Limbic and paralimbic respiratory modulation: From inhibition to enhancement

Chaitanya, Ganne; Hampson, Johnson P.; Tóth, Emília; Hupp, Norma J.; Hampson, Jaison; Pati, Sandipan; Lhatoo, Samden D.; Lacuey, Nuria

doi:10.1111/epi.17244

Cited by 7 publications

(9 citation statements)

References 46 publications

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“…These findings provide new insights into forebrain breathing modulation, and identify important nodes of a limbic/paralimbic breathing modulation network. These results identify, for the first time, amygdala, anterior insula, and thalamus as regions that increase MV, and support our previous observations of a similar role of anterior cingulate and temporal pole in breathing enhancement 15 . We found that such enhancement responses are dependent on specific stimulation paradigms, as previously suspected 15 .…”

Section: Discussionsupporting

confidence: 92%

“…These results identify, for the first time, amygdala, anterior insula, and thalamus as regions that increase MV, and support our previous observations of a similar role of anterior cingulate and temporal pole in breathing enhancement 15 . We found that such enhancement responses are dependent on specific stimulation paradigms, as previously suspected 15 . In amygdala, we found that low‐frequency (<1 Hz) stimulation was associated with a 45.44% greater increase in MV compared to higher (≥10 Hz) frequencies.…”

Section: Discussionsupporting

confidence: 91%

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Stimulation‐induced respiratory enhancement in corticothalamic regions

Talavera¹,

Chaitanya²,

Hupp³

et al. 2023

Epilepsia

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Objective We aimed to identify corticothalamic areas and electrical stimulation paradigms that optimally enhance breathing. Methods Twenty‐nine patients with medically intractable epilepsy were prospectively recruited in an epilepsy monitoring unit while undergoing stereoelectroencephalographic evaluation. Direct electrical stimulation in cortical and thalamic regions was carried out using low (<1 Hz) and high (≥10 Hz) frequencies, and low (<5 mA) and high (≥5 mA) current intensities, with pulse width of .1 ms. Electrocardiography, arterial oxygen saturation (SpO2), end‐tidal carbon dioxide (ETCO2), oronasal airflow, and abdominal and thoracic plethysmography were monitored continuously during stimulations. Airflow signal was used to estimate breathing rate, tidal volume, and minute ventilation (MV) changes during stimulation, compared to baseline. Results Electrical stimulation increased MV in the amygdala, anterior cingulate, anterior insula, temporal pole, and thalamus, with an average increase in MV of 20.8% ± 28.9% (range = 0.2%–165.6%) in 19 patients. MV changes were associated with SpO2 and ETCO2 changes (p < .001). Effects on respiration were parameter and site dependent. Within amygdala, low‐frequency stimulation of the medial region produced 78.49% greater MV change (p < .001) compared to high‐frequency stimulation. Longer stimulation produced greater MV changes (an increase of 4.47% in MV for every additional 10 s, p = .04). Significance Stimulation of amygdala, anterior cingulate gyrus, anterior insula, temporal pole, and thalamus, using certain stimulation paradigms, enhances respiration. Among tested paradigms, low‐frequency, low‐intensity, long‐duration stimulation of the medial amygdala is the most effective breathing enhancement stimulation strategy. Such approaches may pave the way for the future development of neuromodulatory techniques that aid rescue from seizure‐related apnea, potentially as a targeted sudden unexpected death in epilepsy prevention method.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Stimulation‐induced respiratory enhancement in corticothalamic regions

Talavera¹,

Chaitanya²,

Hupp³

et al. 2023

Epilepsia

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“…Human studies have provided evidence for a role of the amygdala in seizure‐related apnea in PWE. Thus, spread of ictal activity to the amygdala is associated with the onset of apnea, and stimulation of the amygdala induces apnea in PWE 207–213 . These findings suggest a possible role of the amygdala in inducing apnea in SUDEP cases.…”

Section: Brain Structures Implicated In Sudepmentioning

confidence: 75%

“…Thus, spread of ictal activity to the amygdala is associated with the onset of apnea, and stimulation of the amygdala induces apnea in PWE. [207][208][209][210][211][212][213] These findings suggest a possible role of the amygdala in inducing apnea in SUDEP cases. However, seizure-related apneas were also reported to have an inconsistent linkage to amygdala seizure spread in a recent patient study.…”

Section: Amygdalamentioning

confidence: 79%

A unified hypothesis of SUDEP: Seizure‐induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray

Faingold

Feng

2023

Epilepsia

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Sudden unexpected death in epilepsy (SUDEP) is a major cause of death in people with epilepsy (PWE). Postictal apnea leading to cardiac arrest is the most common sequence of terminal events in witnessed cases of SUDEP, and postconvulsive central apnea has been proposed as a potential biomarker of SUDEP susceptibility. Research in SUDEP animal models has led to the serotonin and adenosine hypotheses of SUDEP. These neurotransmitters influence respiration, seizures, and lethality in animal models of SUDEP, and are implicated in human SUDEP cases. Adenosine released during seizures is proposed to be an important seizure termination mechanism. However, adenosine also depresses respiration, and this effect is mediated, in part, by inhibition of neuronal activity in subcortical structures that modulate respiration, including the periaqueductal gray (PAG). Drugs that enhance the action of adenosine increase postictal death in SUDEP models. Serotonin is also released during seizures, but enhances respiration in response to an elevated carbon dioxide level, which often occurs postictally. This effect of serotonin can potentially compensate, in part, for the adenosine‐mediated respiratory depression, acting to facilitate autoresuscitation and other restorative respiratory response mechanisms. A number of drugs that enhance the action of serotonin prevent postictal death in several SUDEP models and reduce postictal respiratory depression in PWE. This effect of serotonergic drugs may be mediated, in part, by actions on brainstem sites that modulate respiration, including the PAG. Enhanced activity in the PAG increases respiration in response to hypoxia and other exigent conditions and can be activated by electrical stimulation. Thus, we propose the unifying hypothesis that seizure‐induced adenosine release leads to respiratory depression. This can be reversed by serotonergic action on autoresuscitation and other restorative respiratory responses acting, in part, via the PAG. Therefore, we hypothesize that serotonergic or direct activation of this brainstem site may be a useful approach for SUDEP prevention.

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“…Possible therapeutic approaches could be based on electrical or optical stimulation of specific brain areas to "rebalance" their E/I activity and maintain cardiorespiratory function during and after seizures (198,236). Electrical stimulation in patients to map epileptic zones can inhibit or enhance respiration (237). Optogenetic neuronal activation has been shown to suppress seizure-induced respiratory arrest and exert an anticonvulsant effect in a SUDEP mouse model (238).…”

Section: Techniques To Study Network Interaction Involved In Sudepmentioning

confidence: 99%

Autonomic dysfunction in epilepsy mouse models with implications for SUDEP research

et al. 2023

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Epilepsy has a high prevalence and can severely impair quality of life and increase the risk of premature death. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in drug-resistant epilepsy and most often results from respiratory and cardiac impairments due to brainstem dysfunction. Epileptic activity can spread widely, influencing neuronal activity in regions outside the epileptic network. The brainstem controls cardiorespiratory activity and arousal and reciprocally connects to cortical, diencephalic, and spinal cord areas. Epileptic activity can propagate trans-synaptically or via spreading depression (SD) to alter brainstem functions and cause cardiorespiratory dysfunction. The mechanisms by which seizures propagate to or otherwise impair brainstem function and trigger the cascading effects that cause SUDEP are poorly understood. We review insights from mouse models combined with new techniques to understand the pathophysiology of epilepsy and SUDEP. These techniques include in vivo, ex vivo, invasive and non-invasive methods in anesthetized and awake mice. Optogenetics combined with electrophysiological and optical manipulation and recording methods offer unique opportunities to study neuronal mechanisms under normal conditions, during and after non-fatal seizures, and in SUDEP. These combined approaches can advance our understanding of brainstem pathophysiology associated with seizures and SUDEP and may suggest strategies to prevent SUDEP.

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Limbic and paralimbic respiratory modulation: From inhibition to enhancement

Cited by 7 publications

References 46 publications

Stimulation‐induced respiratory enhancement in corticothalamic regions

Stimulation‐induced respiratory enhancement in corticothalamic regions

A unified hypothesis of SUDEP: Seizure‐induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray

Autonomic dysfunction in epilepsy mouse models with implications for SUDEP research

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