The next move in neuromodulation therapy: a question of timing

The effect of time-varying electrical currents (AC) on neuronal activity is currently the focus of intense translational and multidisciplinary research efforts. Thanks to a broad range of neuromodulation modalities, it is indeed possible to induce, more or less invasively, electrical currents in brain tissue. On the non-invasive side, transcranial alternating stimulation (tACS), or transcranial magnetic stimulation (TMS) have demonstrated their potential for the symptomatic treatment of neurological disorders. In the domain of more invasive stimulation techniques, deep brain stimulation (DBS), or cortical stimulation (electrical motor cortex stimulation, EMCS) have proven extremely successful therapies for Parkinson's Disease (PD) or pain management, and are used in tens of thousands of patients worldwide (over 100,000 patients for DBS only). The underlying mechanisms are increasingly understood, even if they remain wrapped in some mystery that refrains the outstanding potential of brain stimulation for treating neurological disorders. However, the basic idea is simple: information processing by the brain is achieved, at least partially, by neuronal electrical oscillations in various frequency ranges, produced by a variety of neuronal networks distributed throughout the brain. Efforts to link the spatiotemporal structure of these neuronal oscillations with brain function and behavior have provided an enormous amount of data that is shaping our understanding of brain function (see Buzsaki and Draguhn, 2004 for a review on the functional significance of brain oscillations). By inducing currents in brain tissue, it is possible to modulate the membrane potential of neurons, thereby resulting in detectable changes in neuronal activity, and to impact associated function of neuronal networks. The most widespread neurostimulation therapy today is DBS, clinically used to treat symptoms in neurological disorders such as in PD (see Modolo and Beuter, 2009 for a review). More than 25 years after its discovery, the technology of DBS has not changed much: high-frequency (>130 Hz) electrical stimulation using biphasic pulses, which are defined by their pulse width and amplitude. One minor recent innovation is the use of current-controlled DBS devices, which keep the stimulation steady at all times to avoid fluctuations in the stimulation signal being delivered and potential associated side effects (Bronstein et al., 2014). Given the tremendous progress of electronics over the last 25 years, and the advance in our qualitative and quantitative understanding of brain function, it is somewhat surprising that more personalized, sophisticated devices have not surfaced yet. Of course, using more advanced neuromodulation technologies would be meaningless if current technology was sufficient. With only 5–10% of patients eligible for DBS, a 1–3% rate of complications during surgery, batteries to replace every 4 years on average (under general anesthesia), stimulation parameters needing manual adjustments, and a complete absence of brain activity monitoring, there is however a consensus on the facts that current technology is not sufficient, and that the next generation of neuromodulation devices has to be pushed forward. Perhaps the most important aspect of all is the ability of novel neuromodulation devices to deliver stimuli with the right timing: with DBS, no matter what the ongoing brain activity is, the same stimulation pattern is continuously repeated. Why is that a limit, and why is it of fundamental importance to improve DBS drastically?