Electrophysiologic Brain Sensing Using Implanted DBS Systems in Neurological and Psychiatric Disorders

Both hyperkinetic and hypokinetic movement disorders are associated with abnormal spatiotemporal activity within the basal ganglia circuitry13,16,17. This can be assessed through measuring local field potentials (LFPs), which represent the product of synchronous neuronal activity at a given site (unsynchronized, random activity being essentially cancelled out)13. Numerous other disorders such as obsessive compulsive disorder, major depression, Tourette's syndrome, epilepsy, eating disorders and cluster headaches are also amenable to successful modulation using DBS6-11. These disorders likely also have unique, disease-specific electrophysiological signatures, the exact nature of which remains to be thoroughly defined. Abnormal electrophysiological activity is useful not only in delineating the pathophysiologic underpinnings of these disorders, but is central to the future development of adaptive DBS systems which respond in real-time to ameliorate pathological brain acticity12. Adaptive DBS may provide further clinical benefit beyond currently employed continuous DBS approaches, with only a fraction of the energy requirements12.

Studies using microelectrode recordings at the time of DBS lead placement as well as recordings from externalised DBS electrodes have identified distinct neurophysiological signatures within different disorders. Examples include excess beta-frequency oscillations in Parkinsonism, alpha and theta frequency oscillations in dystonia and gamma oscillations in dyskinesia. These neurophysiologic biomarkers of disease can be affected by the application of high-frequency DBS. Future closed-loop DBS systems may rely on real-time suppression of such abnormal basal ganglia activity.

LFPs in Parkinson's disease

A significant body of work has confirmed that beta-frequency oscillations, recorded from both the subthalamic nucleus and the internal portion of the globus pallidus, correlate with severity of bradykinesia and rigidity in Parkinson's disease13,16-18. These beta-frequency oscillations are coherent across simultaneous recordings in different nuclei of the same patient, implying that these represent a network-level dysfunction in Parkinson's disease16,19. The amplitude/power of abnormal beta-frequency LFPs correlates with the severity of motor impairment in Parkinson's disease15,18. Moreover, beta-frequency LFPs can be suppressed both by levodopa administration, or by the application of high-frequency DBS20,21; in both scenarios the degree of suppression in beta-oscillations correlates with the degree of clinical motor improvement. Beta oscillations may therefore represent an electrophysiological parkinsonian symptom correlate which can act as a biomarker of the motor state. Hence, they may be useful signals on which to base stimulation using adaptive DBS technologies. However, some observations, such as the suppression of beta frequency oscillations during periods of tremor, have cast doubt on the robustness of this potential biomarker.

Other LFP frequency alterations have also been observed to correlate with clinical symptomatology in PD. For instance, synchronisation at frequencies in the gamma range (60-90Hz) have been correlated with dyskinesia, as have synchronisation at lower frequencies (4-8Hz)22,23. High-frequency oscillations in the 250Hz range have also been found to associate with parkinsonian clinical states and to shift to even higher frequencies (350Hz) following levodopa administration24. In contrast to beta-frequencies, changes in high-frequency LFPs do appear to correlate with tremor25.