Article Figures & Data
Figures
- Figure 1.
BG architecture. The STN is the only excitatory nucleus within the BG. STN activity excites the GPi and substantia nigra pars reticulata (SNr), the two BG output structures, via direct projections, but also has an indirect inhibitory impact on the GPi via the GPe (Smith et al., 1994; Shink and Smith, 1995; Nambu et al., 2000). The projections between the STN and the GPe, as well as the GPe and the striatum form two recurrent loops potentially promoting oscillations. Excitatory projections are shown in red, inhibitory projections in blue.
- Figure 2.
Stronger γ synchronization coincides with increased movement vigor. A, A larger proportion of cells engages in movement-related STN γ synchronization when movements are larger. The task required Parkinson’s patients to perform cued forearm pronation movements. The peak frequency of the movement-related γ increase is similar for small, medium and large movements in the STN (B) and in the GPi (D). A + B are adapted from Lofredi et al. (2018), and D is adapted from Brücke et al. (2012). In both studies the peak of γ synchronization seems to follow movement onset. Although not visible here, more subtle changes in synchronization may already occur earlier, similar to the increase in STN-GPi γ coherence as shown in C. C, An early increase in γ coherence (highlighted by the rectangle) was visible between simultaneously recorded STN and GPi LFP activity already after the warning signal (W), which preceded the go signal (G) and movement onset (M) by 2.5 s. This early increase was only apparent on dopaminergic medication in one patient. The sample size was small as simultaneous STN and GPi LFP recordings in humans are very rare. Note that the y-axis is vertically flipped compared with B + D. C is adapted from Cassidy et al. (2002) by permission of Oxford University Press.
- Figure 3.
Synchronization within and between sites. A, Synchronization between individual neurons can happen intermittently in bursts of variable lengths within one site. Large-scale local synchronization is reflected as oscillation in the local field potential (LFP). B, I will refer to synchronization between sites as phase coupling. Measures of phase coupling can be obtained by recording LFP activity (or EEG/MEG activity) in two anatomically separate sites and by testing whether the phase of the two oscillatory signals is consistently aligned. In this example, the subcortical sites are driven by cortical activity, with the phases being systematically offset, reflecting conduction delays. Only the green cells representing selected ensembles are synchronized and coupled; the gray cells are not recruited to join the oscillating activity. Directed coherence, Granger causality or dynamic causal modeling (DCM) can be used to make inferences about the directionality of coupling, asking what region is the driver. However, it is important to keep in mind that two recorded sites can be phase-coupled also as a result of being driven by a third site that may have not been recorded (Buzsáki and Schomburg, 2015). Note that phase coupling can but does not need to be accompanied by amplitude coupling. In the example shown in B, the amplitude in subcortical sites increased as the cortical amplitude increased. However, in sites that show strong oscillatory activity at baseline, the EEG/MEG amplitude may decrease when a subset of cells becomes coupled with another site.
- Figure 4.
Spike timing-dependent mechanisms of interactions. A, If the spike timing of cortical neurons becomes synchronized, they maximize their impact on downstream cells where their outputs converge, resulting in stronger and faster depolarization (mechanism 1: shift in spike timing). B, γ Oscillations reflecting asymmetric periods of excitation and inhibition could result in prolonged thalamic disinhibition and rebound activity, boosting thalamic firing rates from relatively low baseline firing rates to reach >100 Hz (Goldberg et al., 2013). C, Hypothetical model of surround inhibition through staggered GPi firing. Note that here surround inhibition does not consist of excitation via the direct pathway and inhibition through the indirect pathway as proposed before (Mink, 1996), but instead emerges from temporal offsets in rhythmic activity. During movement onset, a substantial number of STN cells synchronously fire at ∼70 Hz, establishing rhythmic activity in the GPi, while some striatal direct-pathway MSNs also increase and inhibit the GPi more focally (dMSN channel 1). Spikes resulting in movement facilitation are coloured in green. The MSN firing rates at movement onset seem to be substantially lower (∼20 Hz; Alexander, 1987) than those of STN cells, hence GPi target ensembles may not be fully silenced, but instead, their bouts of rhythmic activity, as found in LFP recordings (Brown et al., 2001; Brücke et al., 2012; Tsang et al., 2012; Singh and Bötzel, 2013), may be shorter and delayed (GPi Ch1) relative to the bouts of non-target ensembles that receive no dMSN inhibition (GPi Ch2). Inhibitory GPe activity, which can reach rates of ∼120 Hz during movement execution, could in principle take on a similar role as the dMSN Ch1 cells in reducing and delaying GPi activity (not shown in the schematic). The delayed bouts of GPi Ch1 ensembles would allow thalamic spiking activity in the pauses between successive GPi spikes to occur earlier in Thal Ch1 versus Thal Ch2. The BG-recipient thalamus projects to cortical L1, modulating pyramidal neurons in deeper layers by targeting their dendritic tufts (Garcia-Munoz and Arbuthnott, 2015). The earlier activation of Ctx Ch1 cells may engage a local network of interneurons closing the door to any Thal Ch2 inputs arriving with a delay.
- Figure 5.
Stop-related activity. A, STN power recorded during finger tapping (left) and successful stopping (right). The γ increase observed during the last regular tapping movement (= the final tap before the stop signal) peaked at around 90 Hz (shown by the arrow), while the γ increase during successful stopping peaked between 60–70 Hz. Peaks at 90 and 65 Hz correspond to γ cycles lasting 11 and 15 ms, respectively (including excitation and inhibition). A lower peak frequency could thus indicate slightly prolonged STN spiking within each cycle. The black curve in the lower panels denotes the finger movement (Left: The finger was first elevated, then it moved down to touch the table at around 300 ms and moved up again. Right: After the auditory stop signal, the downward movement stopped quickly, just after the γ increase.) A is adapted from Fischer et al. (2017). B, Proposed mechanism: increased drive to the STN after the stop signal may result in prolonged excitation and longer γ cycles (red dashed lines) compared with movement-related activity (black lines, also see Fig. 4B). The shifted rhythm is passed on to the GPi. GPi inhibition, cortical excitation and TRN inhibition converge in the thalamus, where they may cancel each other out.
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