A torque-based method demonstrates increased rigidity in Parkinson’s disease during low-frequency stimulation

Low-frequency oscillations in the basal ganglia are prominent in patients with Parkinson’s disease off medication. Correlative and more recent interventional studies potentially implicate these rhythms in the pathophysiology of Parkinson’s disease. However, effect sizes have generally been small and limited to bradykinesia. In this study, we investigate whether these effects extend to rigidity and are maintained in the on-medication state. We studied 24 sides in 12 patients on levodopa during bilateral stimulation of the STN at 5, 10, 20, 50, 130 Hz and in the off-stimulation state. Passive rigidity at the wrist was assessed clinically and with a torque-based mechanical device. Low-frequency stimulation at ≤20 Hz increased rigidity by 24 % overall (p = 0.035), whereas high-frequency stimulation (130 Hz) reduced rigidity by 18 % (p = 0.033). The effects of low-frequency stimulation (5, 10 and 20 Hz) were well correlated with each other for both flexion and extension (r = 0.725 ± SEM 0.016 and 0.568 ± 0.009, respectively). Clinical assessments were unable to show an effect of low-frequency stimulation but did show a significant effect at 130 Hz (p = 0.002). This study provides evidence consistent with a mechanistic link between oscillatory activity at low frequency and Parkinsonian rigidity and, in addition, validates a new method for rigidity quantification at the wrist

Corrective movements in response to displacements in visual feedback are more effective during periods of 13-35 Hz oscillatory synchrony in the human corticospinal system.

Oscillatory synchronization in the beta (approximately 20 Hz) band is a common feature of human motor control, manifest at cortical and muscular levels during tonic contraction. Here we test the hypothesis that the influence of visual feedback on performance in a positional hold task is increased during bursts of beta-band synchrony in the corticospinal motor system. Healthy subjects were instructed to extend their forefinger while receiving high-gain visual feedback of finger position on a PC screen. Small step displacements of the feedback signal were triggered either by bursts of beta oscillations in scalp electroencephalogram or randomly with respect to cortical beta activity, and the resulting positional corrections expressed as a percentage of the step displacement. Corrective responses to beta and randomly triggered step changes in visual feedback were 41.7+/-4.9 and 31.5+/-6.8%, respectively (P<0.05). A marked increase in the coherence in the beta band was also found between muscle activity and cortical activity during the beta-triggered condition. The results suggest that phasic elevations of beta activity in the corticospinal motor system are associated with an increase in the gain of the motor response to visual feedback during a tonic hold task. Beta activity may index a motor state in which processing relevant to the control of positional hold tasks is promoted, with behavioural consequences

Anticipatory changes in beta synchrony in the human corticospinal system and associated improvements in task performance.

Synchronized oscillatory activity in the beta frequency band (13-30 Hz) can be detected in the cerebral motor cortex of healthy humans in the form of corticomuscular coherence. Elevated beta activity is associated with impaired processing of new movements and with more efficient postural or tonic contraction. Accordingly, beta activity is suppressed prior to voluntary movements, rebounding thereafter in the face of peripheral afferance. However, it remains to be established whether synchronized activity in the beta band can be up-regulated in a task-appropriate way independently of confounding changes in sensory afferance. Here we show that there is a systematic and prospective increase in beta synchrony prior to an expected postural challenge. This up-regulation of beta synchrony is associated with improved behavioural performance. We instructed nine healthy subjects to perform a reaction-time movement of the index finger in response to an imperative visual cue or to resist a stretch to the finger in the same direction. These events were preceded by congruent and less common incongruent warning cues. Beta synchrony was temporally increased when subjects were warned of an impending stretch and decreased following a warning cue signalling a forthcoming reaction-time task. Finger positions were less successfully maintained in the face of stretches and reaction times were longer when warning cues were incongruent. The results suggest that the beta state is modulated in a task-relevant way with accompanying behavioural consequences

Local field potential recordings from the pedunculopontine nucleus in a Parkinsonian patient.

The pedunculopontine nucleus has recently been introduced as a new therapeutic target for deep brain stimulation in patients suffering from Parkinson's disease, particularly those with severe gait and postural impairment. Stimulation at this site is typically delivered at low frequencies in contrast to the high frequency stimulation required for therapeutic benefit in the subthalamic nucleus. Therefore, we looked for and demonstrated evidence of low frequency synchronization of activity in the pedunculopontine nucleus of a patient with Parkinson's disease that increased after treatment with dopamine and which might be mimicked by local deep brain stimulation at low frequency

Amplitude modulation of oscillatory activity in the subthalamic nucleus during movement.

Depth recordings in patients with Parkinson's disease (PD) have demonstrated exaggerated local field potential (LFP) activity at frequencies between 10 and 30 Hz in the subthalamic nucleus (STN). This activity is modulated prior to single phasic movements, possibly as part of the feedforward organization of incipient voluntary movement, and after single phasic movements, as a consequence of afferent feedback processes. Here we test the hypothesis that this activity is also modulated during repetitive movements, reflecting a role in ongoing performance. Accordingly, we recorded LFP activity from the contralateral STN of seven patients with PD withdrawn from anti-parkinsonian medication while they performed repetitive index finger to thumb taps. Cross-correlograms of LFP activity at different frequencies in the 10-30 Hz band with finger position showed that LFP activity was modulated in amplitude by finger tapping. The modulation was higher at the beginning of each recording when tapping performance was better, and diminished as tapping became more bradykinetic over time. The best modulations were seen over those frequencies that were maximal in the power spectrum of the corresponding LFP, and for a given side were most marked at the contact pair that exhibited the highest power at these frequencies. In conclusion, subthalamic activity in the 10-30-Hz band is amplitude modulated during movement. This process fails as bradykinesia increases

Oscillatory activity in the pedunculopontine area of patients with Parkinson's disease.

The pedunculopontine nucleus (PPN) has recently been introduced as a new therapeutic target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD). In a recent case report it was demonstrated that alpha frequency oscillations appear in PPN after the administration of levodopa in PD, indicating a possible physiological role of these oscillations. Here we confirm this result and investigate the functional connectivity and reactivity of subcortical alpha activity by recording LFP activity from the PPN area and EEG in six patients with PD while at rest and in four of them while they performed ipsi- and contralateral self-paced joystick movements. Levodopa strongly promoted 7-11 Hz oscillatory synchronization in the region of PPN and coupling of this activity with similar activity in the cortical EEG. Such coupling was bidirectional. Moreover, the 7-11 Hz oscillatory synchronization in the PPN area increased about 3 s prior to self-paced movements, but only following levodopa treatment. These findings suggest that alpha oscillations in the PPN area may represent a physiological pattern of activity. The subcortical oscillations are coupled to cortical alpha activity and possibly allied to motor related attentional processes

Modulation by dopamine of human basal ganglia involvement in feedback control of movement.

We learn new motor tasks by trial and error, repeating what works best and avoiding past mistakes. To repeat what works best we must register a satisfactory outcome, and in a study [1] we showed the existence of an evoked activity in the basal ganglia that correlates with accuracy of task performance and is associated with reiteration of successful motor parameters in subsequent movements. Here we report evidence that the signaling of positive trial outcome relies on dopaminergic input to the basal ganglia, by recording from the subthalamic nucleus (STN) in patients with nigrostriatal denervation due to Parkinson's Disease (PD) who have undergone functional neurosurgery. Correlations between subthalamic evoked activities and trial accuracy were weak and behavioral performance remained poor while patients were untreated; however, both improved after the dopamine prodrug levodopa was re-introduced. The results suggest that the midbrain dopaminergic system may be important, not only in signaling explicit positive outcomes or rewards in tasks requiring choices between options [2,3], but also in trial-to-trial learning and in reinforcing the selection of optimal parameters in more automatic motor control

Dopaminergic therapy promotes lateralized motor activity in the subthalamic area in Parkinson's disease.

Treatment of patients with Parkinson's disease with levodopa has profound effects on both movement and the pattern of movement-related reactivity in the subthalamic nucleus (STN), as reflected in the local field potential (LFP). The most striking change is the promotion of reactivity in the gamma frequency band, but it remains unclear whether the latter is itself a pathological feature, possibly associated with levodopa induced dyskinesias, or is primarily physiological. Gamma band reactivity in the cerebral cortex of humans without Parkinson's disease occurs contralateral to movement, so we posited that lateralization of subcortical gamma reactivity should occur following levodopa if the latter restores a more physiological pattern in patients with Parkinson's disease. Accordingly, we studied movement-related changes in STN LFP activity in 11 Parkinson's disease patients (age 59 +/- 2.7 years, three females) while they performed ipsi- and contralateral self-paced joystick movements ON and OFF levodopa. A bilaterally symmetrical gamma band power increase occurred around movement onset in the OFF state. Following levodopa this feature became significantly more pronounced in the subthalamic region contralateral to movement. The physiological nature of this asymmetric pattern of gamma reactivity was confirmed in the STN of two tremor patients without Parkinson's disease. Although levodopa treatment in the Parkinson's disease patients did not lead to lateralization of power suppression at lower frequencies (8-30 Hz), it did increase the degree of power suppression. These findings suggest that dopaminergic therapy restores a more physiological pattern of reactivity in the STN of patients with Parkinson's disease