Since the FDA approved deep brain stimulation (DBS) for Parkinson’s disease in 2002, over 140,000 patients have undergone the procedure worldwide. In DBS, neurosurgeons carefully position a tiny lead with four electrical contacts adjacent to a part of the basal ganglia – typically, either the globus pallidus internus or the subthalamic nucleus (the procedure is generally done on both sides of the brain). In dopamine-deprived Parkinson’s disease patients, these key structures – which form a critical circuit incorporating the thalamus and motor cortex – become over active, and the dysfunctional circuit produces the characteristic motor symptoms of tremor, rigidity and slowness of movement. But remarkably, attaching the leads to a pulse generator and firing electrical bursts at a frequency of around 130 Hz in the region of those structures, modifies the pathological circuit activity and mitigates the motor symptoms—in some but not all patients.
As DBS seemed to electrically “quiet” the same regions that neurosurgeons had previously removed in operations like pallidotomies, some clinicians initially referred to DBS as a “reversible lesion.” But basic researchers soon concluded that this theory of how DBS worked was flawed. In careful animal experiments it turned out that while the high frequency stimulation inhibited the neuronal cell bodies, the electricity also acted on axons projecting from those cell bodies and also on other axons passing through that area. And those axons were not inhibited but rather excited by the DBS.
Neuroscientists were forced to concede that DBS operated via a more complex process, one that changed the “pattern” of the brain’s electrical activity. To understand this shift in thinking, we must talk a bit about brain waves. Anatomically distinct brain regions consist of large populations of neurons, and as they fire these neurons produce oscillatory waves that can vibrate at many different frequencies. These oscillations not only encode critical information, but also provide a way for distinct (and often distant) brain centers to talk to each other. It’s helpful to think of the neurons in structures like the subthalamic nucleus and the motor cortex as instruments in a band: sometimes the instruments come together and play the same music in sync (i.e. talking to each other) and at other times, they break away to play by themselves (i.e. do other things). One kind of oscillation, the beta wave (which vibrates at between 12 and 30 Hz), is thought to be important in enabling the basal ganglia and motor cortex to talk to each other. According to Mass General’s Todd Herrington, beta rhythm is a “holding” rhythm: “It typically kicks in when a person holds a posture and goes away when the individual engages in a new activity like a movement. ” But in people with Parkinson’s disease, beta rhythm can be very strong and doesn’t abate during movement as it does in healthy people. Like members of a jazz band stuck playing the same few bars over and over, the neurons in the basal ganglia and motor cortex get trapped in this holding rhythm.
In an important series of studies, Peter Brown and colleagues have argued that this excessive beta wave synchrony is indeed pathological. Their work suggests that, given this insight, there may be more effective ways of carrying out the DBS procedure. Rather than simply turning on the stimulator and leaving it running indefinitely, a better way might be to first monitor the brain to search for signs of pathological oscillations. Only when the high levels of beta rhythm power are detected is the stimulator turned on to break up the excessive synchronization. This is referred to as a “closed loop” DBS procedure.
UCSF neurosurgeon Phil Starr and colleagues have recently demonstrated that one precise mechanism causing excessive synchrony involves the beta waves coupling to higher frequency gamma waves in the motor cortex. The University of California-San Francisco team implanted DBS leads on the motor cortex (the surface of the brain) and also in the subthalamic nucleus. Starr and his team found that in the motor cortex region the cells were entrained to beta rhythms in the basal ganglia – in a process called phase-amplitude coupling.
In pilot studies, both Brown and Starr have demonstrated that when the DBS stimulator is turned on the excessive synchronization diminishes and the motor symptoms improve. There may be significant advantages to using DBS in a so-called “closed loop” modality to break up excessive synchrony when it is needed, rather than leaving it turned on indefinitely as in classical DBS. The closed loop approach not only preserves the battery and minimizes side effects; it appears (in pilot studies at least) to produce more effective relief from motor symptoms.
But Brown and Starr are not the only researchers exploring the new frontier of DBS. There is an alternative and potentially much simpler way of breaking up excessive synchrony and getting the brain back on track. It’s called coordinated reset neuromodulation. According to Stanford neurosurgeon Peter Tass, “when there is excessive beta synchrony, there is a large population of neurons that is entrained to this beta rhythm.” All you need to do to disrupt this pathological music, says Tass, is to administer brief resetting high frequency pulse trains via different electrodes at different times. This simple act divides the neuronal population into subpopulations, ultimately leading to network desynchronization (freeing up the members of the jazz band to play other music), which in turn leads to the network “unlearning” the pathological connectivity between neurons.
What is striking is that unlike classical DBS where the pathological circuit activity returns within seconds of turning off the stimulator, in coordinated reset DBS (CR-DBS) the benefits of desynchronization persist. When CR-DBS was given to non-human primates for just 2 hours a day over 5 days, the benefits persisted for up to 30 days. And in a pilot study of 6 human patients, when CR-DBS was given twice daily for three days, researchers measured an average lowering of beta power of 42% and an average reduction in clinical impairment of 24%.
Plans are in the works to test both closed loop DBS and CR-DBS on larger groups of patients in the coming year. If it pans out, we may be on the verge of an exciting new chapter in Deep Brain Stimulation; one that achieves a more reliable benefit with reduced risks of unwanted side effects
