Hyperkinetic states are common in human movement disorders, but their neural basis remains uncertain. One such condition is dyskinesia, a serious adverse effect of medical and surgical treatment for Parkinson's disease (PD). To study this, we used a novel, totally implanted, bidirectional neural interface to obtain multisite long-term recordings. We focus our analysis on two patients with PD who experienced frequent dyskinesia and studied them both at rest and during voluntary movement. We show that dyskinesia is associated with a narrowband gamma oscillation in motor cortex between 60 and 90 Hz, a similar, though weaker, oscillation in subthalamic nucleus, and strong phase coherence between the two. Dyskinesia-related oscillations are minimally affected by voluntary movement. When dyskinesia persists during therapeutic deep brain stimulation (DBS), the peak frequency of this signal shifts to half the stimulation frequency. These findings suggest a circuit-level mechanism for the generation of dyskinesia as well as a promising control signal for closed-loop DBS.

Neural recordings in humans using invasive devices can elucidate the circuits underlying brain disorders, but have so far been limited to short recordings from externalized brain leads in a hospital setting or from implanted sensing devices that provide only intermittent, brief streaming of time series data. Here we report the use of an implantable two-way neural interface for wireless, multichannel streaming of field potentials in five patients with Parkinson’s disease for up to 15 months after implantation. Bilateral 4-channel motor cortex and basal ganglia field potentials streamed at home for over 2,600 hours were paired with behavioral data from wearable monitors for the neural decoding of states of inadequate or excessive movement. We validated patient-specific neurophysiological biomarkers during normal daily activities and used those patterns for adaptive deep brain stimulation. This technological approach may be widely applicable to brain disorders treatable by invasive neuromodulation.

OBJECTIVE Dysfunction of distributed neural networks underlies many brain disorders. Development of neuromodulation therapies depends on a better understanding of these networks. Invasive human brain recordings have a favorable temporal and spatial resolution for the analysis of network phenomena, but have generally been limited to acute intraoperative recording or short term recording through temporarily externalized leads. Here we describe our initial experience with an investigational, totally implantable, first generation, bidirectional neural interface that allows for both continuous therapeutic stimulation and recordings of field potentials at multiple sites in a neural network. METHODS We implanted five Parkinson’s disease patients with Activa PC+S (Medtronic Inc.), under a physician-sponsored Food and Drug Administration investigational device exemption. The device was attached to a quadripolar lead placed in the subdural space over motor cortex, for recording of electrocorticography (ECoG) potentials, and to a quadripolar lead in subthalamic nucleus (STN) for both therapeutic stimulation and recording of local field potentials (LFPs). We recorded from each patient at multiple time points over a one year period. RESULTS There were no serious surgical complications or interruptions of DBS therapy. Signals in both cortex and STN were relatively stable over time, despite a gradual increase in electrode impedance. We were able to identify canonical movement related changes in specific frequency bands in motor cortex in most but not all recordings. CONCLUSION Acquisition of chronic multisite field potentials in humans is feasible. Device performance characteristics described here may inform the design of the next generation of totally implantable neural interfaces. This research tool provides a platform for translation of discoveries in brain network dynamics to improved neurostimulation paradigms.

The retrosplenial cortex (RSP), a brain region frequently linked to processes of spatial navigation, contains neurons that discharge as a function of a rat's head direction (HD). HD cells have been identified throughout the limbic system including the anterodorsal thalamus (ADN) and postsubiculum (PoS), both of which are reciprocally connected to the RSP. The functional relationship between HD cells in the RSP and those found in other limbic regions is presently unknown, but given the intimate connectivity between the RSP and regions such as the ADN and PoS, and the reported loss of spatial orientation in rodents and humans with RSP damage, it is likely that the RSP plays an important role in processing the limbic HD signal. To test this hypothesis, we produced neurotoxic or electrolytic lesions of the RSP and recorded HD cells in the ADN of female Long-Evans rats. HD cells remained present in the ADN after RSP lesions, but the stability of their preferred firing directions was significantly reduced even in the presence of a salient visual landmark. Subsequent tests revealed that lesions of the RSP moderately impaired landmark control over the cells' preferred firing directions, but spared the cells directional stability when animals were required to update their orientation using self-movement cues. Together, these results suggest that the RSP plays a prominent role in processing landmark information for accurate HD cell orientation and may explain the poor directional sense in humans that follows damage to the RSP.