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Xu Zhang https://orcid.org/0000-0003-1988-7767 and Sabato Santaniello https://orcid.org/0000-0002-2133-9471 [email protected]Authors Info & Affiliations
Edited by Terrence J. Sejnowski, Salk Institute for Biological Studies, La Jolla, CA, and approved May 21, 2019 (received for review October 13, 2018)
Xu Zhang https://orcid.org/0000-0003-1988-7767 and Sabato Santaniello https://orcid.org/0000-0002-2133-9471 [email protected]Authors Info & Affiliations
Edited by Terrence J. Sejnowski, Salk Institute for Biological Studies, La Jolla, CA, and approved May 21, 2019 (received for review October 13, 2018)
Significance
We investigated the mechanisms of tremor generation in essential tremor (ET). Using computational modeling we show that tremor-related activity can originate from the olivocerebellar loop in response to a dysfunction and compensatory up-regulation of GABA receptors in the dentate nucleus of cerebellum. The emerging tremor-related activity then projects to thalamus and reaches the corticothalamic motor loop. Consistent with clinical observations, the study shows that the tremor frequency decreases as the up-regulation becomes stronger and increases as high-frequency stimulation is delivered to the thalamus. Our results provide an explanation of how local synaptic abnormalities would lead to widespread tremor-related neural activity in ET and suggest that compensatory processes in degenerative diseases may underlie brain dysfunction.
Abstract
Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABAA α1-receptor subunits and up-regulation of α2/3-receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.
Essential tremor (ET) is a progressive neurological disease and among the most prevalent movement disorders (1). ET is characterized by a 4- to 12-Hz kinetic tremor that occurs in the upper limbs and may eventually spread to the neck and jaws, or accompany gait symptoms (2, 3). Clinically, only ∼50% of the ET patients receive benefits from medications, while for the rest of the population, deep brain stimulation (DBS) of the ventral intermediate thalamus (Vim) is the main alternative therapy (4). Despite large interest, the origins of ET remain unclear. It has been hypothesized that tremor has a central origin in the brainstem (5), where pacemaker neurons with prominent subthreshold oscillations in the range of ET frequencies have been identified in the inferior olivary nucleus (ION) (6, 7). Further evidence in support of this hypothesis has been provided by animal studies involving the injection of the neurotoxin harmaline (8, 9), which primarily targets ION neurons and causes generalized kinetic tremor. However, no consistent structural or functional change has been observed in the ION of ET patients compared with healthy controls (10–12). Evidence suggests, instead, that ET is associated with microstructural changes and neuronal dysfunctions in the cerebellum (13–15) including a loss of dendritic spines in Purkinje cells in the cerebellar cortex, a decrease in GABAA and GABAB receptors in the dentate nucleus, and a deficit of bound GABA transmitters (16–19). These changes have been correlated with the tremor severity (13) and may lead to significant alterations in the motor network (20, 21). It remains unclear, though, how these changes may relate to tremor.
Studies involving genetically modified mice (22, 23) have shown that the deletion of GABAA receptor α1 subunits results in the loss of 50% of all GABAA receptors in the cerebellar structures and that such deletion is associated with kinetic tremor and motor incoordination, which are both characteristics of ET. Furthermore, it has been reported that the loss of α1 subunits is partially compensated by an overexpression of α2 and α3 subunits (23, 24), which colocalize with the α1 subunits in the cerebellar nuclei and the molecular layer of the cerebellar cortex in rodents as well as humans (25, 26) and are responsible for longer opening of ion channels and slowly decaying synaptic currents (27–29). Finally, an increase of tonic GABAA receptor-mediated currents has been reported in case of loss of α1 subunits (30). Altogether, these studies indicate that a substantial modulation of the temporal dynamics of the GABAergic currents may occur in the cerebellum under ET condition.
Here we constructed a computational model of the cortico-cerebello-thalamo-cortical (CCTC) loop and investigated whether changes to the dynamics of the GABAergic currents to the dentate nucleus may elicit tremor-related neuronal activity along the CCTC loop. The model includes single-compartment neurons from the brainstem (ION), the cerebellum (dentate nucleus and cerebellar cortex), the Vim, and the motor cortex (MC) according to a network topology derived from the primates’ anatomy. The model reproduces the average firing rates and discharge patterns of single units in nonhuman primates and mice under normal conditions as well as tremor conditions for all modeled structures, where the recordings under tremor conditions were derived from animal studies involving the neurotoxin harmaline.
We show through numerical simulations that a progressive combination of reduced synaptic conductance and prolonged decay of the GABAergic currents in the synapses between Purkinje cells and deep cerebellar neurons may facilitate sustained oscillatory activity at the frequency of tremor in the olivocerebellar loop, i.e., ION, cerebellar cortex, and dentate nucleus. The oscillations propagate to the thalamocortical system (Vim-MC) and induce a sustained bursting activity in the Vim with characteristics that are consistent with the activity of tremor cells in ET patients (31, 32). Consistent with clinical observations (33, 34), the frequency of the oscillatory activity slowly decreases by ∼1 Hz as the manipulation of GABAergic currents progresses and is instead increased by about 0.4 Hz when electrical stimulation at the frequency of therapeutic DBS (185 Hz) is applied to Vim. DBS also reduces the range of GABAergic settings that can sustain tremor-related oscillations, thus suggesting that even though primarily targeting the thalamocortical system, thalamic DBS may exert secondary effects on the olivocerebellar loop in ET patients. Finally, we show that neural oscillations leading to tremor-related bursting activity in the Vim can originate from a localized perturbation applied to a small portion of olivary neurons and spread through the entire cortico-olivo-cerebellar network, which further indicates the robustness of tremor-related neural dynamics and supports a possible network origin for ET.
Results
The CCTC network model (Fig. 1A) includes (i) the olivocerebellar loop, including eight ION neurons in the brainstem (SI Appendix, Fig. S1 A–D), 40 Purkinje cells (PC) and four granular layer clusters (GrL) in the cerebellar cortex (each GrL cluster includes one granule cell, one Golgi cell, and one stellate cell), and one glutamatergic deep cerebellar projection neuron (DCN) and one nucleoolivary neuron (NO) in the dentate nucleus (SI Appendix, Fig. S1 E–H); (ii) the thalamocortical system, including the Vim [1 thalamocortical neuron (TC)] and the MC (20 pyramidal neurons [PYN] and two fast-spiking interneurons [FSI]), (SI Appendix, Table S1). The connections between different neuron types are modeled using conductance-based synapses (SI Appendix, Table S2) and were constrained to reproduce the neuronal activity observed in vivo in PCs and DCN from healthy nonhuman primates during voluntary arm movements (SI Appendix, Fig. S2) (35). The connection graphs are reported in SI Appendix, Fig. S3, and were determined to be consistent with the neuronal anatomy in humans and animal models as these structures are largely conserved across species (36). The relay functions of the red nucleus (RN) along the dentato-rubro-olivary pathway (37–39) and of the pontine nuclei (PN) along the cortico-ponto-cerebellar pathway (40, 41), as well as the interneuron network (IN) in the cerebellar cortex (gray circles in Fig. 1A), are not explicitly modeled and are subsumed in the latency between presynaptic and postsynaptic structures (SI Appendix, Note 1).
Overall, the spread of tremor-related oscillations across multiple olivocerebellar loops indicates that under GABAergic dysfunction, the olivocerebellar system is highly susceptible to perturbations and can rapidly converge to global, tremor-related oscillatory dynamics.
Discussion
The cellular origins of ET have been intensively investigated over the past 20 y. The presence of tremor cells in the cerebellum-recipient regions of thalamus in ET patients (31) indicates that the cerebellothalamic pathway is pivotal to the generation of tremor. Moreover, ref. 58 reported an abnormal eyeblink conditioning in patients with ET, which suggests that the olivocerebellar system may be functionally impaired. Furthermore, studies (16, 59, 60) have reported several microstructural alterations in the cerebellar cortex of ET patients, including a diffused loss of the Purkinje cells, reduced dendritic arborizations, and axonal swellings, which may severely alter the cerebellar activity. Studies (17–19) have also reported a significant increment of GABAA receptor binding sites in the cerebellum and, locally, a significant decrease of GABAA and GABAB receptors in the dentate nucleus in ET patients. Finally, disorders that involve cerebellar dysfunction like motor learning impairment are frequently reported in ET subjects (61) along with a generalized hyperactivation of the cerebellar structures during movements (13, 62). Altogether, these results have contributed to the hypothesis that a cerebellar dysfunction may lead to pathologic activity along the cerebellothalamic pathway. It is unclear, though, how tremor-related activity in the Vim could result from such a variety of changes reported in the cerebellum. Our model provides a mechanistic explanation that reconciles several, apparently contradicting experimental observations. The following predictions are made.
We investigated the mechanisms of tremor generation in essential tremor (ET). Using computational modeling we show that tremor-related activity can originate from the olivocerebellar loop in response to a dysfunction and compensatory up-regulation of GABA receptors in the dentate nucleus of cerebellum. The emerging tremor-related activity then projects to thalamus and reaches the corticothalamic motor loop. Consistent with clinical observations, the study shows that the tremor frequency decreases as the up-regulation becomes stronger and increases as high-frequency stimulation is delivered to the thalamus. Our results provide an explanation of how local synaptic abnormalities would lead to widespread tremor-related neural activity in ET and suggest that compensatory processes in degenerative diseases may underlie brain dysfunction.
Abstract
Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABAA α1-receptor subunits and up-regulation of α2/3-receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.
Essential tremor (ET) is a progressive neurological disease and among the most prevalent movement disorders (1). ET is characterized by a 4- to 12-Hz kinetic tremor that occurs in the upper limbs and may eventually spread to the neck and jaws, or accompany gait symptoms (2, 3). Clinically, only ∼50% of the ET patients receive benefits from medications, while for the rest of the population, deep brain stimulation (DBS) of the ventral intermediate thalamus (Vim) is the main alternative therapy (4). Despite large interest, the origins of ET remain unclear. It has been hypothesized that tremor has a central origin in the brainstem (5), where pacemaker neurons with prominent subthreshold oscillations in the range of ET frequencies have been identified in the inferior olivary nucleus (ION) (6, 7). Further evidence in support of this hypothesis has been provided by animal studies involving the injection of the neurotoxin harmaline (8, 9), which primarily targets ION neurons and causes generalized kinetic tremor. However, no consistent structural or functional change has been observed in the ION of ET patients compared with healthy controls (10–12). Evidence suggests, instead, that ET is associated with microstructural changes and neuronal dysfunctions in the cerebellum (13–15) including a loss of dendritic spines in Purkinje cells in the cerebellar cortex, a decrease in GABAA and GABAB receptors in the dentate nucleus, and a deficit of bound GABA transmitters (16–19). These changes have been correlated with the tremor severity (13) and may lead to significant alterations in the motor network (20, 21). It remains unclear, though, how these changes may relate to tremor.
Studies involving genetically modified mice (22, 23) have shown that the deletion of GABAA receptor α1 subunits results in the loss of 50% of all GABAA receptors in the cerebellar structures and that such deletion is associated with kinetic tremor and motor incoordination, which are both characteristics of ET. Furthermore, it has been reported that the loss of α1 subunits is partially compensated by an overexpression of α2 and α3 subunits (23, 24), which colocalize with the α1 subunits in the cerebellar nuclei and the molecular layer of the cerebellar cortex in rodents as well as humans (25, 26) and are responsible for longer opening of ion channels and slowly decaying synaptic currents (27–29). Finally, an increase of tonic GABAA receptor-mediated currents has been reported in case of loss of α1 subunits (30). Altogether, these studies indicate that a substantial modulation of the temporal dynamics of the GABAergic currents may occur in the cerebellum under ET condition.
Here we constructed a computational model of the cortico-cerebello-thalamo-cortical (CCTC) loop and investigated whether changes to the dynamics of the GABAergic currents to the dentate nucleus may elicit tremor-related neuronal activity along the CCTC loop. The model includes single-compartment neurons from the brainstem (ION), the cerebellum (dentate nucleus and cerebellar cortex), the Vim, and the motor cortex (MC) according to a network topology derived from the primates’ anatomy. The model reproduces the average firing rates and discharge patterns of single units in nonhuman primates and mice under normal conditions as well as tremor conditions for all modeled structures, where the recordings under tremor conditions were derived from animal studies involving the neurotoxin harmaline.
We show through numerical simulations that a progressive combination of reduced synaptic conductance and prolonged decay of the GABAergic currents in the synapses between Purkinje cells and deep cerebellar neurons may facilitate sustained oscillatory activity at the frequency of tremor in the olivocerebellar loop, i.e., ION, cerebellar cortex, and dentate nucleus. The oscillations propagate to the thalamocortical system (Vim-MC) and induce a sustained bursting activity in the Vim with characteristics that are consistent with the activity of tremor cells in ET patients (31, 32). Consistent with clinical observations (33, 34), the frequency of the oscillatory activity slowly decreases by ∼1 Hz as the manipulation of GABAergic currents progresses and is instead increased by about 0.4 Hz when electrical stimulation at the frequency of therapeutic DBS (185 Hz) is applied to Vim. DBS also reduces the range of GABAergic settings that can sustain tremor-related oscillations, thus suggesting that even though primarily targeting the thalamocortical system, thalamic DBS may exert secondary effects on the olivocerebellar loop in ET patients. Finally, we show that neural oscillations leading to tremor-related bursting activity in the Vim can originate from a localized perturbation applied to a small portion of olivary neurons and spread through the entire cortico-olivo-cerebellar network, which further indicates the robustness of tremor-related neural dynamics and supports a possible network origin for ET.
Results
The CCTC network model (Fig. 1A) includes (i) the olivocerebellar loop, including eight ION neurons in the brainstem (SI Appendix, Fig. S1 A–D), 40 Purkinje cells (PC) and four granular layer clusters (GrL) in the cerebellar cortex (each GrL cluster includes one granule cell, one Golgi cell, and one stellate cell), and one glutamatergic deep cerebellar projection neuron (DCN) and one nucleoolivary neuron (NO) in the dentate nucleus (SI Appendix, Fig. S1 E–H); (ii) the thalamocortical system, including the Vim [1 thalamocortical neuron (TC)] and the MC (20 pyramidal neurons [PYN] and two fast-spiking interneurons [FSI]), (SI Appendix, Table S1). The connections between different neuron types are modeled using conductance-based synapses (SI Appendix, Table S2) and were constrained to reproduce the neuronal activity observed in vivo in PCs and DCN from healthy nonhuman primates during voluntary arm movements (SI Appendix, Fig. S2) (35). The connection graphs are reported in SI Appendix, Fig. S3, and were determined to be consistent with the neuronal anatomy in humans and animal models as these structures are largely conserved across species (36). The relay functions of the red nucleus (RN) along the dentato-rubro-olivary pathway (37–39) and of the pontine nuclei (PN) along the cortico-ponto-cerebellar pathway (40, 41), as well as the interneuron network (IN) in the cerebellar cortex (gray circles in Fig. 1A), are not explicitly modeled and are subsumed in the latency between presynaptic and postsynaptic structures (SI Appendix, Note 1).
Overall, the spread of tremor-related oscillations across multiple olivocerebellar loops indicates that under GABAergic dysfunction, the olivocerebellar system is highly susceptible to perturbations and can rapidly converge to global, tremor-related oscillatory dynamics.
Discussion
The cellular origins of ET have been intensively investigated over the past 20 y. The presence of tremor cells in the cerebellum-recipient regions of thalamus in ET patients (31) indicates that the cerebellothalamic pathway is pivotal to the generation of tremor. Moreover, ref. 58 reported an abnormal eyeblink conditioning in patients with ET, which suggests that the olivocerebellar system may be functionally impaired. Furthermore, studies (16, 59, 60) have reported several microstructural alterations in the cerebellar cortex of ET patients, including a diffused loss of the Purkinje cells, reduced dendritic arborizations, and axonal swellings, which may severely alter the cerebellar activity. Studies (17–19) have also reported a significant increment of GABAA receptor binding sites in the cerebellum and, locally, a significant decrease of GABAA and GABAB receptors in the dentate nucleus in ET patients. Finally, disorders that involve cerebellar dysfunction like motor learning impairment are frequently reported in ET subjects (61) along with a generalized hyperactivation of the cerebellar structures during movements (13, 62). Altogether, these results have contributed to the hypothesis that a cerebellar dysfunction may lead to pathologic activity along the cerebellothalamic pathway. It is unclear, though, how tremor-related activity in the Vim could result from such a variety of changes reported in the cerebellum. Our model provides a mechanistic explanation that reconciles several, apparently contradicting experimental observations. The following predictions are made.
Tremor Oscillations May Have Network Origins.
Studies (15, 20, 21, 63) have reported diffused alterations to the functional networks among cerebellum, thalamus, and cortices during motor tasks in ET subjects, including a significant reduction of the connectivity between cortical and cerebellar motor areas as well as between cerebellar cortex and dentate nuclei, and an increment in low-frequency oscillatory activity in the motor cortices. Both the reduction in connectivity and the increment in low-frequency oscillations positively correlated with the severity of kinetic tremor, thus suggesting a link between network dysfunctions and tremor. Although it is unclear how oscillations in the cerebellum affect the activity of the cerebral cortex, it has been suggested that the structural alterations in the cerebellum may alter the cerebellar output to the cortico-thalamo-cerebellar networks, thus contributing to the disruption of the connectivity in these functional networks (20).
Our study identifies a potential network-based mechanism to sustain and amplify tremor-related neural oscillations. We predict that such oscillations are sustained by the interplay between inferior olivary nucleus, dentate nucleus, and cerebellar cortex. The oscillatory activity propagates along the olivocerebellar pathway into the cerebellum and reenters the olivary nucleus through the dentato-rubro-olivary pathway. In addition, localized perturbations to a small portion of neurons in the inferior olive nucleus can initiate neural oscillations that quickly spread to a larger network and eventually alter the thalamocortical discharge patterns. This prediction reconciles the role of the inferior olivary nucleus in maintaining neural oscillations with the lack of olivary dysfunctions reported in ET patients (10–12) and suggests that the olivary neurons may be recruited into tremor oscillations via the dentato-rubro-olivary pathway because of their intrinsic pacemaker capabilities, with no need for specific alterations of the ion channels or synapses.
Although there is little knowledge about the dentato-rubro-olivary pathway, studies in ET patients have recently suggested that this pathway may be involved in tremor generation (64, 65). It is also known that drugs (e.g., alcohol) that interfere with the synaptic transmissions along this pathway can attenuate tremor symptoms and reduce the size of Purkinje cells’ complex spikes following climbing fiber activation (66, 67). Our model predicts that the reduction in complex spikes would result in shorter hyperpolarization and weaker rebound firing of the deep cerebellar neurons and therefore cause a decreased activity of the dentato-rubro-olivary pathway, which is consistent with observations reported in ref. 66. We expect that the manipulation of this pathway in animal models, e.g., via optogenetic stimulation of the red nucleus, might help further assess the role in ET.
Slow-Decaying GABAergic Currents in the Dentate Nucleus Contribute to Sustained Neural Oscillations.It has been speculated that the loss of Purkinje cells and the structural changes to the cerebellar cortex may cause a reorganization of the Purkinje cell functional network as well as the interface between climbing fibers and Purkinje cells (2). This reorganization would result in a reduced GABAergic modulation of the dentate nuclei and a facilitation of the pacemaker activity of the DCN cells, which would eventually propagate to the thalamus (2). Our study suggests that a nonspecific reduction in the GABAergic currents to the DCN can increase its average firing rate and thus the glutamatergic input to the thalamus, but it does not lead to a rhythmic activity in the tremor band either in the DCN or Vim. This is supported by the observation that deep cerebellar neurons rarely exhibit spontaneous pacemaker activity at frequencies within the tremor band (68). This is also consistent with earlier studies, e.g., ref. 69, which reported that the degeneration of Purkinje cells alone may be insufficient to elicit sustained oscillations in the Vim, while highly synchronized afferent currents from the deep cerebellar structures are required to recruit the thalamocortical neurons.
Our study suggests that the temporal dynamics of the GABAergic currents may be critical for tremor generation. Although none of the parametric changes that we applied to the GABAergic currents were sufficient to initiate tremor-related network oscillations in our model, we found that a specific range of GABAergic currents to the dentate nucleus can make these oscillations outlast the initial perturbation and self-sustain. This suggests that the role of the cerebellar dysfunctions in ET may be related to the preservation, amplification, and propagation of the tremor oscillations. Moreover, the need for an initial perturbation may be linked to the fact that tremor oscillations in the thalamus are enabled by voluntary movement, while absent at rest (31).
On the other hand, the preservation of network oscillations depends on the dynamics of the GABAergic currents. Specifically, the GABAergic dysfunctions between Purkinje cells and dentate neurons may reduce the fast α1-subunit–mediated currents and increase the slowly decaying currents mediated by the up-regulated α2/3 subunits (23–26). Our model predicts that such currents can facilitate the after-hyperpolarization rebound of the deep cerebellar neurons, which robustly activates the olivary neurons at a preferred phase of their subthreshold oscillations, thus facilitating the synchronization along the olivocerebellar loop. Also, other ET-related pathologies such as the increased Purkinje cell axonal branching, recurrent collaterals, and terminal axonal sprouting may further amplify such synchronization and therefore exacerbate tremor symptoms, even with substantial losses of inferior olive neurons and Purkinje cells (70, 71).
Finally, our model shows that the range of tremor-related GABAergic currents to the dentate nucleus increases as the synaptic current from the nucleoolivary neurons to the inferior olivary nucleus (NO→ION) decreases. This is mediated by an increment of the connectivity between olivary neurons, which occurs because the modeled NO→ION pathway has an inhibitory effect on the gap junctions between olivary neurons. The net effect is consistent with the regulatory action of the NO→ION pathway on the neuronal coupling in the inferior olivary nucleus (72). However, the interaction between ION and NO neurons involves additional connections, such as the projections from climbing fibers to NO neurons (73), which are currently neglected in our model and may contribute a negative feedback to the ION neurons. In addition, the specific localization of the NO synapses on the ION neurons and the morphology of the dendrites of ION neurons may significantly steer the synchronization within the inferior olivary nucleus (72, 74–76). Accordingly, it is plausible that the NO–ION connectivity may affect the network oscillations. For instance, it is possible that the adaptation of the discharge pattern of NO and ION neurons may result in a wider range of oscillation frequencies across the entire network than in our model. Similarly, as the ION neurons form groups of densely coupled neurons interspersed with areas of weak coupling (75), it is possible that different circuits along the olivocerebellar pathway have oscillations at slightly different frequencies, thus resulting in a more complex spreading of the neural oscillations through the network.
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Studies (15, 20, 21, 63) have reported diffused alterations to the functional networks among cerebellum, thalamus, and cortices during motor tasks in ET subjects, including a significant reduction of the connectivity between cortical and cerebellar motor areas as well as between cerebellar cortex and dentate nuclei, and an increment in low-frequency oscillatory activity in the motor cortices. Both the reduction in connectivity and the increment in low-frequency oscillations positively correlated with the severity of kinetic tremor, thus suggesting a link between network dysfunctions and tremor. Although it is unclear how oscillations in the cerebellum affect the activity of the cerebral cortex, it has been suggested that the structural alterations in the cerebellum may alter the cerebellar output to the cortico-thalamo-cerebellar networks, thus contributing to the disruption of the connectivity in these functional networks (20).
Our study identifies a potential network-based mechanism to sustain and amplify tremor-related neural oscillations. We predict that such oscillations are sustained by the interplay between inferior olivary nucleus, dentate nucleus, and cerebellar cortex. The oscillatory activity propagates along the olivocerebellar pathway into the cerebellum and reenters the olivary nucleus through the dentato-rubro-olivary pathway. In addition, localized perturbations to a small portion of neurons in the inferior olive nucleus can initiate neural oscillations that quickly spread to a larger network and eventually alter the thalamocortical discharge patterns. This prediction reconciles the role of the inferior olivary nucleus in maintaining neural oscillations with the lack of olivary dysfunctions reported in ET patients (10–12) and suggests that the olivary neurons may be recruited into tremor oscillations via the dentato-rubro-olivary pathway because of their intrinsic pacemaker capabilities, with no need for specific alterations of the ion channels or synapses.
Although there is little knowledge about the dentato-rubro-olivary pathway, studies in ET patients have recently suggested that this pathway may be involved in tremor generation (64, 65). It is also known that drugs (e.g., alcohol) that interfere with the synaptic transmissions along this pathway can attenuate tremor symptoms and reduce the size of Purkinje cells’ complex spikes following climbing fiber activation (66, 67). Our model predicts that the reduction in complex spikes would result in shorter hyperpolarization and weaker rebound firing of the deep cerebellar neurons and therefore cause a decreased activity of the dentato-rubro-olivary pathway, which is consistent with observations reported in ref. 66. We expect that the manipulation of this pathway in animal models, e.g., via optogenetic stimulation of the red nucleus, might help further assess the role in ET.
Slow-Decaying GABAergic Currents in the Dentate Nucleus Contribute to Sustained Neural Oscillations.It has been speculated that the loss of Purkinje cells and the structural changes to the cerebellar cortex may cause a reorganization of the Purkinje cell functional network as well as the interface between climbing fibers and Purkinje cells (2). This reorganization would result in a reduced GABAergic modulation of the dentate nuclei and a facilitation of the pacemaker activity of the DCN cells, which would eventually propagate to the thalamus (2). Our study suggests that a nonspecific reduction in the GABAergic currents to the DCN can increase its average firing rate and thus the glutamatergic input to the thalamus, but it does not lead to a rhythmic activity in the tremor band either in the DCN or Vim. This is supported by the observation that deep cerebellar neurons rarely exhibit spontaneous pacemaker activity at frequencies within the tremor band (68). This is also consistent with earlier studies, e.g., ref. 69, which reported that the degeneration of Purkinje cells alone may be insufficient to elicit sustained oscillations in the Vim, while highly synchronized afferent currents from the deep cerebellar structures are required to recruit the thalamocortical neurons.
Our study suggests that the temporal dynamics of the GABAergic currents may be critical for tremor generation. Although none of the parametric changes that we applied to the GABAergic currents were sufficient to initiate tremor-related network oscillations in our model, we found that a specific range of GABAergic currents to the dentate nucleus can make these oscillations outlast the initial perturbation and self-sustain. This suggests that the role of the cerebellar dysfunctions in ET may be related to the preservation, amplification, and propagation of the tremor oscillations. Moreover, the need for an initial perturbation may be linked to the fact that tremor oscillations in the thalamus are enabled by voluntary movement, while absent at rest (31).
On the other hand, the preservation of network oscillations depends on the dynamics of the GABAergic currents. Specifically, the GABAergic dysfunctions between Purkinje cells and dentate neurons may reduce the fast α1-subunit–mediated currents and increase the slowly decaying currents mediated by the up-regulated α2/3 subunits (23–26). Our model predicts that such currents can facilitate the after-hyperpolarization rebound of the deep cerebellar neurons, which robustly activates the olivary neurons at a preferred phase of their subthreshold oscillations, thus facilitating the synchronization along the olivocerebellar loop. Also, other ET-related pathologies such as the increased Purkinje cell axonal branching, recurrent collaterals, and terminal axonal sprouting may further amplify such synchronization and therefore exacerbate tremor symptoms, even with substantial losses of inferior olive neurons and Purkinje cells (70, 71).
Finally, our model shows that the range of tremor-related GABAergic currents to the dentate nucleus increases as the synaptic current from the nucleoolivary neurons to the inferior olivary nucleus (NO→ION) decreases. This is mediated by an increment of the connectivity between olivary neurons, which occurs because the modeled NO→ION pathway has an inhibitory effect on the gap junctions between olivary neurons. The net effect is consistent with the regulatory action of the NO→ION pathway on the neuronal coupling in the inferior olivary nucleus (72). However, the interaction between ION and NO neurons involves additional connections, such as the projections from climbing fibers to NO neurons (73), which are currently neglected in our model and may contribute a negative feedback to the ION neurons. In addition, the specific localization of the NO synapses on the ION neurons and the morphology of the dendrites of ION neurons may significantly steer the synchronization within the inferior olivary nucleus (72, 74–76). Accordingly, it is plausible that the NO–ION connectivity may affect the network oscillations. For instance, it is possible that the adaptation of the discharge pattern of NO and ION neurons may result in a wider range of oscillation frequencies across the entire network than in our model. Similarly, as the ION neurons form groups of densely coupled neurons interspersed with areas of weak coupling (75), it is possible that different circuits along the olivocerebellar pathway have oscillations at slightly different frequencies, thus resulting in a more complex spreading of the neural oscillations through the network.
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