High thalamocortical theta coherence in patients with Parkinson's disease

Abstract

Research investigating the pathophysiology of Parkinson's disease (PD) mostly focuses on basal ganglia dysfunction. However, the main output from the basal ganglia is via the thalamus, and corticothalamic feedback constitutes the primary source of synapses in the thalamus. We therefore focus on the thalamocortical interplay. During the surgical intervention in six patients, local field potentials (LFPs) were recorded from pallidal-recipient thalamic nuclei VA and VLa. Simultaneously, EEG was recorded from several sites on the scalp. The highest thalamocortical coherence was found in the theta frequency band (4-9 Hz) with a mean peak frequency of 7.5 Hz. The magnitude of thalamocortical theta coherence was comparable to the magnitude of EEG coherence between scalp electrode pairs. Thalamocortical theta coherence reached 70% and was maximal with frontal scalp sites on both hemispheres. In the 13-20 Hz beta frequency band, maximal coherence was comparatively low but localized on the scalp ipsilateral to the site of thalamic LFP recording. The high thalamocortical coherence underlines the importance of thalamic function for the genesis of scalp EEG. We discuss the PD pathophysiology within the framework of dysrhythmic thalamocortical interplay, which has important consequences for the choice of therapeutic strategy in patients with severe forms of PD.

Figure 1.

Spectral analysis of EEG and LFP. A, B, Power spectral density (units 10*log10 μV² Hz⁻¹) of scalp EEG at site C3 (A) and thalamic LFP (B) in patient 3. C, The coherence between EEG and LFP is significant from 7 to 9 Hz (full-width at half-maximum = 1.5 Hz) in the theta band. The 95% confidence interval (black ribbon) indicates significantly non-zero coherence also around 16 Hz in the β band. D, Phase ϕ between EEG and LFP. The slope dϕ/df was transformed into latency.

Figure 2.

Theta coherence maxima and thalamocortical latencies. A, Plotted are the maximal coherence values in the 4–9 Hz theta band of all electrode pairs containing the thalamic site (○) or the most frontal scalp site (+, Fpz or AFz) from all patients. The abscissa denotes the distance between the electrode sites of each pair. The corticocortical coherence falls off with distance. The thalamocortical coherence reaches high values for frontal electrode sites (markers ○ and + overlaid). B, The spread of thalamocortical latencies is of the same order of magnitude as the period T = 125 ms of the 8 Hz wave (interval between dotted lines).

Figure 3.

Theta coherence is maximal to frontal sites. A, For the patient group, the medians of thalamocortical theta coherence maxima are plotted on the topography of the scalp EEG sites. The frontal maximum reflects the finding that thalamocortical coherence was maximal with frontal sites for all patients. B, The medians (○) in A are plotted together with all corresponding coherence maxima (+).

Figure 4.

β Coherence is lateralized. The medians of thalamocortical β coherence maxima are plotted on the topography of the scalp EEG sites. Coherences in the β band are lower than in the theta band. A, The patient subgroup with LFP recording in the left thalamus shows maximal coherence with left central sites. B, The medians (○) in A are plotted together with all corresponding coherence maxima (+). C, The patient subgroup with LFP recording in the right thalamus shows maximal coherence with right central sites. D, The medians (○) in C are plotted together with all corresponding coherence maxima (+).

Figure 5.

Schema of thalamocortical circuits. We consider the three thalamocortical modules (A–C) to be identical. Module A is depicted in more detail (Jones, 2001). One module includes the following: (1) cortical layers (I, IV, V, and VI) with pyramidal cells and one gray GABAergic inhibitory cell; (2) nucleus reticularis (RT; gray GABAergic inhibitory cells); and (3) thalamus (TH), represented by one specific cell (e.g., in VA, VL) and one non-specific cell (e.g., in CL). The specific thalamic cell projects to the apical dendrites of both layer V and VI pyramidal cells, and collaterals sustain reticular feedback and cortical feedforward inhibitions. The nonspecific thalamic cell projects to the RT and to the layer V pyramidal neuron and has a divergent connection onto the neighboring module. The corticothalamic feedback connection is depicted as intramodular onto the RT and its thalamic relay cell and divergent intra- and cross-modular onto three thalamic relay cells. There are also divergent cross-modular reticulothalamic projections. The open arrows underline the cross-modular passages through thalamocortical, corticothalamic, reticulothalamic, and corticocortical pathways.

Figure 6.

LTS burst in thalamic nucleus VA. A, LTS bursting cell recorded in thalamic nucleus VA. Within the burst, the duration of each successive interspike interval increases progressively. The amplitude of the second spike was diminished with respect to the first in 80% of bursts (for discussion, see Llinas and Steriade, 2006). B, Two-dimensional interspike interval plot, for which the abscissa indicates the interspike interval to the previous spike and the ordinate indicates the interspike interval to the subsequent spike. The points at the bottom right represent the first spikes of bursts. C, The interspike interval histogram shows a bimodal distribution of a short intraburst interspike interval and a long interburst interspike interval of ∼225 ms. D, Mean and average of all interspike intervals grouped with respect to burst length show the progressive lengthening of the interspike interval and its small variation over all bursts. The number of bursts in each category is noted below the respective curve. E, The length of the first interspike interval decreases logarithmically (r² = 0.99) as a function of the number of spikes in the burst. F, The rhythmicity of the LTS burst activity, with a lag of ∼225 ms, is confirmed by the autocorrelation histogram. ISI, Interspike interval.