Deep brain stimulation (DBS) is increasingly applied to the treatment of brain disorders, but its mechanism of action remains unknown. Here, we evaluate the effect of basal ganglia DBS on cortical function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the β rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive β phase locking of motor cortex neurons.

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. Its molecular pathophysiology is poorly understood, in part due to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1)3, THAP1 (DYT6)4, and CIZ15 have been identified. Using exome sequencing in two PTD families we identified a novel causative gene, GNAL, with a nonsense p.S293X mutation resulting in premature stop codon in one family and a missense p.V137M mutation in the other. Screening of GNAL in 39 PTD families, revealed six additional novel mutations in this gene. Impaired function of several of the mutations was shown by bioluminescence resonance energy transfer (BRET) assays.

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.

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.

Caregiver QOL in PNES does not differ from caregiver QOL in ES, while patient QOL is worse in PNES. Caregiver burden emerges as a consistent correlate of caregiver QOL both in ES and PNES. These findings advocate for consideration of caregiver burden and QOL in PNES in clinical practice and for future research paradigms.