Failure to breathe persists without air hunger or alarm following amygdala seizures.

Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level-dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.

Phase dynamics of cerebral blood flow in subarachnoid haemorrhage in response to sodium nitrite infusion.

Aneurysmal subarachnoid haemorrhage (SAH) is a devastating subset of stroke. One of the major determinates of morbidity is the development of delayed cerebral ischemia (DCI). Disruption of the nitric oxide (NO) pathway and consequently the control of cerebral blood flow (CBF), known as cerebral autoregulation, is believed to play a role in its pathophysiology. Through the pharmacological manipulation of in vivo NO levels using an exogenous NO donor we sought to explore this relationship. Phase synchronisation index (PSI), an expression of the interdependence between CBF and arterial blood pressure (ABP) and thus cerebral autoregulation, was calculated before and during sodium nitrite administration in 10 high-grade SAH patients acutely post-rupture. In patients that did not develop DCI, there was a significant increase in PSI around 0.1 Hz during the administration of sodium nitrite (33%; p-value 0.006). In patients that developed DCI, PSI did not change significantly. Synchronisation between ABP and CBF at 0.1 Hz has been proposed as a mechanism by which organ perfusion is maintained, during periods of physiological stress. These findings suggest that functional NO depletion plays a role in impaired cerebral autoregulation following SAH, but the development of DCI may have a distinct pathophysiological aetiology.

Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia.

Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema.

The cortical connectivity of the periaqueductal gray and the conditioned response to the threat of breathlessness.

Previously we observed differential activation in individual columns of the periaqueductal grey (PAG) during breathlessness and its conditioned anticipation (Faull et al., 2016b). Here, we have extended this work by determining how the individual columns of the PAG interact with higher cortical centres, both at rest and in the context of breathlessness threat. Activation was observed in ventrolateral PAG (vlPAG) and lateral PAG (lPAG), where activity scaled with breathlessness intensity ratings, revealing a potential interface between sensation and cognition during breathlessness. At rest the lPAG was functionally correlated with cortical sensorimotor areas, conducive to facilitating fight/flight responses, and demonstrated increased synchronicity with the amygdala during breathlessness. The vlPAG showed fronto-limbic correlations at rest, whereas during breathlessness anticipation, reduced functional synchronicity was seen to both lPAG and motor structures, conducive to freezing behaviours. These results move us towards understanding how the PAG might be intricately involved in human responses to threat.

Conditioned respiratory threat in the subdivisions of the human periaqueductal gray.

The sensation of breathlessness is the most threatening symptom of respiratory disease. The different subdivisions of the midbrain periaqueductal gray (PAG) are intricately (and differentially) involved in integrating behavioural responses to threat in animals, while the PAG has previously only been considered as a single entity in human research. Here we investigate how these individual PAG columns are differently involved with respiratory threat. Eighteen healthy subjects were conditioned to associate shapes with certain or uncertain impending respiratory load, and scanned the following day during anticipation and application of inspiratory loading using 7 T functional MRI. We showed activity in the ventrolateral PAG (vlPAG) during anticipation of resistive loading, with activity in the lateral PAG (lPAG) during resistive loading, revealing spatially and temporally distinct functions within this structure. We propose that lPAG is involved with sensorimotor responses to breathlessness, while the vlPAG operates within the threat perception network for impending breathlessness.