Background Subthalamic deep brain stimulation is superior to medical therapy for the motor symptoms of advanced Parkinson’s disease, and additional evidence suggests that it improves refractory symptoms of essential tremor, primary generalized dystonia, and obsessive-compulsive disorder. Despite this, its therapeutic mechanism is unknown. We hypothesized that subthalamic stimulation activates cerebral cortex at short latencies after stimulus onset during clinically effective stimulation for Parkinson disease. Methods In 5 subjects (6 hemispheres) electroencephalography measured the response of cortex to subthalamic stimulation across a range of stimulation voltages and frequencies. Novel analytical techniques reversed the anode and cathode electrode contacts and summed the resulting pair of event related potentials to suppress the stimulation artifact. Results Subthalamic brain stimulation at 20 Hertz activates somatosensory cortex at discrete latencies (mean latencies 1.0 ± 0.4, 5.7 ± 1.1, and 22.2 ± 1.8 milliseconds, denoted R1, R2, and R3, respectively). The amplitude of the short latency peak (R1) during clinically effective high frequency stimulation is nonlinearly dependent on stimulation voltage (p < 0.001, repeated measures analysis of variance), and its latency is less variable than that of R3 (1.02 versus 19.46 milliseconds, p < 0.001, Levene’s test). Conclusions Clinically effective subthalamic brain stimulation in humans with Parkinson disease activates cerebral cortex at one millisecond after stimulus onset, most likely by antidromic activation. Our findings suggest that alteration of the precise timing of action potentials in cortical neurons with axonal projections to the subthalamic region is an important component of the therapeutic mechanism of subthalamic brain stimulation.

Background Differentiating whether an action leads to an outcome by chance or by an underlying statistical regularity that signals environmental change profoundly affects adaptive behavior. Prior studies have shown that anxious individuals may not appropriately differentiate between these situations. This investigation aims to precisely quantify the process deficit in anxious individuals and determine the degree to which these process dysfunctions are specific to anxiety. Methods 122 subjects recruited as part of an ongoing large clinical population study completed a change point detection task. Reinforcement learning models were used to explicate observed behavioral differences in Low Anxiety (OASIS<=8) and High Anxiety (OASIS>=9) groups. Results High anxious individuals used a sub-optimal decision strategy characterized by a higher lose-shift rate. Computational models and simulations revealed that this difference was due to a higher base learning rate. These findings are better explained in a context-dependent reinforcement learning model. Conclusions Anxious subjects’ exaggerated response to uncertainty leads to a suboptimal decision strategy that makes it difficult for these individuals to determine whether an action is associated with an outcome by chance or by some statistical regularity. These findings have important implications for developing new behavioral intervention strategies utilizing learning models.

Multiple studies have shown bilateral improvement in motor symptoms in Parkinson disease (PD) following unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal segment of the globus pallidus, yet the mechanism(s) underlying this phenomenon are poorly understood. We hypothesized that STN neuronal activity is altered by contralateral STN DBS. This hypothesis was tested intraoperatively in humans with advanced PD using microelectrode recordings of the STN during contralateral STN DBS. We demonstrate alterations in the discharge pattern of STN neurons in response to contralateral STN DBS including short latency, temporally precise, stimulation frequency-independent responses consistent with antidromic activation. Furthermore, the total discharge frequency during contralateral high frequency stimulation (160 Hz) was greater than during low frequency stimulation (30 Hz) and the resting state. These findings demonstrate complex responses to DBS and imply that output activation throughout the basal ganglia-thalamic-cortical network rather than local inhibition is a therapeutic mechanism of DBS.

Deep brain stimulation relieves disabling symptoms of neurologic and psychiatric diseases when medical treatments fail, yet its therapeutic mechanism is unknown. We hypothesized that ventral intermediate nucleus stimulation for essential tremor activates cortex at short latencies and that this potential is related to suppression of tremor in the contralateral arm. We measured cortical activity with electroencephalography in 5 subjects (7 brain hemispheres) across a range of stimulator settings, and reversal of the anode and cathode electrode contacts minimized the stimulus artifact, allowing visualization of brain activity. Regression quantified the relationship between stimulation parameters and both the peak of the short latency potential and tremor suppression. Stimulation generated a polyphasic event related potential in ipsilateral sensorimotor cortex with peaks at discrete latencies beginning less than one millisecond after stimulus onset (mean latencies 0.9±0.2, 5.6±0.7, and 13.9±1.4 milliseconds, denoted R1, R2, and R3, respectively). R1 showed more fixed timing than the subsequent peaks in the response (p<0.0001, Levene’s test), and R1 amplitude and frequency were both closely associated with tremor suppression (p<0.0001, respectively). These findings demonstrate that effective ventral intermediate nucleus thalamic stimulation for essential tremor activates cerebral cortex at approximately one millisecond after the stimulus pulse. The association between this short latency potential and tremor suppression suggests that deep brain stimulation may improve tremor by synchronizing the precise timing of discharges in nearby axons, and by extension the distributed motor network, to the stimulation frequency or one of its subharmonics.

Deep brain stimulation (DBS) in Parkinson's disease (PD) is frequency-dependent. Past studies of the effect of DBS frequency, however, involved scrutiny of too few frequencies to eliminate risk of undersampling. Also, these studies presented averaged measures across subjects; high intersubject variability makes these measures problematic. In this study, 6 subjects with PD were tested in a drug-minimal state. Following 10 minutes of stimulation at the new frequency, all available frequencies were tested. Hand-opening and hand-closing amplitude and frequency were measured in 3 epochs of 15 seconds each. Multiple frequencies (low and high) resulted in peaks of increased movement amplitudes. Peaks were specific and varied among individuals. No clear relationship between stimulation frequency and movement frequency was discovered. In light of the findings, a wider range of stimulation frequencies should be examined, particularly lower frequencies. Most current theories of PD pathophysiology and DBS mechanisms of action fail to explain results of the kind demonstrated herein.