Treatment of disorders associated with inflammation
Stimulation of neural activity in a nerve supplying the spleen, wherein the nerve is adjacent to the splenic artery at a position where the splenic artery is not in direct contact with the pancreas, can modulate pro- and anti-inflammatory molecules levels, thereby reducing inflammation and providing ways of treating disorders, such as disorders associated with inflammation. The invention provides improved ways of reducing inflammation with minimized off-target effects, in particular surgical trauma.
1. A system for stimulating the neural activity of a splenic arterial nerve, the system comprising:
at least one electrode in signaling contact with the nerve at a site where the splenic artery is not in direct contact with the pancreas; and
at least one controller electrically coupled to the at least one electrode, the at least one controller configured to control the operation of the least one electrode to apply an electrical signal to the nerve, wherein a charge density per phase applied to the nerve by the electrical signal is between 5 μC to 1100 μC per cm2 per phase, wherein the electrical signal produces an improvement in a physiological parameter in a subject, and wherein the improvement in the physiological parameter is one or more of a group consisting of: a reduction in a pro-inflammatory cytokine, an increase in an anti-inflammatory cytokine, an increase in a catecholamine, a change in an immune cell population, a change in an immune cell surface co-stimulatory molecule, a reduction in a factor involved in the inflammation cascade, a change in a level of an immune response mediator, and a decrease in splenic blood flow.
2. The system of claim 1 , wherein the site is a position of the splenic artery separated from the surface of the pancreas by a distance in a range of from 0.5 cm to 4 cm.
3. The system of claim 1 , wherein the site is at a splenic arterial loop.
4. The system of claim 1 , wherein the electrical signal comprises a pulse train, the pulse train comprising a plurality of pulses.
5. The system of claim 4 , wherein the pulses are charge-balanced and biphasic.
6. The system of claim 1 , further comprising at least one detector configured to detect one or more of a group consisting of: systemic arterial blood pressure, blood flow rate in the spleen, blood flow rate in the splenic artery, blood flow rate in the splenic vein, spleen volume, splenic tissue perfusion, neural activity in the nerve, impedance of the at least one electrode, and stimulator voltage compliance.
7. The system of claim 6 , wherein the at least one controller is further configured to apply an electrical signal to the nerve for determining correct placement of the neural interface in signaling contact with the nerve prior to applying the electrical signal to the nerve, wherein the electrical signal has a frequency of ≤300 Hz and is applied continuously for a duration of ≥3 hours.
8. The system of claim 7 , wherein the at least one detector is further configured to detect spleen volume, and wherein the at least one controller is further configured to determine if the detected spleen volume is lower than baseline spleen volume and, if so, to indicate to an operator that the neural interface has been placed in signaling contact with the nerve correctly.
9. The system of claim 8 , wherein the at least one detector is further configured to measure spleen volume using ultrasound.
10. The system of claim 6 , wherein the at least one detector is further configured to detect one or more of a group consisting of: systemic arterial blood pressure, blood flow rate in the spleen, blood flow rate in the splenic artery, and blood flow rate in the splenic vein, and wherein the at least one controller is further configured to determine if a detected blood pressure or blood flow rate is different than a baseline blood pressure or blood flow rate and, if so, to indicate to an operator that the neural interface has been placed in signaling contact with the nerve correctly.
11. The system of claim 10 , wherein the at least one detector is further configured to detect impedance of the at least one electrode, and wherein the at least one controller is further configured to determine if the detected impedance is different than baseline impedance and, if so, to indicate to an operator that the neural interface has been placed in signaling contact with the nerve correctly.
12. A method of reversibly stimulating neural activity in a nerve supplying the spleen, the method comprising:
providing the system of claim 1 ;
positioning at least one electrode in signaling contact with the nerve adjacent to a splenic arterial loop; and
controlling the operation of the least one electrode with at least one controller to apply an electrical signal to the nerve to reversibly stimulate neural activity.
13. The method of claim 12 , wherein the method is for treating a disorder associated with inflammation in a subject.
14. A method of determining whether a neural interface is correctly placed in signaling contact with a splenic arterial nerve at a site where the splenic artery is not in direct contact with the pancreas, the method comprising:
providing the system of claim 1 ;
positioning the neural interface around a nerve at a site where the splenic artery is not in direct contact with the pancreas;
controlling the operation of the least one electrode with at least one controller to apply an electrical signal to the nerve;
determining one or more of a: a change in blood flow rate or pressure in the spleen, splenic artery, or splenic vein, a decrease in spleen volume, an increase in neural activity in the nerve, a change of heart rate, a change of systemic arterial blood pressure, a decrease in impedance of the at least one electrode, and a decrease in a stimulator voltage compliance; and
indicating to an operator that the neural interface had been placed correctly in signaling contact with the nerve.
15. The method of claim 14 , wherein the site is at a position of the splenic artery separated from the surface of the pancreas by a distance in a range of 0.5 cm to 4 cm.
16. The method of claim 15 , wherein the site is at a splenic arterial loop.