Title: Role of cerebellar GABAergic dysfunctions in the origins of essential tremor
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 GABA A α 1 -receptor subunits and up-regulation of α 2/3 -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. more »« less
Anderson, Collin J.; Figueroa, Karla P.; Dorval, Alan D.; Pulst, Stefan M.(
, Annals of Neurology)
Objective
Degenerative cerebellar ataxias (DCAs) affect up to 1 in 5,000 people worldwide, leading to incoordination, tremor, and falls. Loss of Purkinje cells, nearly universal across DCAs, dysregulates the dentatothalamocortical network. To address the paucity of treatment strategies, we developed an electrical stimulation‐based therapy for DCAs targeting the dorsal dentate nucleus.
Methods
We tested this therapeutic strategy in the Wistar Furthshakerrat model of Purkinje cell loss resulting in tremor and ataxia. We implantedshakerrats with stimulating electrodes targeted to the dorsal dentate nucleus and tested a spectrum of frequencies ranging from 4 to 180 Hz.
Results
Stimulation at 30 Hz most effectively reduced motor symptoms. Stimulation frequencies >100 Hz, commonly used for parkinsonism and essential tremor, worsened incoordination, and frequencies within the tremor physiologic range may worsen tremor.
Interpretation
Low‐frequency deep cerebellar stimulation may provide a novel strategy for treating motor symptoms of degenerative cerebellar ataxias. Ann Neurol 2019;85:681–690
Wang, Mien Brabeeba; Lynch, Nancy; Halassa, Michael(
, Thalamocortical Interactions Gordon Research Conference 2024)
Animals flexibly select actions that maximize future rewards despite facing uncertainty in sen-
sory inputs, action-outcome associations or contexts. The computational and circuit mechanisms
underlying this ability are poorly understood.
A clue to such computations can be found in the neural systems involved in representing sensory
features, sensorimotor-outcome associations and contexts. Specifically, the basal ganglia (BG) have
been implicated in forming sensorimotor-outcome association [1] while the thalamocortical loop
between the prefrontal cortex (PFC) and mediodorsal thalamus (MD) has been shown to engage in
contextual representations [2, 3]. Interestingly, both human and non-human animal experiments
indicate that the MD represents different forms of uncertainty [3, 4]. However, finding evidence
for uncertainty representation gives little insight into how it is utilized to drive behavior.
Normative theories have excelled at providing such computational insights. For example, de-
ploying traditional machine learning algorithms to fit human decision-making behavior has clarified
how associative uncertainty alters exploratory behavior [5, 6]. However, despite their computa-
tional insight and ability to fit behaviors, normative models cannot be directly related to neural
mechanisms. Therefore, a critical gap exists between what we know about the neural representa-
tion of uncertainty on one end and the computational functions uncertainty serves in cognition.
This gap can be filled with mechanistic neural models that can approximate normative models as
well as generate experimentally observed neural representations.
In this work, we build a mechanistic cortico-thalamo-BG loop network model that directly
fills this gap. The model includes computationally-relevant mechanistic details of both BG and
thalamocortical circuits such as distributional activities of dopamine [7] and thalamocortical pro-
jection modulating cortical effective connectivity [3] and plasticity [8] via interneurons. We show
that our network can more efficiently and flexibly explore various environments compared to com-
monly used machine learning algorithms and we show that the mechanistic features we include
are crucial for handling different types of uncertainty in decision-making. Furthermore, through
derivation and mathematical proofs, we approximate our models to two novel normative theories.
We show mathematically the first has near-optimal performance on bandit tasks. The second is
a generalization on the well-known CUMSUM algorithm, which is known to be optimal on single
change point detection tasks [9]. Our normative model expands on this by detecting multiple
sequential contextual changes. To our knowledge, our work is the first to link computational in-
sights, normative models and neural realization together in decision-making under various forms
of uncertainty.
Farrens, Andria J.; Vahdat, Shahabeddin; Sergi, Fabrizio(
, The Journal of Neuroscience)
Dynamic adaptation is an error-driven process of adjusting planned motor actions to changes in task dynamics (Shadmehr, 2017). Adapted motor plans are consolidated into memories that contribute to better performance on re-exposure. Consolidation begins within 15 min following training (Criscimagna-Hemminger and Shadmehr, 2008), and can be measured via changes in resting state functional connectivity (rsFC). For dynamic adaptation, rsFC has not been quantified on this timescale, nor has its relationship to adaptative behavior been established. We used a functional magnetic resonance imaging (fMRI)-compatible robot, the MR-SoftWrist (Erwin et al., 2017), to quantify rsFC specific to dynamic adaptation of wrist movements and subsequent memory formation in a mixed-sex cohort of human participants. We acquired fMRI during a motor execution and a dynamic adaptation task to localize brain networks of interest, and quantified rsFC within these networks in three 10-min windows occurring immediately before and after each task. The next day, we assessed behavioral retention. We used a mixed model of rsFC measured in each time window to identify changes in rsFC with task performance, and linear regression to identify the relationship between rsFC and behavior. Following the dynamic adaptation task, rsFC increased within the cortico-cerebellar network and decreased interhemispherically within the cortical sensorimotor network. Increases within the cortico-cerebellar network were specific to dynamic adaptation, as they were associated with behavioral measures of adaptation and retention, indicating that this network has a functional role in consolidation. Instead, decreases in rsFC within the cortical sensorimotor network were associated with motor control processes independent from adaptation and retention.
SIGNIFICANCE STATEMENTMotor memory consolidation processes have been studied via functional magnetic resonance imaging (fMRI) by analyzing changes in resting state functional connectivity (rsFC) occurring more than 30 min after adaptation. However, it is unknown whether consolidation processes are detectable immediately (<15 min) following dynamic adaptation. We used an fMRI-compatible wrist robot to localize brain regions involved in dynamic adaptation in the cortico-thalamic-cerebellar (CTC) and cortical sensorimotor networks and quantified changes in rsFC within each network immediately after adaptation. Different patterns of change in rsFC were observed compared with studies conducted at longer latencies. Increases in rsFC in the cortico-cerebellar network were specific to adaptation and retention, while interhemispheric decreases in the cortical sensorimotor network were associated with alternate motor control processes but not with memory formation.
Nicholson, David A.; Roberts, Todd F.; Sober, Samuel J.(
, Journal of Comparative Neurology)
Abstract
The thalamostriatal system is a major network in the mammalian brain, originating principally from the intralaminar nuclei of thalamus. Its functions remain unclear, but a subset of these projections provides a pathway through which the cerebellum communicates with the basal ganglia. Both the cerebellum and basal ganglia play crucial roles in motor control. Although songbirds have yielded key insights into the neural basis of vocal learning, it is unknown whether a thalamostriatal system exists in the songbird brain. Thalamic nucleus DLM is an important part of the song system, the network of nuclei required for learning and producing song. DLM receives output from song system basal ganglia nucleus Area X and sits within dorsal thalamus, the proposed avian homolog of the mammalian intralaminar nuclei that also receives projections from the cerebellar nuclei. Using a viral vector that specifically labels presynaptic axon segments, we show in Bengalese finches that dorsal thalamus projects to Area X, the basal ganglia nucleus of the song system, and to surrounding medial striatum. To identify the sources of thalamic input to Area X, we map DLM and cerebellar‐recipient dorsal thalamus (DTCbN). Surprisingly, we find both DLM and dorsal anterior DTCbNadjacent to DLM project to Area X. In contrast, the ventral medial subregion of DTCbNprojects to medial striatum outside Area X. Our results suggest the basal ganglia in the song system, like the mammalian basal ganglia, integrate feedback from the thalamic region to which they project as well as thalamic regions that receive cerebellar output.
Zhang, Xu, and Santaniello, Sabato. Role of cerebellar GABAergic dysfunctions in the origins of essential tremor. Retrieved from https://par.nsf.gov/biblio/10135432. Proceedings of the National Academy of Sciences 116.27 Web. doi:10.1073/pnas.1817689116.
Zhang, Xu, & Santaniello, Sabato. Role of cerebellar GABAergic dysfunctions in the origins of essential tremor. Proceedings of the National Academy of Sciences, 116 (27). Retrieved from https://par.nsf.gov/biblio/10135432. https://doi.org/10.1073/pnas.1817689116
@article{osti_10135432,
place = {Country unknown/Code not available},
title = {Role of cerebellar GABAergic dysfunctions in the origins of essential tremor},
url = {https://par.nsf.gov/biblio/10135432},
DOI = {10.1073/pnas.1817689116},
abstractNote = {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 GABA A α 1 -receptor subunits and up-regulation of α 2/3 -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.},
journal = {Proceedings of the National Academy of Sciences},
volume = {116},
number = {27},
author = {Zhang, Xu and Santaniello, Sabato},
}
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