Characteristics of oscillatory pallidal neurons in patients with Parkinson's disease

Highlights

• Neurons in the GPi of PD patients have rapid firing rates, supporting the rate model

• Some neurons oscillate at β frequency and likely correlate with bradykinesia

• Some neurons oscillate at tremor frequency with high coherence to tremor

• Tremor coherence shows that each body part has a separate oscillator

• A few examples were found where tremor precedes bursting activity in the GPi

Abstract

Background

Excessive neuronal activity in the globus pallidus internus (GPi) is believed to promote parkinsonian akinesia/bradykinesia, but not tremor. Parkinsonian tremor is thought to result from dysfunction in the basal ganglia and cerebello-thalamo-cortical circuits. Whether the GPi is involved in tremorgenesis has not been fully elucidated. This study was designed to quantify the characteristics of oscillatory GPi neurons in patients with Parkinson's disease.

Methods

Nine patients undergoing surgery were studied. Microelectrode recordings in the GPi and electromyographic (EMG) activity in the limbs were recorded and the mean spontaneous firing rates (MSFRs) were calculated. Spectral analysis was used to assess neuronal oscillatory patterns. Coherence analysis was applied to explore the relationship between oscillatory neurons and EMG.

Results

Of 79 GPi neurons, 50.6% oscillated at the tremor frequency; 25.3% oscillated at β frequency, and 24.1% did not oscillate. The MSFR of all neurons was 81.5 ± 7.4 spikes/s. Among neurons oscillating at tremor frequency, 40% were coherent with the tremor. In four neurons, the pattern changed from tremor frequency to β frequency or vice versa. It appeared that the tremor began before the GPi fired bursts.

Conclusion

Some neuronal activity in the GPi correlates with tremor and this correlation might be due to either feedback, maintenance, or initiation. Since there were examples of EMG tremor prior to GPi activity, initiation seems least likely. The data further support the prediction of the classic pathophysiology model of Parkinson's disease.

Introduction

Parkinson's disease (PD) is characterized by bradykinesia, rigidity, and resting tremor. The symptoms are mainly caused by the degeneration of dopamine neurons in the substantia nigra pars compacta [1,2]. The relief afforded by pallidotomy and stimulation of the internal globus pallidus (GPi) imply a key role of the GPi in the control of movement [3]. It is one of the two output nuclei of the basal ganglia (GPi and substantial nigra pars reticulata), receives inputs from pathways in the basal ganglia, and projects primarily to the motor thalamus, indirectly influencing the cortex [4,5]. Although the clinical importance of the GPi in PD is clear, its role in relation to the motor symptoms (bradykinesia, rigidity, and tremor) is still poorly understood.

Pathological neuronal activity in the basal ganglia is associated with the motor symptoms of PD [4]. The GPi projects to the pallidal receiving area of the motor thalamus through inhibitory connections mediated by γ-aminobutyric acid [4,5]. According to the classical model of the pathophysiology of PD, the inhibitory projections are overactive, excessively inhibiting thalamic neurons to produce slowness and bradykinesia [5,6]. However, their relationship with resting tremor remains elusive [[7], [8], [9]]. Rather, parkinsonian tremor has been hypothesized to result from malfunctions in both the basal ganglia and cerebello-thalamo-cortical circuits [9,10]. Evidence has shown that the basal ganglia circuit evokes the onset of tremor and the cerebellar circuit determines its amplitude [[9], [10], [11]], but how the interplay of neuronal activity between basal ganglia and cerebellar circuits promotes parkinsonian tremor remains unclear.

In accordance with the “rate model”, an enhanced rate of neuronal discharge in the GPi has been reported in animal models of PD [12,13] and in parkinsonian patients during stereotactic neurosurgery [14,15]. These findings indicate that the firing rates are elevated in the parkinsonian state, though not all studies have shown the predicted changes in firing rate [[16], [17], [18]].

In addition, the increased neuronal bursting in the GPi and the subthalamic nucleus (STN) has provided an alternative theory for the manifestations of PD [19,20]. These studies also found neurons oscillating at the tremor frequency in the GPi [16,20,21], the STN [22,23], and the thalamus [24,25]. These neurons fired at the same frequency as the tremor, were often correlated with the muscular activity of the tremor [20,21,23], and were mostly found in the ventral oral anterior (Voa), ventral oral posterior (Vop), and ventral intermediate (Vim) nuclei of the thalamus [24,25]. The Voa and Vop nuclei receive major input from the GPi, whereas the Vim nucleus, an excellent target for the relief of tremor, receives primary input from the cerebellum. Interference with all these regions can effectively improve tremor. These results support the idea that PD tremor is due to an abnormal interaction between the basal ganglia and cerebellothalamic circuits [8, 9, 10, 11]. A more recent hypothesis has been proposed, that decreased dopamine in the GPi triggers hyperactivity in the cerebellothalamic circuit, producing resting tremor [10,11]. Although a recent study [26,27] has provided data on how deep brain stimulation (DBS) of the GPi modulates thalamic neuronal activity in the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) primate model of PD, it remains unknown how the interplay between these two circuits might result in parkinsonian tremor.

Numerous local field potential and microelectrode recording studies have explored the causal relationship between β oscillation and parkinsonian symptoms. These studies have revealed neurons with oscillating bursts in the β range (10–30 Hz) in the STN and GPi [15,[28], [29], [30]]. The pathological β oscillations have been reported to be inhibited by volitional movement [31,32], dopamine administration [28,29,33,34], and STN stimulation in some studies, but not in others (30, 35, 36, 37). Some studies have also demonstrated that STN neurons with β oscillation are directly correlated with akinesia/rigidity [[30], [31], [32],38]. Moreover, the level of inhibition of β oscillations during dopamine therapy is correlated with improvement of the hypokinetic symptoms, such as akinesia/bradykinesia and rigidity, but not tremor [3,30,38]. These data suggest that the abnormal β oscillation is a result of dopamine depletion in the basal ganglia [32,33] and is tightly correlated with akinesia/bradykinesia and rigidity.

Although the bulk of evidence demonstrates increased neuronal firing rates and pathological oscillatory patterns in the basal ganglia, the role of the GPi in parkinsonian rigidity, bradykinesia, and tremor remains unclear. The aim of this study was to quantify the characteristics of oscillatory neurons in the GPi in relation to parkinsonian symptoms. In particular, we addressed whether the GPi plays an important role in tremorgenesis.