Long-term potentiation (LTP) involves the process of establishing an association between the firing of two cells or groups of cells. For instance, Hebb's rule essentially states that if an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing cell B, an increase in the strength of the chemical synapse between the cells takes place such that A's efficiency, as one of the cells firing B, is increased. LTP has been shown to last from minutes to several months. Conditions for establishing LTP are favorable when a pre-synaptic neuron and a post-synaptic neuron are both depolarized in a synchronous manner. An opposite effect, long-term depression (LTD), has also been established. LTD is the weakening of a neuronal synapse that lasts from hours to months. In the cerebellar Purkinje cells, LTD results from strong synaptic stimulation. By contrast, in the hippocampus, LTD results from persistent weak synaptic stimulation, or when a pre-synaptic neuron and a postsynaptic neuron discharge in an asynchronous manner. Since the establishment of Hebb's original rule, additional “Hebb's Rules” have been proposed for the prediction of self-organization of neuronal systems, and these rules appear to govern the process by which the brain is effectively sculpted over time in order to master the demands of the environment.
Neurons and other electrically excitable cells (including cardiac cells and some endocrine cells) have spontaneous firing rates: they discharge action potentials at a baseline rate, in the absence of external stimulation or suppression. This spontaneous firing rate is affected by temperature. Generally, the warmer an electrically excitable cell, the faster the spontaneous firing rate, and the colder the cell, the slower the firing rate. When cells become extremely warm, such as in a very high fever, they have a high propensity to fire. At extremes, such an increase in firing rates may manifest as a risk of a febrile seizure.
Neuromodulation is the control of nerve activity, and is usually implemented for the purpose of treating disease. In the strictest sense, neuromodulation may be accomplished with a surgical intervention like cutting an aberrant nerve tract. However, the semi-permanent nature of a surgical procedure leaves little room for later adjustment and optimization. Likewise, it could be asserted that neuromodulation can be accomplished with chemical agents or medications. Chemical agents or medications may be undesirable because, for example, many medications are difficult to deliver to specific anatomy, and because the titration (increasing or decreasing the dose of a medication) is a slow and imprecise way to achieve a desired effect on a specific target. Consequently, the term neuromodulation usually implies the use of energy-delivering devices.
Several categories of device-based neuromodulation methods are known in the art. These include electrical neuromodulation, magnetic neuromodulation and opto-genetic neuromodulation.
Electrical nerve stimulation is well-established. Examples of electrical approaches include transcutaneous electrical nerve stimulation (TENS) units, and the surgically implanted electrodes of deep brain stimulation (DBS). TENS units are used to lessen superficial nerve pain within skin and muscle. Because the device is non-invasive and has a low power output, its use involves little risk. However, the efficacy of TENS is limited to nerve distributions very close to the surface. Additionally, TENS has little focusing ability for targeting with close tolerances. Moreover, its therapeutic use shows a fairly small effective treatment area. DBS is a useful approach for treating conditions including Parkinson's disease, essential tremor, epilepsy, chronic pain, depression and obsessive-compulsive disorder. In the case of Parkinson's disease, a multi-contact electrode may be neurosurgically implanted in the subthalamic nucleus of a patient. Once connected to a pulse generation unit similar to a cardiac pacemaker device, the electrodes may be electrically pulsed at various rates, effectively driving the activity of the neurons immediately adjacent to the electrode contacts, using currents of about 3 amps and voltages between 1 and 10. Subsequently, various configurations of electrode pairs or monopolar configurations may be empirically tested on the patient for effect and tolerability. At a later time, the circuit configuration or pulse parameters may be changed by the physician in charge, usually without the need to physically disturb the implanted electrode. One disadvantage of DBS is that, by definition, it requires a highly invasive and risky neurosurgical implantation procedure. If the site of implantation is later deemed suboptimal, or if the device physically fails, more surgery is required.
Magnetic stimulation involves the discharge of large capacitors into an electrically conductive coil placed external to a patient's brain or body. As electrical current runs through the coil, a magnetic field is induced, which in turn, induces an electric field in nerve membranes and surrounding fluid. This forces nerves to depolarize with each discharge of the capacitors in the machine. Magnetic stimulation, when delivered at rates of 5-20 Hz, tend to be stimulating to nerves that it affects, for some time after the magnetic pulse delivery has stopped. Pulse rates of less than 1 Hz tend to suppress the activity of affected nerves after stimulation has ended. Very fast pulse trains (e.g., 50 Hz), punctuated by absence of pulses 6-9 times per second (“theta rhythm”) also tend to suppress the activity of affected neurons. Magnetic neuromodulation, in the form of repetitive transcranial magnetic stimulation, is useful for the treatment of depression, and likely several other neurological and psychiatric conditions. The derived effects may last from minutes to months after the end of magnetic treatment. One limitation of magnetic neuromodulation is the difficulty in achieving tight focus of the effect, since magnetic fields capable of penetrating to useful depth tend to be large in footprint, as dictated by the Biot-Savart Law.
Opto-genetic neuromodulation is a newly discovered approach which has the advantages of being neuron-type specific. Using this approach, light-sensitive ion channels or pumps are genetically transferred to the targeted neurons of the brain to be stimulated. A flashing light from an implanted device provides a signal to these channels or pumps to activate. This leads to either neuronal depolarization, or neuronal hyperpolarization, depending upon the nature of the light-sensitive channel or pump. Opto-genetic approaches lend themselves to both neuronal up-regulation and down-regulation. Disadvantages include the requirement of implanted hardware, and the need for the genetic modification of targeted neurons.
Ultrasound is mechanical vibration at frequencies above the range of human hearing, or above 16 kHz. Most medical uses for ultrasound use frequencies in the range of 1 to 20 MHz. Low to medium intensity ultrasound products are widely used by physicians, nurses, physical therapists, masseurs and athletic trainers. The most common applications are probably warming stiff, swollen or painful joints or muscles in a manner similar to a hot compress, but with better penetration. Many ultrasound products have been commercially available for years, including consumer-grade massage machines. By design, the power on these devices is designed to be too low to warm or otherwise affect structures more than two centimeters or so below the surface. Also, these devices are not capable of tight focus at depth, nor are there means for accurately aiming such devices toward precise structural coordinates within the body. As ultrasound of sufficient strength can cause pain in peripheral nerves with each pulse, it is likely that mechanical perturbations caused by ultrasound can cause nerves to discharge.