In Parkinson's disease (PD), the oscillatory activity recorded from the basal ganglia shows dopamine-dependent changes. In the "off" parkinsonian motor state, there is prominent activity in the beta band (12-30 Hz) that is mostly attenuated after dopaminergic therapy ("on" medication state). The on state is also characterized by activity in the gamma (60 -80 Hz) and high-frequency (300 Hz) bands that is modulated by movement. We recorded local field potentials from a group of 15 PD patients (three females) treated with bilateral deep brain stimulation of the subthalamic nucleus, using a high sampling rate (2 kHz) and filters suitable to study high-frequency activity (0.3-1000 Hz). We observed high-frequency oscillations (HFOs) in both the off and on motor states. In the off state, the amplitude of the HFOs was coupled to the phase of the abnormal beta activity. The beta-coupled HFOs showed little or even negative movement-related changes in amplitude. Moreover, the degree of movement-related modulation of the HFOs correlated negatively with the rigidity/ bradykinesia scores. In the on motor state, the HFOs were liberated from this beta coupling, and they displayed marked movementrelated amplitude modulation. Cross-frequency interactions between the phase of slow activities and the amplitude of fast frequencies have been attributed an important role in information processing in cortical structures. Our findings suggest that nonlinear coupling between frequencies may not only be a physiological mechanism (as shown previously) but also that it may participate in the pathophysiology of parkinsonism.
Temporal discrimination thresholds (TDT) for recognition of paired sensory (tactile, auditory and visual) stimuli given over a wide range of time intervals were assessed in 44 patients with Parkinson's disease (PD) and 20 age-matched normal subjects. A significant increment in TDT for all three sensory modalities was found in PD patients compared with controls. This abnormality was greatly attenuated for about 2 h by a single levodopa/carbidopa (250/25 mg) tablet. A significant correlation was found between disease severity as assessed clinically and TDT. Patients with more severe PD had higher TDT values. The study of the peripheral median nerve and cortical somatosensory evoked potential recovery curves following double electrical stimulation of the index finger showed no differences between patients and control subjects, nor changes from 'off' to 'on' motor state which could explain the findings. These results indicate the existence of an abnormality of timing mechanisms in PD.
We compared the performance of 44 patients with Parkinson's disease (PD), tested 12-24 h after withdrawal of dopaminergic medication, with 20 age-matched controls, on a verbal test for time estimation and in several time reproduction tasks. Patients with PD underestimated the duration of a time interval in the verbal time estimation task and showed overproduction of time intervals when required to reproduce a short time sample. Absolute errors were greater in the reproduction of longer time intervals in both control and PD patients, but especially in the latter. The presentation of time markers at faster rates had a detrimental effect on the performance of the patients but not of the controls. Patients with more severe PD performed worse on the time estimation and reproduction tasks compared with those with milder disease. Administration of levodopa-carbidopa (205/25 mg, p.o.) significantly reduced absolute errors in time estimation and reproduction in conditions where time markers were presented at the two faster rates of 5 Hz and 3.3 Hz. Performance in these two latter tests best discriminated patients and controls and had a positive significant association with simple reaction time and movement time. These results lead us to suggest that time estimation, i.e. the 'internal clock', is abnormally slow in PD.
The pathophysiology of levodopa-induced dyskinesias (LID) in Parkinson's disease is not well understood. We have recorded local field potentials (LFP) from macroelectrodes implanted in the subthalamic nucleus (STN) of 14 patients with Parkinson's disease following surgical treatment with deep brain stimulation. Patients were studied in the 'Off' medication state and in the 'On' motor state after administration of levodopa-carbidopa (po) or apomorphine (sc) that elicited dyskinesias in 11 patients. The logarithm of the power spectrum of the LFP in selected frequency bands (4-10, 11-30 and 60-80 Hz) was compared between the 'Off' and 'On' medication states. A peak in the 11-30 Hz band was recorded in the 'Off' medication state and reduced by 45.2% (P < 0.001) in the 'On' state. The 'On' was also associated with an increment of 77. 6% (P < 0.001) in the 4-10 Hz band in all patients who showed dyskinesias and of 17.8% (P < 0.001) in the 60-80 Hz band in the majority of patients. When dyskinesias were only present in one limb (n = 2), the 4-10 Hz peak was only recorded in the contralateral STN. These findings suggest that the 4-10 Hz oscillation is associated with the expression of LID in Parkinson's disease.
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