Abnormal activity patterns of STN neurons play an important role in the pathophysiolgy of PD. As these patterns change with different phases of movement, it is important that they be assessed using active, reproducible tasks as described above. However, discerning which patterns are pathological is limited by the inability to record STN activity in normal humans. In addition to normal monkeys, STN activity can be evaluated in primates rendered Parkinsonian by the administration of 1-methyl-4-phenyl-2,3,6-tetrahydropyridine (MPTP). However, this approach has limitations in that MPTP-treated animals only approximate human PD, and such animals are frequently unable to perform complex behavioral tasks. An alternative comparison involves administration of dopaminergic agonists to human subjects intra-operatively; however, this prolongs surgery time and does not restore a normal state since long-term processes such as changes in receptor density are still present. Hence, no single comparison is perfect, but all have the potential to yield important insights in relation to the primary models of BG physiology.
The rate model posits that information is encoded by neuronal firing rates. In accordance with the rate model, the direct pathway is thought to facilitate movement, while the indirect pathway is thought to suppress movement. The antagonistic relationship between these pathways is governed by differential responses of striatal neurons to dopamine, with D1- direct pathway neurons being excited by dopamine, while D2-striatal neurons of the indirect pathway are inhibited. Thus in PD, the loss of dopamine results in less direct pathway activation and more indirect pathway activation – resulting in disinhibition of the GPi, suppression of the thalamus, and decreased cortical activity. Moreover, the extent and duration of movement-related increases in firing rates and periodic bursting patterns are altered with placement of lesions in the STN of normal monkeys (Wichmann et al., 1994b
). However, the power of oscillatory activity observed in GPi did not diminish with STN lesioning despite symptomatic tremor changes. During torque movement, Wichmann and colleagues found 40% of STN arm cells demonstrated significant activity changes (of which 90% were increased discharge rates) (Wichmann et al., 1994a
). By comparison the present study observed a similar 44% change in neuronal activity; however, in contrast we observed 57% of these neurons with increased discharge rates. The rate model has thus been used to describe hypokinetic aspects in PD, although other features such as tremor and dystonia are less clearly explained. The data presented above supports the basic prediction of the rate model in that the firing rate of STN excited neurons is greater in human PD patients compared to other neuron types in normal monkeys. Thus, the above data illustrates the importance of determining neuron response type (i.e., excited or inhibited) before a direct comparison can be made between individuals. Although the overall trend is consistent with the model, direct comparisons of firing rates between humans and primates must be interpreted with caution. However, comparisons between the distribution of different response types (i.e., the proportion of inhibited and excited neurons) may be more meaningful.
Like the rate model, the selectivity model predicts that information is encoded by neuronal rates. However, the selectivity model suggests that inputs to the GPi form a center-surround organization wherein direct pathway activity facilitates desired movements while STN activity (of the indirect pathway) inhibits unwanted behaviors. Dysregulation or depletion of dopamine may result in an inability to select desired or inhibit unwanted behaviors. Although this is an intriguing idea, there is little physiological data to support a center-surround organization in the GPi. Furthermore, the model suggests that for any movement, there are many competing movement programs, although this has not been clearly demonstrated.
The pattern model suggests that BG neuronal burst patterns differ between normal and pathological conditions. In the BG of animals given MPTP, burst occurrence and duration are often greater than that in normals (Wichmannn and Soares, 2006
). Thus, interactions between both burst length and intra- and inter-burst intervals are believed to alter information processing in the pallidum and subthalamic nucleus in Parkinsonian states (Beurrier et al., 1999
; Bevan et al., 2000
). The data presented here are consistent with the pattern model since mean burst rate and intra-burst frequencies were greater in the PD human than the normal monkey.
The oscillatory model suggests that BG nuclei encode information in specific frequency bands. The present study suggests that some degree of oscillatory changes relative to movement is present in the normal STN – possibly a normal property of the BG-cortical network. For example, Courtenmanche et al. (2003) reported widespread coherent beta-band oscillations in the striatum of normal behaving monkeys. However, there is considerable evidence that excessive oscillatory activity in BG neurons may contribute to the pathophysiology of PD. Abnormal oscillations of the BG are not limited to a single frequency, but instead appear to span a number of distinct frequency bands. Of note, previous studies suggest dopamine levels may play a role in regulating oscillatory activity in the BG as dopamine depletion has been shown to increase oscillatory power in the beta band (Sharotta et al., 2005
; Brown, 2002
). This is reversible by administration of dopamine agonists. The identification of abnormal oscillatory activity in the BG was described in both the PD human and the MPTP monkey (Miller and DeLong, 1987
; Filion and Tremblay 1991
). The relationship between oscillations and tremor is complex, such that beta-band oscillations can be observed in the presence and absence of tremor. Moreover, the frequency of beta-band oscillations is greater than the commonly observed 5 Hz tremor frequency. Hence, it has been suggested that abnormal beta-band oscillatory patterns may disrupt thalamo-cortical processing, resulting in akinesia (Rivlin-Etzion et al., 2006
). Moreover, the observed ~300 Hz inter-burst frequency in PD humans may account for the observations of Foffani and colleagues who reported 300 Hz oscillatory activity in the local field potentials of the Parkinsonian STN (Foffani et al., 2003
). Although not examined in this study due to analysis limitations, considerable attention has been paid to tremor related oscillatory activity of STN neurons in the range of 2-4 Hz (Rodriguez et al., 1998
; Magarrinoc-Ascone et al., 2000
; Levy et al., 2001
). Importantly, Levy et al. (2001)
demonstrated in the PD human that both the tremor and the 2-4 Hz STN oscillatory activity are concurrently attenuated with the administration of apomorphine. Tremor-related oscillations can be observed in single neurons (either alone or in the presence of beta-band oscillations) and may significantly contribute to the abnormal oscillatory activities seen in PD (Levy et al., 2001
Current models of BG physiology and pathophysiology have been useful in explaining specific attributes of PD such as tremor, bradykinesia and dystonia. However, no single model captures all physiological and clinical attributes observed in PD since specific studies refute various aspects of each model (Gale et al., 2007). One explanation for this shortcoming may be that each model tends to focus on a single characteristic of neuronal activity, such as firing rates, oscillatory characteristics, or burst patterns. Indeed, the findings of this study can be consistent with each model when the analysis is considered in isolation. However, as demonstrated by examining the variance in each measure of neuronal activity, a consistent pattern emerges. Specifically, across all modes of analysis (i.e. firing rate, burst rate, directional selectivity and spectral analysis), STN neurons in PD demonstrate less variability than do STN neurons of the normal primate.
We present the following hypothesis to account for these observations. In the normal condition, the BG-thalamic-cortical network dynamically modulates neuronal activity, and possibly the degree of correlation, in order to appropriately select or facilitate motor behavior. PD results in a multifactorial disruption of activity leading to a saturation of global and/or local neuronal patterns such as oscillations, synchronicity, firing rates, and bursting. The net effect is a reduction in the dynamic range of the affected neurons across multiple dimensions, which effectively reduces their information carrying capacity. Deep brain stimulation may work by either reducing these pathologic effects (allowing the neurons to have a more normal dynamic range), or by functionally taking the circuit off-line. Understanding which of these mechanisms is at play, should be an important component of future research, and will hopefully allow for the continued rational evolution of DBS therapies. Direct comparisons will therefore be required (between neurons with identical response types) between normal and MPTP monkeys during motor behaviors to support the above findings. Of note, the most salient implication of these findings for neurophysiologists is the various responses of neurons observed during microelectrode recording sessions. Before neuronal dynamics can be fully assessed in Parkinsonian patients or animals, the response to movement (excited, inhibited, or unresponsive) should be determined in each cell to avoid investigator bias or misinterpretation.