Brain, Vol. 125, No. 6, 1175-1176,
June 2002
© 2002 Guarantors of Brain
Editorial |
Neural rhythms in Parkinson’s disease
1 St Mary’s Hospital and National Hospital for Neurology and Neurosurgery, London, UK
Neurologists should take brain rhythms seriously. Classical neurophysiology has focused on the encoding of information through changes in the firing rate of neurones, the salience of a stimulus or initiation of a motor response being accompanied by increases or decreases in neuronal activity. Yet when networks of neurones interact the result is often rhythmic activity within defined frequency ranges that can engage in temporal synchronization and de-synchronization. Neurologists are predisposed to consider all rhythmicity as pathological. After all, in our working lives we diagnose essential tremor and the tremor of Parkinson’s disease and many of our concepts of diseases such as epilepsy are bound up with ideas of widespread rhythmic synchronization of neural elements resulting in loss of consciousness and violent involuntary movement.
Over recent years a more sophisticated appreciation of neural rhythmicity and temporal synchronization has emerged. Neurophysiologists can now record simultaneously from networks of neurones in cortical and sub-cortical structures of humans and animals. We are beginning to understand that brain rhythms, their synchronization and de-synchronization, form an important and possibly fundamental part of the orchestration of perception, motor action and conscious experience (Singer, 1993
; Farmer, 1998) and that disruption of oscillation and/or temporal synchronization may be a fundamental mechanism of neurological disease.
Levy and colleagues in this issue of Brain (Levy et al., 2002) report the results of sophisticated micro- and macro-electrode recordings from sub-thalamic nucleus (STN) in conscious patients undergoing neurosurgical treatment for advanced Parkinson’s disease. Their data consists of action potentials recorded from micro-electrodes and local field potentials recorded using macro-electrodes. Using Fourier analysis they have identified the dominant frequencies of oscillatory activity in action potential spike trains and local field potentials. Application of coherence analysis to such data enables the determination of correlation and phase relationships between frequency components of different signals. Calculation of the coherence allows researchers to focus on the interaction between salient frequencies within the signals; furthermore, interactions between frequencies of different types of signal, for example spike trains recorded from single STN neurones and local field potential waveforms can be examined. These types of analysis allow changes in the strength (power) of a signal or the strength of its interaction with another signal (coherence) to be plotted over the time course within which experimental manipulation or treatment occurs.
The study by Levy et al. (2002) contains a number of important insights. (i) The frequency range (15–30 Hz) of rhythms detected in STN is the same as that found in healthy humans to modulate motor unit activity during isometric muscle contraction (Farmer et al., 1993). (ii) The 15–30 Hz frequency range is the same range as the coherence found between motor cortex MEG, EEG or local field potentials and contralateral EMG during steady muscle contraction in humans and primates (Conway et al., 1995; Salenius et al., 1997; Baker et al., 1997). (iii) The 15–30 Hz STN oscillations are diminished by voluntary movement in a way analogous to the suppression of human motor cortex beta EEG oscillations (Pfurtscheller, 1981) and motor cortex–muscle 15–30 Hz coherence in primates and humans (Baker et al., 1997; Kilner et al., 2000). (iv) Whilst we do not know if STN 15–30 Hz oscillations are present in non-Parkinsonian individuals, Levy et al. (2002) show that treatment with apomorphine and levodopa suppresses the oscillations with a time course that correlates with improvement of the ‘off’ symptoms of Parkinson’s. (v) Suppression of 15–30 Hz STN oscillations with voluntary movement occurs independently of changes in the firing rate of STN neurones, indicating that their temporal pattern of discharge conveys additional information to their firing rate. (vi) The 15–30 Hz oscillations are detected in the temporal patterning of STN neurone spike trains as well as at the level of local field potentials. (vii) The oscillations do not relate in any clear way to Parkinsonian tremor and when considered in the light of the work of other groups (see below) may relate more to mechanisms of akinesia.
The work of Brown and colleagues (Brown et al., 2001; Marsden et al., 2001) has shown that in Parkinson’s patients there is coherence between the motor cortex EEG and 15–30 Hz STN local field potential oscillations. Thus the Parkinsonian STN is driven by 15–30 Hz motor cortex oscillations. This leads to the hypothesis that the Parkinsonian motor cortex-basal ganglia may be held abnormally in a 15–30 Hz oscillatory state; yet as discussed above, these are the same coherent frequencies as those detected between motor cortex and muscle during postural maintenance in healthy humans. Levy et al. (2002) show that voluntary movement in Parkinson’s disease is associated with reduction of 15–30 Hz STN oscillations in a way analogous to the movement-related suppression of 15–30 Hz motor cortex–muscle coherence in healthy subjects. However, in Parkinson’s disease voluntary movement itself may be suppressed due to the presence of these oscillations in STN and other basal ganglia structures, possibly brought about by abnormal access to the basal ganglia of motor cortex oscillations. Exogenous dopaminergic stimulation in Parkinson’s disease may improve movement through reduction of the abnormal STN 15–30 Hz oscillations and promotion of faster (
70 Hz) oscillations (Brown et al., 2001); likewise, interruption either as the result of neurosurgical lesioning of STN or high frequency functional stimulation of STN results in ‘release’ of the 15–30 Hz ‘hold’ pattern and reduction of akinesia. Brown et al. (2001) and Levy et al. (2002) make the important assertion that the clinical efficacy of high frequency STN stimulation in Parkinson’s may be the result of oscillatory patterning rather than depolarizing block, and observe that low frequency functional stimulation of STN at 15 Hz, i.e. within the 15–30 Hz range of STN oscillations detected in the Parkinsonian state, worsens akinesia.
An intriguing model of abnormal basal ganglia function is emerging in which the temporal patterns as well as the firing rates of neuronal activity are important. Levy et al. (2002) propose that as a result of dopamine depletion 15–30 Hz cortical beta oscillations gain access to the basal ganglia through the cortical-subthalamic pathway, these then promote oscillatory synchronization in the wider basal ganglia and contribute to the symptoms of Parkinson’s disease. It could be proposed that because of abnormal access of 15–30 Hz motor cortex oscillations to the basal ganglia, Parkinsonian patients are held in a state that may have evolved to assist healthy humans during normal position holding through provision of synchronous and therefore more effective 15–30 Hz motor cortex drive to spinal motoneurone pools. Reduction of the basal ganglia 15–30 Hz oscillations through dopaminergic drugs, neurosurgical lesioning or high frequency stimulation releases the system from this ‘hold’ state and partially overcomes akinesia.
Attractive though the above considerations seem, important inconsistencies remain which will need to be addressed through further experimentation. For example, one might predict that 15–30 Hz cortex–muscle coherence and muscle–muscle coherence will be increased in Parkinson’s disease and be abolished less effectively by attempted movement. In fact for the first of these points the opposite is the case, Salenius et al. (2002) have shown that during voluntary tonic contraction in untreated Parkinson’s disease there is increased motor cortex MEG to EMG coherence at 5–12 Hz and reduced 15–30 Hz coherence; L-Dopa reduces 5–12 Hz coherence and enhances 15–30 and 35–60 Hz MEG-EMG coherence. During therapeutic stimulation of the basal ganglia increases in 15–30 Hz muscle coherence have been observed which correlate with improvements in bradykinesia. Therefore, just as earlier models of basal ganglia function that have focused exclusively on firing rates of neurones in STN and globus pallidus have been shown to be incomplete, we should be cautious about over mechanistic functional interpretations of oscillatory activity. However, we can look forward to exciting developments when experimenters examine changes in neural oscillations in more regions of the basal ganglia and motor cortex; and in addition to studying tonic muscle contraction, use coherence techniques to examine in greater detail oscillation changes associated with the abnormalities of complex movement and the transitions between tonic contraction and movement which patients suffering from Parkinson’s disease find so problematic.
The primary importance of the now substantial body of work on cortical and subcortical 15–30 Hz oscillations in healthy subjects and those with Parkinson’s disease, of which the paper by Levy et al. (2002) is an important part, is that consideration of temporal patterning effects of oscillation and temporal synchronization, in addition to the effects of the firing rate of neurones, adds a new dimension to our understanding of normal and abnormal neurophysiology of movement.
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