Unilateral subthalamotomy in Parkinson's disease: Cognitive, psychiatric and neuroimaging changes

Obeso, Ignacio; Casabona, Enrique; Rodríguez‐Rojas, Rafael; Bringas, María Luisa; Macıás, R.; Pavón, Nancy; Obeso, José A.; Jahanshahi, Marjan

doi:10.1016/j.cortex.2017.06.006

Cited by 16 publications

(17 citation statements)

References 41 publications

(56 reference statements)

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“…Subthalamotomy is still quite a common treatment amongst patients in advanced stages of PD where patients stop responding to L-DOPA (wearing-off) or chronic L-DOPA therapy results in motor complications such as L-DOPA Induced Dyskinesias (LID) (Alvarez et al, 2009; Obeso et al, 2017). It was reported that STN lesioning exhibits neuroprotective effect which acts as an antiglutamatergic effect in neurotoxic animal models (Piallat et al, 1996; Chen et al, 2000; Carvalho and Nikkhah, 2001; Paul et al, 2004; Wallace et al, 2007; Jourdain et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity

Muddapu

Mandali

Chakravarthy

et al. 2019

Front. Neural Circuits

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Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). Although many mechanisms have been suggested, a decisive root cause of this cell loss is unknown. A couple of the proposed mechanisms, however, show potential for the development of a novel line of PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells compared to other dopaminergic clusters; the other is the SubThalamic Nucleus (STN)-induced excitotoxicity in SNc. To investigate the latter hypothesis computationally, we developed a spiking neuron network-model of SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in ‘stress' variable; when the stress in a SNc neuron exceeds a stress threshold, the neuron dies. The model shows that the interaction between SNc and STN involves a positive-feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway-effect, leading to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned mechanisms of SNc cell loss. Our simulation results show that the excitotoxic cause of SNc cell loss might initiate by weak-excitotoxicity mediated by energy deficit, followed by strong-excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies were simulated to test their efficacy in slowing down SNc cell loss. Among them, glutamate inhibition, dopamine restoration, subthalamotomy and deep brain stimulation showed superior neuroprotective-effects in the proposed model.

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Section: Methodsmentioning

confidence: 99%

A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity

Muddapu

Mandali

Chakravarthy

et al. 2019

Front. Neural Circuits

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“…Even unilateral subthalamotomy, despite good motor affordability and an apparent improvement of general cognitive status (Obeso et al ., ), may lead to reduction of semantic verbal fluency (left subthalamotomy), as well to hyper‐emotionality plus increased impulsivity and disinhibition (right hemisphere); bit sequelae being linked to larger lesion volumes.…”

Section: Open Questions Discontinuation Of Dbs? Stn‐dbs Vs Lesioning?mentioning

confidence: 99%

Mechanisms of action underlying the efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson's disease: central role of disease severity

Cerroni

Mazzone

Liguori

et al. 2018

Eur J of Neuroscience

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Despite consensus on some neurophysiological hallmarks of the Parkinsonian state (such as beta) band increase) a single mechanism is unlikely to explain the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN). Most experimental evidence to date correlates with an extreme degree of nigral neurodegeneration and not with different stages of PD progression. It seems inappropriate to combine substantially different patients - newly diagnosed, early fluctuators or advanced dyskinetic individuals - within the same group. An efficacious STN-DBS imposes a new activity pattern within brain circuits, favouring alpha- and gamma-like neuronal discharge, and restores the thalamo-cortical transmission pathway through axonal activation. In addition, stimulation via the dorsal contacts of the macro-electrode may affect cortical activation antidromically. However, basal ganglia (BG) modulation remains cardinal for 'OFF'-'ON' transition (as revealed by cGMP increase occurring during STN-DBS in the substantia nigra pars reticulata and internal globus pallidus). New research promises to clarify to what extent STN-DBS restores striato-centric bidirectional plasticity, and whether non-neuronal cellular actions (microglia, neurovascular) play a part. Future studies will assess whether extremely anticipated DBS or lesioning in selected patients are capable of providing neuroprotection to the synuclein-mediated alterations of synaptic efficiency. This review addresses these open issues through the specific mechanisms prevailing in a given disease stage. In patients undergoing early protocol, alteration in endogenous transmitters and recovery of plasticity are concurrent players. In advanced stages, re-modulation of endogenous band frequencies, disruption of pathological pattern and/or antidromic cortical activation are, likely, the prominent modes.

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“…Subthalamotomy is still quite a prevalent treatment amongst patients in advanced stages of PD where patients stop responding to L-DOPA (wearing-off) or chronic L-DOPA therapy results in motor complications such as L-DOPA Induced Dyskinesias (LID) (Alvarez et al, 2009;Obeso et al, 2017). It was reported that STN lesioning exhibits neuroprotective effect which acts as an antiglutamatergic effect in neurotoxic animal models (Piallat et al, 1996;Chen et al, 2000;Carvalho and Nikkhah, 2001;Paul et al, 2004;Wallace et al, 2007;Jourdain et al, 2014).…”

Section: Subthalamotomymentioning

confidence: 99%

A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

Muddapu

Mandali

Chakravarthy

et al. 2018

Preprint

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Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). A full understanding of the underlying pathogenesis of this cell loss is unavailable, though a number of mechanisms have been indicated in the literature. A couple of these mechanisms, however, show potential for the development of radical and promising PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells by virtue of their excessive energy demands; the other is the excitotoxicity caused by excessive glutamate release onto SNc by an overactive Subthalamic Nucleus (STN). To investigate the latter hypothesis computationally, we developed a spiking neuron network model of the SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in a 'stress' variable; when the stress in a SNc neuron exceeds a stress threshold the neuron dies. The model shows that the interaction between SNc and STN involves a positive feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway effect that leads to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned PD mechanisms: metabolic vulnerability and glutamate excitotoxicity. Our simulation results show that the excitotoxic cause of SNc cell loss in PD might be initiated by weak excitotoxicity mediated by energy deficit, followed by strong excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies are simulated in the model to test their efficacy in slowing down or arresting SNc cell loss. Among the current therapeutics,

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Unilateral subthalamotomy in Parkinson's disease: Cognitive, psychiatric and neuroimaging changes

Cited by 16 publications

References 41 publications

A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity

A Computational Model of Loss of Dopaminergic Cells in Parkinson's Disease Due to Glutamate-Induced Excitotoxicity

Mechanisms of action underlying the efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson's disease: central role of disease severity

A computational model of loss of dopaminergic cells in Parkinson’s disease due to glutamate-induced excitotoxicity

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