A Network Model of Local Field Potential Activity in Essential Tremor and the Impact of Deep Brain Stimulation

Yousif, Nada; Mace, Michael; Pavese, Nicola; Borisyuk, Roman; Nandi, Dipankar; Bain, Peter G.

doi:10.1371/journal.pcbi.1005326

Cited by 31 publications

(85 citation statements)

References 62 publications

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“…Disrupting transmission of a tremor signal is consistent with the clinical evidence that thermal ablations in thalamus can also be effective at alleviating tremor [61,62]. It is not yet clear whether it is the reduction of tremor frequency activity in VIM, the regularization of output, the effect of antidromic drive, or perhaps several effects, that is important in reducing physiological tremor, and the ultimate source of pathological tremor oscillatory activity in VIM remains to be determined fully [67].…”

Section: Models Revealed That Axons and Cell Bodies Respond Differentsupporting

confidence: 71%

“…An attractive candidate mechanism for DBS-mediated tremor relief in ET (and PD) is that the high frequency stimulation disrupts transmission of a tremor frequency signal in the thalamus to downstream targets [61,62]. Indeed, reduction of pathological oscillatory activity may be a hallmark of successful DBS in other areas as well.…”

Section: Leveraging Computational Models For Understanding Etmentioning

confidence: 99%

“…Incorporating additional work on connectomics of brain areas implicated in ET pathology into network models may also help to drive development of new hypotheses [62]. Understanding the normal role of the cerebellar–thalamic–cortical pathway in motor behavior and motor learning will likely yield additional insight into the modes of its failure, giving rise to tremor as well as other, more subtle, motor deficits.…”

Section: Future Opportunities For Computational Modeling To Improve Ementioning

confidence: 99%

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Computational modeling to improve treatments for essential tremor

Lee

Asaad

Jones

2016

Drug Discovery Today: Disease Models

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Essential tremor (ET) is a neurological disorder of unknown etiology that is typically characterized by an involuntary periodic movement of the upper limbs. No longer considered monosymptomatic, ET patients often have additional motor and even cognitive impairments. Although there are several pharmacological treatments, no drugs have been developed specifically for ET [1], and 30–70% of patients are medication-refractory [2]. A subset of medication-refractory patients may benefit from electrical deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus (VIM), which receives cerebellar inputs. Abnormal cerebellar input to VIM is presumed to be a major contributor to tremor symptoms, which is alleviated by DBS. Computational modeling of the effects of DBS in VIM has been a powerful tool to design DBS protocols to reduce tremor activity. However, far less is known about how these therapies affect non-tremor symptoms, and more experimental and computational modeling work is required to address these growing considerations. Models capable of addressing multiple facets of ET will lead to novel, more efficient treatment.

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Section: Models Revealed That Axons and Cell Bodies Respond Differentsupporting

confidence: 71%

Section: Leveraging Computational Models For Understanding Etmentioning

confidence: 99%

Section: Future Opportunities For Computational Modeling To Improve Ementioning

confidence: 99%

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Computational modeling to improve treatments for essential tremor

Lee

Asaad

Jones

2016

Drug Discovery Today: Disease Models

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“…Both of these networks demonstrated tremor frequency field activity, but their mechanisms of generation and responses to non-tremor activity were distinct, suggesting that potentially different treatment strategies may be necessary to alleviate different generators of tremor activity. Though recent computational work has investigated various aspects of network level dynamics of tremor frequency activity in a mean-field sense [65], to our knowledge, this is the first time the VIM-TRN network with cellular biophysics has been simulated to investigate the cellular and network level origins of tremor periodic activity in ET.…”

Section: Discussionmentioning

confidence: 99%

“…An improved understanding of the cellular and circuit mechanisms generating tremor frequency neural activity in ET may lead to more effective pharmacological or electrical treatments. Prior computational modeling has investigated multiple aspects of the timing of deep brain stimulation on thalamic cells, including rebound bursting [3,5,32,59], and recent work investigated mean field tremor activity in thalamus [65]. Yet to our knowledge, within the VIM, whether tremor frequency neural activity is intrinsically or extrinsically modulated has not been fully established and is essential to understand mechanisms of generation toward improving treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Biophysical modeling of VIM to assess contributions of oscillatory activity to essential tremor

Lee

Segar

Asaad

et al. 2018

Preprint

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Essential tremor (ET) is the most common movement disorder, in which the primary symptom is a prominent, involuntary 4-10 Hz rhythmic movement. The presence of tremor frequency activity in the ventral intermediate nucleus of the thalamus (VIM) is well established, but it is often assumed that it is driven by cerebellar tremor frequency activity, while the role of intrinsic oscillatory activity in VIM is not clear. An improved understanding of the mechanisms of tremor and non-tremor activity in the VIM may lead to better pharmacological and neuromodulatory therapies. We recorded local field activity during tremor in the VIM from 5 patients during deep brain electrode implantation surgery to constrain a biophysically-principled computational model of tremor field activity in the VIM, coupled with the thalamic reticular nucleus (TRN). We compared tremor frequency activity in the model generated either by extrinsic tremor-periodic drive or by intrinsic VIM-TRN interaction. Extrinsic and intrinsic tremor frequency oscillations in the model depended on T-type Ca 2+ channels in different ways. Both also depended on GABA modulation in a site-and type-specific manner. These results suggested that efficacy of pharmacological manipulations may depend upon the mechanisms generating tremor activity in VIM. Simulated non-tremor-related cerebellar drive decreased extrinsic tremor activity but increased intrinsic tremor activity. Intrinsic tremor power was increased with an external tremor frequency drive, suggesting that both mechanisms may be important to understand the emergence and cessation of tremor activity in VIM. Our results lead to experimentally testable predictions on modulating tremor frequency activity that can help to improve future treatment strategies for ET. 2. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/339846 doi: bioRxiv preprint first posted online Jun. 7, 2018; Biophysical Modeling of VIM Activity in ET S. Lee et al. Significance StatementEssential Tremor (ET) is a movement disorder in which the primary symptom is a prominent, involuntary, and rhythmic shaking, often of the arms. Electrical activity in many areas of the brain exhibit rhythmicity that is related to the patient's tremor. One such area resides in a brain structure called the thalamus, but it is not fully known what gives rise to the tremor-related activity. Here, we recorded electrical activity from the thalamus in ET patients and created a computational model of this activity in the thalamus. Model results suggest how to differentiate tremor mechanisms and how these differences may contribute to other impairments in ET. Knowledge of the biophysical mechanisms contributing to tremor can ultimately lead to improvements in treatments to improve symptoms of ET.

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Hallmarks of neurodegenerative disease: A systems pharmacology perspective

Bloomingdale

Karelina

Ramakrishnan

et al. 2022

CPT Pharmacom & Syst Pharma

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Age‐related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease‐modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.

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A Network Model of Local Field Potential Activity in Essential Tremor and the Impact of Deep Brain Stimulation

Cited by 31 publications

References 62 publications

Computational modeling to improve treatments for essential tremor

Computational modeling to improve treatments for essential tremor

Biophysical modeling of VIM to assess contributions of oscillatory activity to essential tremor

Hallmarks of neurodegenerative disease: A systems pharmacology perspective

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