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.

Cerebellar morphological differences and associations with extrinsic factors in bipolar disorder type I.

BACKGROUND: The neural underpinnings of bipolar disorder (BD) remain poorly understood. The cerebellum is ideally positioned to modulate emotional regulation circuitry yet has been understudied in BD. Literature suggests differences in cerebellar activity and metabolism in BD, however findings on structural differences remain contradictory. Potential reasons include combining BD subtypes, small sample sizes, and potential moderators such as genetics, adverse childhood experiences (ACEs), and pharmacotherapy. METHODS: We collected 3 T MRI scans from participants with (N = 131) and without (N = 81) BD type I, as well as blood and questionnaires. We assessed differences in cerebellar volumes and explored potentially influential factors. RESULTS: The cerebellar cortex was smaller bilaterally in participants with BD. Polygenic propensity score did not predict any cerebellar volumes, suggesting that non-genetic factors may have greater influence on the cerebellar volume difference we observed in BD. Proportionate cerebellar white matter volumes appeared larger with more ACEs, but this may result from reduced ICV. Time from onset and symptom burden were not associated with cerebellar volumes. Finally, taking sedatives was associated with larger cerebellar white matter and non-significantly larger cortical volume. LIMITATIONS: This study was cross-sectional, limiting interpretation of possible mechanisms. Most of our participants were White, which could limit the generalizability. Additionally, we did not account for potential polypharmacy interactions. CONCLUSIONS: These findings suggest that external factors, such as sedatives and childhood experiences, may influence cerebellum structure in BD and may mask underlying differences. Accounting for such variables may be critical for consistent findings in future studies.

Functional connectivity of the cerebellar vermis in bipolar disorder and associations with mood.

Purpose: Studies of the neural underpinnings of bipolar type I disorder have focused on the emotional control network. However, there is also growing evidence for cerebellar involvement, including abnormal structure, function, and metabolism. Here, we sought to assess functional connectivity of the cerebellar vermis with the cerebrum in bipolar disorder and to assess whether connectivity might depend on mood. Methods: This cross-sectional study enrolled 128 participants with bipolar type I disorder and 83 control comparison participants who completed a 3 T magnetic resonance imaging (MRI) study, which included anatomical as well as resting state Blood Oxygenation Level Dependent (BOLD) imaging. Functional connectivity of the cerebellar vermis to all other brain regions was assessed. Based on quality control metrics of the fMRI data, 109 participants with bipolar disorder and 79 controls were included in the statistical analysis comparing connectivity of the vermis. In addition, the data was explored for the potential impacts of mood, symptom burden, and medication in those with bipolar disorder. Results: Functional connectivity between the cerebellar vermis and the cerebrum was found to be aberrant in bipolar disorder. The connectivity of the vermis was found to be greater in bipolar disorder to regions involved in motor control and emotion (trending), while reduced connectivity was observed to a region associated with language production. In the participants with bipolar disorder, past depression symptom burden affected connectivity; however, no effects of medication were observed. Functional connectivity between the cerebellar vermis and all other regions revealed an inverse association with current mood ratings. Conclusion: Together the findings may suggest that the cerebellum plays a compensatory role in bipolar disorder. The proximity of the cerebellar vermis to the skull may make this region a potential target for treatment with transcranial magnetic stimulation.

Functional Connectivity of the Cerebellar Vermis in Bipolar Disorder and Associations with Mood.

Purpose: Studies of the neural underpinnings of bipolar type I disorder have focused on the emotional control network. However, there is also growing evidence for cerebellar involvement, including abnormal structure, function, and metabolism. Here, we sought to assess functional connectivity of the cerebellum with the cerebrum in bipolar disorder and to assess whether any effects might depend on mood. Methods: This cross-sectional study enrolled 128 participants with bipolar type I disorder and 83 control comparison participants who completed a 3T MRI scan, which included anatomical imaging as well as resting state BOLD imaging. Functional connectivity of the cerebellar vermis to all other brain regions was assessed. Based on quality control metrics of the fMRI data, 109 participants with bipolar disorder and 79 controls were used to in the statistical analysis comparing connectivity of the vermis as well as associations with mood. Potential impacts of medications were also explored. Results: Functional connectivity of the cerebellar vermis in bipolar disorder was found to differ significantly between brain regions known to be involved in the control of emotion, motor function, and language. While connections with emotion and motor control areas were significantly stronger in bipolar disorder, connection to a region associated language production was significantly weaker. In the participants with bipolar disorder, ratings of depression and mania were inversely associated with vermis functional connectivity. No effect of medications on these connections were observed. Conclusion: Together the findings suggest cerebellum may play a compensatory role in bipolar disorder and when it can no longer fulfill this role, depression and mania develop. The proximity of the cerebellar vermis to the skull may make this region a potential target for treatment with transcranial magnetic stimulation.

Intoxicating effects of alcohol depend on acid-sensing ion channels.

Persons at risk for developing alcohol use disorder (AUD) differ in their sensitivity to acute alcohol intoxication. Alcohol effects are complex and thought to depend on multiple mechanisms. Here, we explored whether acid-sensing ion channels (ASICs) might play a role. We tested ASIC function in transfected CHO cells and amygdala principal neurons, and found alcohol potentiated currents mediated by ASIC1A homomeric channels, but not ASIC1A/2 A heteromeric channels. Supporting a role for ASIC1A in the intoxicating effects of alcohol in vivo, we observed marked alcohol-induced changes on local field potentials in basolateral amygdala, which differed significantly in Asic1a-/- mice, particularly in the gamma, delta, and theta frequency ranges. Altered electrophysiological responses to alcohol in mice lacking ASIC1A, were accompanied by changes in multiple behavioral measures. Alcohol administration during amygdala-dependent fear conditioning dramatically diminished context and cue-evoked memory on subsequent days after the alcohol had cleared. There was a significant alcohol by genotype interaction. Context- and cue-evoked memory were notably worse in Asic1a-/- mice. We further examined acute stimulating and sedating effects of alcohol on locomotor activity, loss of righting reflex, and in an acute intoxication severity scale. We found loss of ASIC1A increased the stimulating effects of alcohol and reduced the sedating effects compared to wild-type mice, despite similar blood alcohol levels. Together these observations suggest a novel role for ASIC1A in the acute intoxicating effects of alcohol in mice. They further suggest that ASICs might contribute to intoxicating effects of alcohol and AUD in humans.

Metabolic abnormalities in the basal ganglia and cerebellum in bipolar disorder: A multi-modal MR study.

AIMS: Bipolar type I disorder (BD) is characterized by severe mood swings and occurs in about 1% of the population. The mechanisms underlying the disorder remain unknown. Prior studies have suggested abnormalities in brain metabolism using 1H and 31P magnetic resonance spectroscopy (MRS). Supporting altered metabolism, in previous studies we found T1ρ relaxation times in the cerebellum were elevated in participants with BD. In addition, T1ρ relaxation times in the basal ganglia were lower in participants with BD experiencing depressed mood. Based on these findings, this study sought to probe brain metabolism with a focus of extending these assessments to the cerebellum. METHODS: This study collected data from 64 participants with Bipolar type I disorder (BD) and 42 controls. Subjects were scanned at both 3T (anatomical, functional, and T1ρ imaging data) and 7T (31P and 1H spectroscopy). Regions of interest defined by the 1H MRS data were used to explore metabolic and functional changes in the cerebellar vermis and putamen. RESULTS: Elevated concentrations of n-Acetyl-l-aspartate (NAA), glutamate, glutathione, taurine, and creatine were found in the cerebellar vermis along with decreased intra-cellular pH. Similar trends were observed in the right putamen for glutamate, creatine, and pH. We also observed a relationship between T1ρ relaxation times and mood in the putamen. We did not observe a significant effect of medications on these measures. LIMITATIONS: The study was cross sectional in design and employed a naturalistic approach for assessing the impact of medications on the results. CONCLUSION: This study supports prior findings of reduced pH in mitochondrial dysfunction in BD while also showing that these differences extend to the cerebellum.

A human amygdala site that inhibits respiration and elicits apnea in pediatric epilepsy.

BACKGROUNDSeizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown.METHODSWe studied 8 pediatric patients with intractable epilepsy undergoing intracranial electroencephalography. We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine-learning algorithm was used to delineate brain regions that inhibit respiration.RESULTSIn 2 patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all 8 subjects (3-17 years old). These effects did not depend on epilepsy type and were relatively specific to the amygdala, as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine-learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the amygdala inhibition of respiration (AIR) site includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons.CONCLUSIONSA focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target.FUNDINGNational Institute of Neurological Disorders and Stroke - Congress of Neurological Surgeons, National Institute of General Medical Sciences, Roy J. Carver Charitable Trust.