to be under autonomic control. For example, stimulation of the STN has been shown to elevate heart rate and arterial blood pressure, regulate sweating and to resist the postural blood pressure fall with head-up tilt (Thornton, J Physiology 2002; 539(2):615-621, Trachani, Clinical Neurology Neurosurgery 2009; E-publication). PAG stimulation has been shown to reduce or elevate systolic blood pressure by 14 mmHg and 16 mmHg, respectively, and resist the postural blood pressure drop on standing (Green, Neuroreport 2005; 16(16):1741-1745, Green, Experimental Physiology 2006; 93(9):102-1028). The PPN lies within the mesencephalic locomotor region (Mogenson,
"Respiratory disease is a major health concern for humans and a common cause of illness and death. Respiratory diseases affect the bronchus and lungs, and include diseases such as chronic obstructive pulmonary disease (COPD), bronchial asthma, lung cancer and bronchial adenoma. Bronchoconstriction is a crucial component underpinning the pathologies of asthma and chronic obstructive pulmonary disease. Treatment of respiratory diseases may involve medication, often administered via inhalation, for example bronchodilators, corticosteroids, antibiotics and anticoagulants. For example, drugs currently used in COPD may be largely classified into corticosteroids, bronchodilators, and combined therapy. Corticosteroids are used for COPD patients with severe or recurrent symptoms, and prolonged dosage is not recommended because side effects such as muscular weakness, functional reduction, and respiratory failure are caused by the agents. Bronchodilators may be sub-classified into beta-2 agonists, anticholinergics, and methylxanthines. Beta-2 agonists induce relaxation of airway smooth muscle, may be sub-classified into fast-acting and slow-acting drugs, and have side effects such as tachycardia, tremor, hypokalemia, and tachyphylaxis. Treatment of respiratory diseases may also include physiotherapy or vaccination.
"Sleep apnea is a sleep disorder characterized by pauses in breathing during sleep. There are three distinct forms of sleep apnea: central, obstructive, and complex (i.e., a combination of central and obstructive). In central sleep apnea breathing is interrupted by the lack of respiratory effort; in obstructive sleep apnea breathing is interrupted by a physical block to airflow despite respiratory effort. Upper airway increased muscle tone and obstruction is a feature of obstructive sleep apnea in addition to autonomic and respiratory deficiencies in standard autonomic tests. Chronic severe obstructive sleep apnea requires treatment to prevent low blood oxygen (hypoxemia), sleep deprivation, and other complications, such as a severe form of congestive heart failure. Treatment may include lifestyle changes, changing sleeping position, devices to keep the airways open during sleep or surgery.
"WO93/01862 and US2007/0106339 disclose methods and devices for treating bronchial constriction and respiratory disorders by providing an electrical impulse to the vagus nerve, a peripheral part of the parasympathetic nervous system (vagus nerve stimulation, VNS). However, the data provided in these applications demonstrate no or little therapeutic improvement. Furthermore, VNS for epilepsy is only partially effective and less so than DBS.
"It is an object of the present invention to provide an alternative method and apparatus for treating respiratory disease and sleep apnea."
In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent application: "Accordingly, according to a first aspect the invention provides a method of influencing bronchoconstriction in a mammal comprising applying a stimulation in one or more regions of the brain of the mammal. According to a second aspect the invention provides a method of treating a respiratory disease or sleep apnea in a mammal comprising applying a stimulation in one or more regions of the brain of the mammal.
"This application of intracranial surgery/DBS for respiratory disease and the like is a large paradigm shift for disease that is currently managed by physicians alone, for example there is no routine surgery for asthma. Although there is a suggested pioneering surgical option for asthma that involves destroying/ablating airway smooth muscle, this is quite destructive especially when you want to protect lung tissue to maximise how much of it can contribute to gas exchange (Cox et al.
"A further advantage over existing drug treatments is that the inventive therapy will be administered when required without the patient necessarily having to activate it. This may be particularly important during severe bronchospasm. There is a concerning phenomenon in near-fatal asthma whereby the patient's perception of dyspnoea is blunted and therefore they under-estimate the degree of airway obstruction and the severity of the asthmatic attack. Accordingly, they do not self-administer life-saving drug therapy sufficiently in the face of potentially-fatal bronchoconstriction (Eckert Eur Respir J 2004, Barreiro Eur respir J 2004, Kikuchi New Eng J Med 1994). The inventive therapy will avoid this dangerous scenario as stimulation therapy can be continuous.
"Furthermore, by targeting the central drive of respiration, the resulting effect is likely to be much more powerful than the targeting of a peripheral drive, such as VNS. VNS only targets one aspect of autonomic function, namely the vagal branch of the parasympathetic nervous system which is a peripheral nerve. The application described herein targets areas within the brain which are part of or directly modulate the complex system of reciprocally-connected parts of the central nervous system known as the central autonomic network (CAN) which is still only slowly being delineated by contemporary neuroscience. The CAN is comprised by structures throughout the neuraxis within the cerebral cortex (including the amygdala, insula and anterior cingulate cortex (ACC)), diencephalon (including the hypothalamus and thalamus), midbrain (PAG), pons (PPN, locus coeruleus (LC), parabrachial nuclei (PBN)), medulla and spinal cord. It is therefore surprising that deep brain stimulation can manipulate such an intricate central neural complex to produce such a beneficial effect on lung function.
"The CAN is involved in the processing and modulation of numerous body systems including endocrine, pain and motor pathways. Influencing the function of the CAN rather than simply one of its many peripheral outflows, such as the vagus nerve, allows this application greater scope therefore to affect more body systems. Whilst VNS therapy is restricted to modulating the peripheral vagal part of the parasympathetic nervous system, the novel application described herein can modulate multiple pathways. Firstly, the CAN modulates the sympathetic nervous system. As sympathetic adrenoreceptors are found on bronchial smooth muscle and produce bronchodilation, this provides an extra source of antagonism against bronchoconstriction. Furthermore, the CAN can modulate motor function and one consequence of this is that skeletal musculature may be beneficially influenced to improve lung function. The PAG projects to medullary centres which drive the phrenic, external intercostals, internal intercostals and pelvic floor musculature which can create greater changes in intrathoracic pressure and therefore contribute to improved respiratory airflow. Another benefit of modulating the activity of parts of the CAN is that it is inextricably linked to pain pathways and the two systems have several structures in common. Such structures include the PAG and ACC which are important modifiers of the pathways which convey noxious sensations such as pain and the unpleasant feeling of dyspnoea. Improvement in discomfort associated with respiratory disease can be crucial to sufferers' quality of life.
"Therefore, as the CAN itself has such a multifaceted effect on various body systems, this application can produce more varied and subtle combinations of beneficial effects for patients with respiratory diseases than simply modulating the vagal autonomic output.
"These methods may be suitable to treat mammals which are suffering from a respiratory disease or sleep apnea. For example, the respiratory disease may be an obstructive lung disease, reversible airways disease, asthma, chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, Ondine's curse, lung cancer, tuberculosis or a lung disease where shortness of breath is a chronic symptom.
"The stimulation preferably causes bronchodilation. The stimulation is preferably deep brain stimulation. The stimulation may be achieved by applying an electrical stimulation and/or a chemical stimulation. For example, the stimulation may include at least one member selected from the group consisting of an electrical stimulation, a magnetic stimulation, an electromagnetic stimulation, a radio frequency stimulation, a biological tissue implantation, a thermal stimulation, an ultrasound stimulation and a chemical stimulation. The stimulation may include generating a voltage differential between at least two electrodes of between about -10V and about +10V with a frequency of between about 0.1 Hz and about 1 kHz, preferably between about 10 and 130 Hz, and a pulse width of 5 .mu.secs and 1000 .mu.secs.
"The one or more regions of the brain may be selected from the periaqueductal grey matter of the midbrain (PAG), the subthalamic nucleus (STN), the pedunculopontine nucleus (PPN), the locus coeruleus (LC), the parabrachial nuclei (PBN), the hypothalamus, the anterior cingulate cortex (ACC), the insula cortex and the amygdala.
"The method may further include feeding back a metric representative of bronchoconstriction, respiratory function including respiratory rate or blood oxygenation in an automated manner, or enabling feedback of a metric representative of bronchoconstriction, respiratory function including respiratory rate, or blood oxygenation in a manual manner, and adjusting the stimulation in response to the metric. Accordingly, advantageously the method allows chronic or on-demand activity depending on the input to the biofeedback loop (e.g. respiratory rate, pO.sub.2).
"Advantageously, this therapy can be used alone or in combination with other traditional therapies such as inhaled bronchodilators and systemic steroids.
"According to further aspects the invention provides an apparatus for influencing bronchoconstriction in a mammal, comprising: a sensor detecting the extent of bronchoconstriction or derangement of respiratory activity or gas exchange in the mammal; a processor in communication with the sensor and generating a control signal based on the extent of bronchoconstriction or derangement of respiratory activity or gas exchange; a signal generator in communication with the processor generating a stimulation signal based on the control signal; and an electrode including at least two conductors in contact with a region of the brain that stimulates the region as a function of the stimulation signal in a manner influencing bronchoconstriction in the mammal.
"The invention also provides an apparatus for influencing blood oxygenation in a mammal, comprising: a sensor detecting the level of oxygen in the blood of the mammal; a processor in communication with the sensor and generating a control signal based on the level of oxygen in the blood of the mammal; a signal generator in communication with the processor generating a stimulation signal based on the control signal; and an electrode including at least two conductors in contact with a region of the brain that stimulates the region as a function of the stimulation signal in a manner influencing blood oxygenation in the mammal.
"The invention also provides an apparatus for stimulating a region in a human brain, comprising: a signal generator adapted to generate a signal; and at least one electrode disposed in a region of a brain in a human subject adapted to produce an output as a function of the signal to stimulate the region in a manner influencing bronchoconstriction or blood oxygenation in the human subject. The signal generator may be coupled to a receiver configured to receive stimulation parameters used for applying the stimulation by at least one member selected from the group consisting of a radio frequency signal, electrical signal, and optical signal.
"Advantageously, these apparatus are active either chronically or on-demand depending on the input to the biofeedback loop (e.g. respiratory rate, pO.sub.2).
BRIEF DESCRIPTION OF THE DRAWINGS
"FIG. 1 shows a schematic representing an instance of such a deep brain electrode stimulator system. (100=Electrode, 200=Stimulation generator.+-.signal processor).
"FIG. 2 shows a schematic of such a deep brain stimulator using feedback from a peripheral pulse oximeter which feeds back to the internal pulse generator via radiofrequency telemetry. (100=Electrode, 200=Stimulation generator.+-.signal processor, 600=Pulse Oximeter).
"FIG. 3 shows a schematic of such a deep brain stimulator using feedback from a thoracic accelerometer which feeds back to the internal pulse generator via radiofrequency telemetry. (100=Electrode, 200=Stimulation generator.+-.signal processor, 500=Accelerometer).
"FIG. 4 shows a schematic of such a deep brain stimulator using feedback from a thoracic accelerometer which feeds back to the internal pulse generator via direct cabling. (100=Electrode, 200=Stimulation generator.+-.signal processor, 500=Accelerometer).
"FIG. 5 shows a schematic of such a deep brain stimulator using feedback from a thoracic pressure gauge attached to a stretchable circumferential girdle which feeds back to the internal pulse generator via radiofrequency telemetry. (100=Electrode, 200=Stimulation generator.+-.signal processor, 300=Thoracic girdle, 400=pressure gauge/manometer).
"FIG. 6 shows a flowchart to describe a feedback mechanism to activate and de-activate stimulation based upon respiratory parameter(s).
"FIG. 7 shows representative electrode locations shown on axial MRI scans (PAG=periaqueductal grey,
"FIG. 8 shows a graph to show improvement in percentage peak expiratory flow rate with stimulation On compared to Off at each target (confidence intervals depict standard errors).
"FIG. 9 shows graphs to show change in Mean PEFR within each patient On and Off stimulation of the periaqueductal grey (PAG), subthalamic nucleus (STN) and pedunculopontine nucleus (PPN).
"FIG. 10 shows flow volume loops from one patient during three trials each of forced expiration with periaqueductal grey (PAG) stimulation On and Off.
"FIG. 11 shows a scatterplot of Thoracic Diameter Change Ratio versus PEFR Improvement with subthalamic nucleus stimulation. Fitted regression line and confidence intervals are shown.
"FIG. 12 shows a scatterplot of Thoracic Diameter Change Ratio versus PEFR Improvement with pedunculopontine stimulation. Fitted regression line and confidence intervals are shown.
"FIG. 13 shows A) Sagittal MNI brain section demonstrating sites of stimulation in the pedunculopontine nucleus (PPN) group. The distribution of the PPN is shaded and overlaid on the atlas. Active electrode contacts are shown and different shades represent different patients. B) Coronal MNI brainstem section demonstrating sites of stimulation in the PPN group. C) Dorsal brainstem schematic demonstrating the PPN, locus coeruleus (LC) and lateral parabrachial nucleus (PBN) (adapted from Niewenhuys et al. 2008). SC=Superior colliculus, IC=Inferior colliculus.
"FIG. 14 shows a composite table and graph depicting improvements in means of Best PEFR for each subject, Mean PEFR and Mean FEV1 in patients with stimulation of either the anterior cingulate cortex (ACC), motor thalamus or hypothalamus compared to no stimulation.
"FIG. 15 shows simultaneous physiological signals in a representative patient. A) Raw LFP signal during exertional respiratory manoeuvre (microvolts); B) Time-frequency spectrogram demonstrating an increase in alpha 7-11 Hz power during maximal inspiration and forced expiration (Hz); C) Respiratory trace showing increases in thoracic circumference 5 during maximal inspiration followed by a rapid in circumference during forced expiration"
URL and more information on this patent application, see: Green,
Keywords for this news article include: Pain, Asthma, Surgery, Thalamus, Treatment, Chalcogens, Pulmonology, Craniofacial, Diencephalon, Therapeutics, Blood Pressure, Otolaryngology, Cancer Vaccines, Medical Devices, Neurostimulator, Sleep Disorders, Bronchial Diseases,
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