Brain, Vol. 127, No. 4, 721-722, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh164
Oscillatory activity in the basal ganglia—relationship to normal physiology and pathophysiology
There is mounting evidence that rhythmic brain oscillatory rhythms play important roles in processes such as perception, motor action and conscious experience, and that disruption or increases of activity in various oscillatory networks may be an important factor in mediating some of the symptoms associated with neurological diseases (Llinas et al., 1999
; Bevan et al., 2002). Rhythmic brain activity is of course well known from the EEG, where several different frequency ranges of oscillatory activity have been well characterized, the best known being the alpha rhythm that is generally observed when the eyes are closed. The oscillatory activity is usually identified and studied in cortical local field potentials (LFPs) and EEG, and reflects local rhythmic synchronized subthreshold activity in presynaptic terminals and the postsynaptic neurons. However, synchronized oscillatory neuronal firing supra-thershold (spike) activity can also be recorded and is likely to be related directly to the LFP oscillations. Oscillatory rhythms can be widespread, and rhythmic activity of the same frequency frequently can be observed to occur over wide cortical areas and even in the LFPs recorded in subcortical regions.
Oscillatory activity in the basal ganglia (BG) has attracted a great deal of interest in the past few years as it is thought to be important in both the normal functioning of the system and the pathophysiology of Parkinson’s disease (see review by Bevan et al., 2002).
Studies of neuronal firing in both humans with Parkinson’s disease and animal models of Parkinson’s disease provide evidence for an increase in oscillatory activity in the external and internal segments of the globus pallidus (GPe and GPi), and the subthalamic nucleus (STN) (e.g. Levy et al., 2000; Raz et al., 2000). Such changes in the patterns of firing of STN and GP neurons may be very important in causing the motor symptoms of PD and perhaps of other BG-mediated movement disorders. In particular, it has been hypothesized that dopamine depletion in Parkinson’s disease leads to a breakdown in the segregation of parallel subcircuits in the BG and to increased synchronized neuronal activity. The abnormal neuronal activity may play a role in the genesis of limb tremor (Deuschl et al., 2000) or dyskinesias (Vitek and Giroux, 2000), and synchronized oscillations of neuronal firing in the whole BG may underlie the clinical features of Parkinson’s disease (Raz et al., 2000; Brown 2003). This hypothesis is based on results of studies using simultaneous microelectrode recording techniques to demonstrate that periodic or ‘oscillatory’ firing rate fluctuations in pallidal neurons of tremulous tremulous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys and of pallidal and STN neurons in Parkinson’s disease patients is synchronized. The oscillatory activity recorded in these situations is in the 15–30 Hz beta range and/or in the 3–10 Hz theta range. The oscillations in the low-frequency range are frequently in synchrony with the tremor.
Several groups have taken advantage of the unique opportunity afforded by the implantation of deep brain stimulating (DBS) electrodes in GPi or STN in Parkinson’s disease patients to make LFP recordings from the contacts of these electrodes before the leads are internalized. These LFP recordings have also identified oscillations in these same two frequency ranges in Parkinson’s disease patients off dopaminergic medication. However, when patients are given dopaminergic medication, the beta oscillations are depressed and oscillations in the high gamma band above 60 Hz become apparent (Brown, 2003). Interestingly, a reduction in beta (<20 Hz) oscillations and an increase in gamma (>20 Hz) oscillations was observed in the GP of MPTP monkeys following inactivation of the STN and amelioration of the parkinsonian symptoms (Wichmann et al., 1994). Such observations suggest that beta oscillatory activity is enhanced and gamma activity depressed in Parkinson’s disease. It is not clear, however, what physiological characteristics are represented by these oscillatory patterns and thus why their alterations might result in the serious motor disturbances associated with Parkinson’s disease.
Brown’s group has started to utilize the LFP recordings in the BG of Parkinson’s disease patients to study the relationship of the oscillatory activity to generation of voluntary movements. In one study, beta activity was found to be reduced during voluntary movement of a joystick (Cassidy et al., 2002). A recently published study examined the beta band activity recorded from DBS electrodes in the STN in relation to a cued reaction time paradigm. Modulation of beta band power following the cue suggested a role for these oscillations in the organization of responses according to the relevance of behavioural cues (Williams et al., 2003).
In the current issue of Brain, Kuhn et al. (2004) provide additional findings that beta oscillatory activity reflects normal physiological processing of voluntary movement-related signals. In this study, they recorded the LFPs from the leads of DBS electrodes implanted in the STN of Parkinson’s disease patients in the few days before the leads were internalized and connected to the stimulator. The authors examined the LFP oscillatory activity in the beta range in a warned go/no-go reaction time task in which an imperative cue instructed the subject to move or not to move. Interestingly, they found that in the ‘go’ trials, the beta band LFP oscillatory activity decreased prior to movement, with an onset latency that strongly correlated with the mean reaction time across patients, and this was followed by a late post-movement increase in magnitude in the beta oscillatory activity. In contrast, in the ‘no-go’ trials, the decrease in beta activity following imperative signals ended earlier compared with the ‘go’ trials and, moreover, started to increase in intensity. The authors interpret these findings as suggesting that the STN is involved in the preparation of externally paced voluntary movements and that the degree of synchronization of STN activity in the beta band may be an important determinant of whether or not motor programming and movement initiation are favoured or suppressed. Recently, it has been reported that beta oscillatory LFPs can also be recorded from the striatum of the normal behaving monkey and that small focal zones in the oculomotor region lose their synchronous beta activity when the monkey performs saccadic eye movements (Courtemanche et al., 2003). These types of findings suggest that the increased tendency of the BG in Parkinson’s disease patients to oscillate in the beta frequency range interferes with the ability to execute a movement, and thus leads to the akinesia and bradykinesia associated with Parkinson’s disease. According to this hypothesis, any therapy that reduces this pathological hyperoscillatory activity, such as a lesion, high-frequency deep brain stimulation or dopaminergic therapy, would alleviate the akinetic symptoms of the disease.
It is not clear, however, in what way the beta oscillatory activity relates to the neuronal activity in the BG and their output to thalamus and brainstem. The LFP oscillations presumably reflect synchronized oscillatory pre- and/or postsynaptic activity in the STN, and such beta band oscillatory activity has indeed been reported to be present in the firing patterns of STN neurons in PD patients. As suggested by this and other studies, the presence of beta oscillatory activity appears to prevent movement, but the mechanism at the present time is a mystery.
1 Department of Physiology, University of Toronto, Toronto, Ontario, Canada 2 Department of Physiology, The Hebrew University Hadassah Medical School, The Hebrew University, Jerusalem, Israel
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