Altered amygdala volumes and microstructure in focal epilepsy patients with tonic-clonic seizures, ictal, and post-convulsive central apnea.

OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined the volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by the presence or absence of FBTCS, ictal central apnea (ICA), and post-convulsive central apnea (PCCA). METHODS: Seventy-three patients with focal impaired awareness seizures without FBTC seizures (FBTCneg group) and 30 with FBTCS (FBTCpos group) recorded during video electroencephalography (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomic and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all patients with epilepsy and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between three groups: healthy subjects, FBTCneg and FBTCpos groups. The FBTCpos group was further subdivided by the presence of ICA and PCCA, verified by VEEG. RESULTS: Bilateral amygdala volumes were significantly increased in the FBTCpos cohort compared to healthy controls and the FBTCneg group. Patients with recorded PCCA had the highest increase in bilateral amygdala volume of the FBTCpos cohort. Amygdala neurite density index (NDI) values were decreased significantly in both the FBTCneg and FBTCpos groups relative to healthy controls, with values in the FBTCpos group being the lowest of the two. The presence of PCCA was associated with significantly lower NDI values vs the non-apnea FBTCpos group (p = 0.004). SIGNIFICANCE: Individuals with FBTCpos and PCCA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

Peri-ictal hypoxia is related to extent of regional brain volume loss accompanying generalized tonic-clonic seizures.

OBJECTIVES: Hypoxia, or abnormally low blood-oxygen levels, often accompanies seizures and may elicit brain structural changes in people with epilepsy which contribute to central processes underlying sudden unexpected death in epilepsy (SUDEP). The extent to which hypoxia may be related to brain structural alterations in this patient group remains unexplored. METHODS: We analyzed high-resolution T1-weighted magnetic resonance imaging (MRI) to determine brain morphometric and volumetric alterations in people with generalized tonic-clonic seizures (GTCS) recorded during long-term video-electroencephalography (VEEG), recruited from two sites (n = 22), together with data from age- and sex-matched healthy controls (n = 43). Subjects were sub-divided into those with mild/moderate (GTCS-hypox-mild/moderate, n = 12) and severe (GTCS-hypox-severe, n = 10) hypoxia, measured by peripheral oxygen saturation (SpO2 ) during VEEG. Whole-brain voxel-based morphometry (VBM) and regional volumetry were used to assess group comparisons and correlations between brain structural measurements as well as the duration and extent of hypoxia during GTCS. RESULTS: Morphometric and volumetric alterations appeared in association with peri-GTCS hypoxia, including volume loss in the periaqueductal gray (PAG), thalamus, hypothalamus, vermis, cerebellum, parabrachial pons, and medulla. Thalamic and PAG volume was significantly reduced in GTCS patients with severe hypoxia compared with GTCS patients with mild/moderate hypoxia. Brainstem volume loss appeared in both hypoxia groups, although it was more extensive in those with severe hypoxia. Significant negative partial correlations emerged between thalamic and hippocampal volume and extent of hypoxia, whereas vermis and accumbens volumes declined with increasing hypoxia duration. SIGNIFICANCE: Brain structural alterations in patients with GTCS are related to the extent of hypoxia in brain sites that serve vital functions. Although the changes are associative only, they provide evidence of injury to regulatory brain sites related to respiratory manifestations of seizures.

Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy.

OBJECTIVE: The processes underlying sudden unexpected death in epilepsy (SUDEP) remain elusive, but centrally mediated cardiovascular or respiratory collapse is suspected. Volume changes in brain areas mediating recovery from extreme cardiorespiratory challenges may indicate failure mechanisms and allow prospective identification of SUDEP risk. METHODS: We retrospectively imaged SUDEP cases (n = 25), patients comparable for age, sex, epilepsy syndrome, localization, and disease duration who were high-risk (n = 25) or low-risk (n = 23), and age- and sex-matched healthy controls (n = 25) with identical high-resolution T1-weighted scans. Regional gray matter volume, determined by voxel-based morphometry, and segmentation-derived structure sizes were compared across groups, controlling for total intracranial volume, age, and sex. RESULTS: Substantial bilateral gray matter loss appeared in SUDEP cases in the medial and lateral cerebellum. This was less prominent in high-risk subjects and absent in low-risk subjects. The periaqueductal gray, left posterior and medial thalamus, left hippocampus, and bilateral posterior cingulate also showed volume loss in SUDEP. High-risk subjects showed left thalamic volume reductions to a lesser extent. Bilateral amygdala, entorhinal, and parahippocampal volumes increased in SUDEP and high-risk patients, with the subcallosal cortex enlarged in SUDEP only. Disease duration correlated negatively with parahippocampal volume. Volumes of the bilateral anterior insula and midbrain in SUDEP cases were larger the closer to SUDEP from magnetic resonance imaging. SIGNIFICANCE: SUDEP victims show significant tissue loss in areas essential for cardiorespiratory recovery and enhanced volumes in areas that trigger hypotension or impede respiratory patterning. Those changes may shed light on SUDEP pathogenesis and prospectively detect patterns identifying those at risk.

The association of serotonin reuptake inhibitors and benzodiazepines with ictal central apnea.

OBJECTIVE: Ictal (ICA) and postconvulsive central apnea (PCCA) have been implicated in sudden unexpected death in epilepsy (SUDEP) pathomechanisms. Previous studies suggest that serotonin reuptake inhibitors (SRIs) and benzodiazepines (BZDs) may influence breathing. The aim of this study was to investigate if chronic use of these drugs alters central apnea occurrence in patients with epilepsy. METHODS: Patients with epilepsy admitted to epilepsy monitoring units (EMUs) in nine centers participating in a SUDEP study were consented. Polygraphic physiological parameters were analyzed, including video-electroencephalography (VEEG), thoracoabdominal excursions, and pulse oximetry. Outpatient medication details were collected. Patients and seizures were divided into SRI, BZD, and control (no SRI or BZD) groups. Ictal central apnea and PCCA, hypoxemia, and electroclinical features were assessed for each group. RESULTS: Four hundred and seventy-six seizures were analyzed (204 patients). The relative risk (RR) for ICA in the SRI group was half that of the control group (p = 0.02). In the BZD group, ICA duration was significantly shorter than in the control group (p = 0.02), as was postictal generalized EEG suppression (PGES) duration (p = 0.021). Both SRI and BZD groups were associated with smaller seizure-associated oxygen desaturation (p = 0.009; p ≪ 0.001). Neither presence nor duration of PCCA was significantly associated with SRI or BZD (p ≫ 0.05). CONCLUSIONS: Seizures in patients taking SRIs have lower occurrence of ICA, and patients on chronic treatment with BZDs have shorter ICA and PGES durations. Preventing or shortening ICA duration by using SRIs and/or BZD in patients with epilepsy may play a possible role in SUDEP risk reduction.

Serum serotonin levels in patients with epileptic seizures.

Profound cardiovascular and/or respiratory dysfunction is part of the terminal cascade in sudden unexpected death in epilepsy (SUDEP). Central control of ventilation is mediated by brainstem rhythm generators, which are influenced by a variety of inputs, many of which use the modulatory neurotransmitter serotonin to mediate important inputs for breathing. The aim of this study was to investigate epileptic seizure-induced changes in serum serotonin levels and whether there are potential implications for SUDEP. Forty-one epileptic patients were pooled into 2 groups based on seizure type as (1) generalized tonic-clonic seizures (GTCS) of genetic generalized epilepsy and focal to bilateral tonic-clonic seizures (FBTCS; n = 19) and (2) focal seizures (n = 26) based on clinical signs using surface video-electroencephalography. Postictal serotonin levels were statistically significantly higher after GTCS and FBTCS compared to interictal levels (P = .002) but not focal seizures (P = .941). The change in serotonin (postictal-interictal) was inversely associated with a shorter duration of tonic phase of generalized seizures. The interictal serotonin level was inversely associated with a shorter period of postictal generalized electroencephalographic suppression. These data suggest that peripheral serum serotonin levels may play a role in seizure features and earlier postseizure recovery; these findings merit further study.

The incidence and significance of periictal apnea in epileptic seizures.

OBJECTIVE: The aim of this study was to investigate periictal central apnea as a seizure semiological feature, its localizing value, and possible relationship with sudden unexpected death in epilepsy (SUDEP) pathomechanisms. METHODS: We prospectively studied polygraphic physiological responses, including inductance plethysmography, peripheral capillary oxygen saturation (SpO2 ), electrocardiography, and video electroencephalography (VEEG) in 473 patients in a multicenter study of SUDEP. Seizures were classified according to the International League Against Epilepsy (ILAE) 2017 seizure classification based on the most prominent clinical signs during VEEG. The putative epileptogenic zone was defined based on clinical history, seizure semiology, neuroimaging, and EEG. RESULTS: Complete datasets were available in 126 patients in 312 seizures. Ictal central apnea (ICA) occurred exclusively in focal epilepsy (51/109 patients [47%] and 103/312 seizures [36.5%]) (P < .001). ICA was the only clinical manifestation in 16/103 (16.5%) seizures, and preceded EEG seizure onset by 8 ± 4.9 s, in 56/103 (54.3%) seizures. ICA ≥60 s was associated with severe hypoxemia (SpO2 <75%). Focal onset impaired awareness (FOIA) motor onset with automatisms and FOA nonmotor onset semiologies were associated with ICA presence (P < .001), ICA duration (P = .002), and moderate/severe hypoxemia (P = .04). Temporal lobe epilepsy was highly associated with ICA in comparison to extratemporal epilepsy (P = .001) and frontal lobe epilepsy (P = .001). Isolated postictal central apnea was not seen; in 3/103 seizures (3%), ICA persisted into the postictal period. SIGNIFICANCE: ICA is a frequent, self-limiting semiological feature of focal epilepsy, often starting before surface EEG onset, and may be the only clinical manifestation of focal seizures. However, prolonged ICA (≥60 s) is associated with severe hypoxemia and may be a potential SUDEP biomarker. ICA is more frequently seen in temporal than extratemporal seizures, and in typical temporal seizure semiologies. ICA rarely persists after seizure end. ICA agnosia is typical, and thus it may remain unrecognized without polygraphic measurements that include breathing parameters.

Non-Gaussian Diffusion Imaging Shows Brain Myelin and Axonal Changes in Obstructive Sleep Apnea.

OBJECTIVE: Obstructive sleep apnea (OSA) is accompanied by brain changes in areas that regulate autonomic, cognitive, and mood functions, which were initially examined by Gaussian-based diffusion tensor imaging measures, but can be better assessed with non-Gaussian measures. We aimed to evaluate axonal and myelin changes in OSA using axial (AK) and radial kurtosis (RK) measures. MATERIALS AND METHODS: We acquired diffusion kurtosis imaging data from 22 OSA and 26 controls; AK and RK maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance. RESULTS: Increased AK, indicating axonal changes, emerged in the insula, hippocampus, amygdala, dorsolateral pons, and cerebellar peduncles and showed more axonal injury over previously identified damage. Higher RK, showing myelin changes, appeared in the hippocampus, amygdala, temporal and frontal lobes, insula, midline pons, and cerebellar peduncles and showed more widespread myelin damage over previously identified injury. CONCLUSIONS: Axial kurtosis and RK measures showed widespread changes over Gaussian-based techniques, suggesting a more sensitive nature of kurtoses to injury.

Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics.

The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of neuroscience-based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.

Associations between brain white matter integrity and disease severity in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway blockage, with continued diaphragmatic efforts to breathe during sleep. Brain structural changes in OSA appear in various regions, including white matter sites that mediate autonomic, mood, cognitive, and respiratory control. However, the relationships between brain white matter changes and disease severity in OSA are unclear. This study examines associations between an index of tissue integrity, magnetization transfer (MT) ratio values (which show MT between free and proton pools associated with tissue membranes and macromolecules), and disease severity (apnea-hypopnea index [AHI]) in OSA subjects. We collected whole-brain MT imaging data from 19 newly diagnosed, treatment-naïve OSA subjects (50.4 ± 8.6 years of age, 13 males, AHI 39.7 ± 24.3 events/hr], using a 3.0-Tesla MRI scanner. With these data, whole-brain MT ratio maps were calculated, normalized to common space, smoothed, and correlated with AHI scores by using partial correlation analyses (covariates, age and gender; P < 0.005). Multiple brain sites in OSA subjects, including superior and inferior frontal regions, ventral medial prefrontal cortex and nearby white matter, midfrontal white matter, insula, cingulate and cingulum bundle, internal and external capsules, caudate nuclei and putamen, basal forebrain, hypothalamus, corpus callosum, and temporal regions, showed principally lateralized negative correlations (P < 0.005). These regions showed significant correlations even with correction for multiple comparisons (cluster-level, family-wise error, P < 0.05), except for a few superior frontal areas. Predominantly negative correlations emerged between local MT values and OSA disease severity, indicating potential usefulness of MT imaging for examining the OSA condition. These findings indicate that OSA severity plays a significant role in white matter injury. © 2016 Wiley Periodicals, Inc.

Ripples on spikes show increased phase-amplitude coupling in mesial temporal lobe epilepsy seizure-onset zones.

OBJECTIVE: Ripples (80-150 Hz) recorded from clinical macroelectrodes have been shown to be an accurate biomarker of epileptogenic brain tissue. We investigated coupling between epileptiform spike phase and ripple amplitude to better understand the mechanisms that generate this type of pathologic ripple (pRipple) event. METHODS: We quantified phase amplitude coupling (PAC) between epileptiform electroencephalography (EEG) spike phase and ripple amplitude recorded from intracranial depth macroelectrodes during episodes of sleep in 12 patients with mesial temporal lobe epilepsy. PAC was determined by (1) a phasor transform that corresponds to the strength and rate of ripples coupled with spikes, and a (2) ripple-triggered average to measure the strength, morphology, and spectral frequency of the modulating and modulated signals. Coupling strength was evaluated in relation to recording sites within and outside the seizure-onset zone (SOZ). RESULTS: Both the phasor transform and ripple-triggered averaging methods showed that ripple amplitude was often robustly coupled with epileptiform EEG spike phase. Coupling was found more regularly inside than outside the SOZ, and coupling strength correlated with the likelihood a macroelectrode's location was within the SOZ (p < 0.01). The ratio of the rate of ripples coupled with EEG spikes inside the SOZ to rates of coupled ripples in non-SOZ was greater than the ratio of rates of ripples on spikes detected irrespective of coupling (p < 0.05). Coupling strength correlated with an increase in mean normalized ripple amplitude (p < 0.01), and a decrease in mean ripple spectral frequency (p < 0.05). SIGNIFICANCE: Generation of low-frequency (80-150 Hz) pRipples in the SOZ involves coupling between epileptiform spike phase and ripple amplitude. The changes in excitability reflected as epileptiform spikes may also cause clusters of pathologically interconnected bursting neurons to grow and synchronize into aberrantly large neuronal assemblies.

Obstructive sleep apnea is associated with low GABA and high glutamate in the insular cortex.

The insular cortex is injured in obstructive sleep apnea (OSA) and responds inappropriately to autonomic challenges, suggesting neural reorganization. The objective of this study was to assess whether the neural changes might result from γ-aminobutyric acid (GABA) and glutamate alterations. We studied 14 OSA patients [mean age ± standard deviation (SD): 47.5 ± 10.5 years; nine male; apnea-hypopnea index (AHI): 29.5 ± 15.6 events h(-1) ] and 22 healthy participants (47.5 ± 10.1 years; 11 male), using magnetic resonance spectroscopy to detect GABA and glutamate levels in insular cortices. We localized the cortices with anatomical scans, and measured neurochemical levels from anterior to mid-regions. Left and right anterior insular cortices showed lower GABA and higher glutamate in OSA versus healthy subjects [GABA left: OSA n = 6: 0.36 ± 0.10 (mean ± SD), healthy n = 5: 0.62 ± 0.18; P < 0.05), right: OSA n = 11: 0.27 ± 0.09, healthy n = 14: 0.45 ± 0.16; P < 0.05; glutamate left: OSA n = 6: 1.61 ± 0.32, healthy n = 8: 0.94 ± 0.34; P < 0.05, right: OSA n = 14: 1.26 ± 0.28, healthy n = 19: 1.02 ± 0.28; P < 0.05]. GABA and glutamate levels were correlated only within the healthy group in the left insula (r: -0.9, P < 0.05). The altered anterior insular levels of GABA and glutamate may modify integration and projections to autonomic areas, contributing to the impaired cardiovascular regulation in OSA.

Structural imaging biomarkers of sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy is a major cause of premature death in people with epilepsy. We aimed to assess whether structural changes potentially attributable to sudden death pathogenesis were present on magnetic resonance imaging in people who subsequently died of sudden unexpected death in epilepsy. In a retrospective, voxel-based analysis of T1 volume scans, we compared grey matter volumes in 12 cases of sudden unexpected death in epilepsy (two definite, 10 probable; eight males), acquired 2 years [median, interquartile range (IQR) 2.8] before death [median (IQR) age at scanning 33.5 (22) years], with 34 people at high risk [age 30.5 (12); 19 males], 19 at low risk [age 30 (7.5); 12 males] of sudden death, and 15 healthy controls [age 37 (16); seven males]. At-risk subjects were defined based on risk factors of sudden unexpected death in epilepsy identified in a recent combined risk factor analysis. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in sudden death cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in cases of sudden unexpected death in epilepsy and subjects at high risk. The extent of reduction correlated with disease duration in all subjects with epilepsy. Increased amygdalo-hippocampal grey matter volume with right-sided changes is consistent with histo-pathological findings reported in sudden infant death syndrome. We speculate that the right-sided predominance reflects asymmetric central influences on autonomic outflow, contributing to cardiac arrhythmia. Pulvinar damage may impair hypoxia regulation. The imaging findings in sudden unexpected death in epilepsy and people at high risk may be useful as a biomarker for risk-stratification in future studies.

Global and regional brain mean diffusivity changes in patients with heart failure.

Heart failure (HF) patients show gray and white matter changes in multiple brain sites, including autonomic and motor coordination areas. It is unclear whether the changes represent acute or chronic tissue pathology, a distinction necessary for understanding pathological processes that can be resolved with diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures. We collected four DTI series from 16 HF (age 55.1 ± 7.8 years, 12 male) and 26 control (49.7 ± 10.8 years, 17 male) subjects with a 3.0-Tesla magnetic resonance imaging scanner. MD maps were realigned, averaged, normalized, and smoothed. Global and regional MD values from autonomic and motor coordination sites were calculated by using normalized MD maps and brain masks; group MD values and whole-brain smoothed MD maps were compared by analysis of covariance (covariates; age and gender). Global brain MD (HF vs. controls, units × 10(-6) mm(2) /sec, 1103.8 ± 76.6 vs. 1035.9 ± 69.4, P = 0.038) and regional autonomic and motor control site values (left insula, 1,085.4 ± 95.7 vs. 975.7 ± 65.4, P = 0.001; right insula, 1,050.2 ± 100.6 vs. 965.7 ± 58.4, P = 0.004; left hypothalamus, 1,419.6 ± 165.2 vs. 1,234.9 ± 136.3, P = 0.002; right hypothalamus, 1,446.5 ± 178.8 vs. 1,273.3 ± 136.9, P = 0.004; left cerebellar cortex, 889.1 ± 81.9 vs. 796.6 ± 46.8, P < 0.001; right cerebellar cortex, 797.8 ± 50.8 vs. 750.3 ± 27.5, P = 0.001; cerebellar deep nuclei, 1,236.1 ± 193.8 vs. 1,071.7 ± 107.1, P = 0.002) were significantly higher in HF vs. control subjects, indicating chronic tissue changes. Whole-brain comparisons showed increased MD values in HF subjects, including limbic, basal-ganglia, thalamic, solitary tract nucleus, frontal, and cerebellar regions. Brain injury occurs in autonomic and motor control areas, which may contribute to deficient function in HF patients. The chronic tissue changes likely result from processes that develop over a prolonged period.

Structural brain alterations in children an average of 5 years after surgery and chemotherapy for brain tumors.

Young children with brain tumors are often treated with high-dose chemotherapy after surgery to avoid brain tissue injury associated with irradiation. The effects of systemic chemotherapy on healthy brain tissue in this population, however, are unclear. Our objective was to compare gray and white matter integrity using MRI procedures in children with brain tumors (n = 7, mean age 8.3 years), treated with surgery and high-dose chemotherapy followed by autologous hematopoietic cell rescue (AuHCR) an average of 5.4 years earlier, to age- and gender-matched healthy controls (n = 9, mean age 9.3 years). Diffusion tensor imaging data were collected to evaluate tissue integrity throughout the brain, as measured by mean diffusivity (MD), a marker of glial, neuronal, and axonal status, and fractional anisotropy (FA), an index of axonal health. Individual MD and FA maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance, with age and sex as covariates. Higher MD values, indicative of injury, emerged in patients compared with controls (p < .05, corrected for multiple comparisons), and were especially apparent in the central thalamus, external capsule, putamen, globus pallidus and pons. Reduced FA values in some regions did not reach significance after correction for multiple comparisons. Children treated with surgery and high-dose chemotherapy with AuHCR for brain tumors an average of 5.4 years earlier show alterations in white and gray matter in multiple brain areas distant from the tumor site, raising the possibility for long-term consequences of the tumor or treatment.

Cerebral blood flow velocity and vasomotor reactivity during autonomic challenges in heart failure.

BACKGROUND: Significant alterations in autonomic nervous system (ANS) function, vasomotor reactivity, and cerebral blood flow may develop from damage to brain ANS regulatory areas in heart failure (HF). This preferentially right-sided injury occurs largely in autonomic structures perfused by the middle cerebral artery. Indications of altered, asymmetrical perfusion raise the potential for further neural damage. OBJECTIVE: To determine whether the extent of middle cerebral artery blood flow velocity and vasomotor reactivity is altered on one side of the brain over the other in HF versus control subjects, three ANS challenges were administered-each challenge recruited ANS regulatory areas potentially injured in HF. METHODS: Transcranial Doppler ultrasonography was used to measure cerebral blood flow velocity and vasomotor reactivity in 40 HF (mean age = 52.7 years, SD = 7.5; 27 men; left ventricular ejection fraction = 26.8, SD = 8.3) and 42 control subjects (mean age = 48.3 years, SD = 6.0; 22 men) during 5% CO2 and hyperventilation, Valsalva, and orthostatic (upper body tilt) challenges. RESULTS: Lower cerebral blood flow velocity and abnormal vasomotor reactivity (p < .01) were noted in HF middle cerebral arteries during all challenges. More right-sided flow velocity reductions appeared in HF, with laterality differences noted during CO2 and orthostatic (p < .05), but not Valsalva challenges. DISCUSSION: Diminished cerebral blood flow velocity and altered vasomotor reactivity were associated with HF, changes being preferentially on the right side; the asymmetry was more pronounced during CO2 and orthostatic challenges. The impaired blood flow regulation may contribute to the lateralized brain pathology in ANS areas, undermining autonomic control in HF.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part II. Age-associated alterations in serotonin receptor binding profiles within medullary nuclei supporting cardiorespiratory homeostasis.

The failure of chemoreflexes, arousal, and/or autoresuscitation to asphyxia may underlie some sudden infant death syndrome (SIDS) cases. In Part I, we showed that some SIDS infants had altered 5-hydroxytryptamine (5-HT)2A/C receptor binding in medullary nuclei supporting chemoreflexes, arousal, and autoresuscitation. Here, using the same dataset, we tested the hypotheses that the prevalence of low 5-HT1A and/or 5-HT2A/C receptor binding (defined as levels below the 95% confidence interval of controls-a new approach), and the percentages of nuclei affected are greater in SIDS versus controls, and that the distribution of low binding varied with age of death. The prevalence and percentage of nuclei with low 5-HT1A and 5-HT2A/C binding in SIDS were twice that of controls. The percentage of nuclei with low 5-HT2A/C binding was greater in older SIDS infants. In >80% of older SIDS infants, low 5-HT2A/C binding characterized the hypoglossal nucleus, vagal dorsal nucleus, nucleus of solitary tract, and nuclei of the olivocerebellar subnetwork (important for blood pressure regulation). Together, our findings from SIDS infants and from animal models of serotonergic dysfunction suggest that some SIDS cases represent a serotonopathy. We present new hypotheses, yet to be tested, about how defects within serotonergic subnetworks may lead to SIDS.

Incidence and Types of Cardiac Arrhythmias in the Peri-Ictal Period in Patients Having a Generalized Convulsive Seizure.

BACKGROUND AND OBJECTIVES: Generalized convulsive seizures (GCSs) are the main risk factor of sudden unexpected death in epilepsy (SUDEP), which is likely due to peri-ictal cardiorespiratory dysfunction. The incidence of GCS-induced cardiac arrhythmias, their relationship to seizure severity markers, and their role in SUDEP physiopathology are unknown. The aim of this study was to analyze the incidence of seizure-induced cardiac arrhythmias, their association with electroclinical features and seizure severity biomarkers, as well as their specific occurrences in SUDEP cases. METHODS: This is an observational, prospective, multicenter study of patients with epilepsy aged 18 years and older with recorded GCS during inpatient video-EEG monitoring for epilepsy evaluation. Exclusion criteria were status epilepticus and an obscured video recording. We analyzed semiologic and cardiorespiratory features through video-EEG (VEEG), electrocardiogram, thoracoabdominal bands, and pulse oximetry. We investigated the presence of bradycardia, asystole, supraventricular tachyarrhythmias (SVTs), premature atrial beats, premature ventricular beats, nonsustained ventricular tachycardia (NSVT), atrial fibrillation (Afib), ventricular fibrillation (VF), atrioventricular block (AVB), exaggerated sinus arrhythmia (ESA), and exaggerated sinus arrhythmia with bradycardia (ESAWB). A board-certified cardiac electrophysiologist diagnosed and classified the arrhythmia types. Bradycardia, asystole, SVT, NSVT, Afib, VF, AVB, and ESAWB were classified as arrhythmias of interest because these were of SUDEP pathophysiology value. The main outcome was the occurrence of seizure-induced arrhythmias of interest during inpatient VEEG monitoring. Moreover, yearly follow-up was conducted to identify SUDEP cases. Binary logistic generalized estimating equations were used to determine clinical-demographic and peri-ictal variables that were predictive of the presence of seizure-induced arrhythmias of interest. The z-score test for 2 population proportions was used to test whether the proportion of seizures and patients with postconvulsive ESAWB or bradycardia differed between SUDEP cases and survivors. RESULTS: This study includes data from 249 patients (mean age 37.2 ± 23.5 years, 55% female) who had 455 seizures. The most common arrhythmia was ESA, with an incidence of 137 of 382 seizures (35.9%) (106/224 patients [47.3%]). There were 50 of 352 seizure-induced arrhythmias of interest (14.2%) in 41 of 204 patients (20.1%). ESAWB was the commonest in 22 of 394 seizures (5.6%) (18/225 patients [8%]), followed by SVT in 18 of 397 seizures (4.5%) (17/228 patients [7.5%]). During follow-up (48.36 ± 31.34 months), 8 SUDEPs occurred. Seizure-induced bradycardia (3.8% vs 12.5%, z = -16.66, p < 0.01) and ESAWB (6.6% vs 25%; z = -3.03, p < 0.01) were over-represented in patients who later died of SUDEP. There was no association between arrhythmias of interest and seizure severity biomarkers (p > 0.05). DISCUSSION: Markers of seizure severity are not related to seizure-induced arrhythmias of interest, suggesting that other factors such as occult cardiac abnormalities may be relevant for their occurrence. Seizure-induced ESAWB and bradycardia were more frequent in SUDEP cases, although this observation was based on a very limited number of SUDEP patients. Further case-control studies are needed to evaluate the yield of arrhythmias of interest along with respiratory changes as potential SUDEP biomarkers.

Neural and physiological responses to a cold pressor challenge in healthy adolescents.

Abnormal autonomic function is common in pediatric diseases. Assessment of central mechanisms underlying autonomic challenges may reveal vulnerabilities antecedent to system failure. Our objective was to characterize central markers and physiological responses to a cold pressor challenge in normal children as a critical step for establishing such screening. We performed functional magnetic resonance imaging (fMRI) and collected physiological measures during cold application to the foot in 24 healthy adolescents (15.5 ± 0.4 years, 13 male). The protocol included a 120-sec baseline, 120-sec right-foot cold water immersion (4°C), and 120-sec recovery. Analyses included heart rate (HR) cross-correlations with fMRI signals. Cold application increased HR 13% 5-7 sec after onset, which remained elevated throughout the challenge. Respiratory rate transiently increased (peak 22%), then declined (nadir 12% below baseline), before normalizing at 75 sec. Cold onset rapidly increased somatosensory cortex and medullary signals, which fell after 25 sec. Right anterior insular cortex signals increased early, followed after 20 sec by the left anterior insula, with HR declining 8 sec later. Amygdalae signals also rose, but signals declined in the posterior cingulate cortex, caudate nucleus, hippocampus, and hypothalamus. Declining signals appeared late in the cerebellar fastigial nuclei (60-120 sec), and in the pons and thalamus. Somatosensory cortex, fastigial nuclei, and hypothalamic responses were principally left-sided, with bilateral responses elsewhere. Late left anterior insula responses likely underlie the HR decline; the late cerebellar pattern may modulate recovery. The laterality, timing, and amplitude of normative responses and rostral response differentiation indicate the complex integration of adolescent autonomic processing and provide indices for pathological comparisons.

Visual assessment of brain magnetic resonance imaging detects injury to cognitive regulatory sites in patients with heart failure.

BACKGROUND: Heart failure (HF) patients exhibit depression and executive function impairments that contribute to HF mortality. Using specialized magnetic resonance imaging (MRI) analysis procedures, brain changes appear in areas regulating these functions (mammillary bodies, hippocampi, and frontal cortex). However, specialized MRI procedures are not part of standard clinical assessment for HF (which is usually a visual evaluation), and it is unclear whether visual MRI examination can detect changes in these structures. METHODS AND RESULTS: Using brain MRI, we visually examined the mammillary bodies and frontal cortex for global and hippocampi for global and regional tissue changes in 17 HF and 50 control subjects. Significantly global changes emerged in the right mammillary body (HF 1.18 ± 1.13 vs control 0.52 ± 0.74; P = .024), right hippocampus (HF 1.53 ± 0.94 vs control 0.80 ± 0.86; P = .005), and left frontal cortex (HF 1.76 ± 1.03 vs control 1.24 ± 0.77; P = .034). Comparison of the visual method with specialized MRI techniques corroborates right hippocampal and left frontal cortical, but not mammillary body, tissue changes. CONCLUSIONS: Visual examination of brain MRI can detect damage in HF in areas regulating depression and executive function, including the right hippocampus and left frontal cortex. Visual MRI assessment in HF may facilitate evaluation of injury to these structures and the assessment of the impact of potential treatments for this damage.

Decreased cortical thickness in central hypoventilation syndrome.

Central hypoventilation syndrome (CHS) is a rare condition characterized by hypoventilation during sleep, reduced ventilatory responsiveness to CO(2) and O(2), impaired perception of air hunger, and autonomic abnormalities. Neural impairments accompany the condition, including structural injury, impaired cerebral autoregulation, and dysfunctional autonomic control. The hypoventilation may induce cortical hypoxic injury, additional to consequences of maldevelopment from PHOX2B mutations present in most CHS subjects. We assessed cortical injury in clinically diagnosed CHS using high-resolution magnetic resonance imaging scans, collected from 14 CHS (mean age ± standard deviation [SD] 17.7 ± 5.0 years; 6 female) and 29 control (mean age ± SD, 17.9 ± 4.3 years; 12 female) subjects. We measured group differences in mean cortical thickness and age-thickness correlations using FreeSurfer software, accounting for age and sex (0.1 false discovery rate). Reduced thickness in CHS appeared in the dorsomedial frontal cortex and anterior cingulate; medial prefrontal, parietal, and posterior cingulate cortices; the insular cortex; anterior and lateral temporal lobes; and mid- and accessory motor strips. Normal age-related cortical thinning in multiple regions did not appear in CHS. The cortical thinning may contribute to CHS cardiovascular and memory deficits and may impair affect and perception of breathlessness. Extensive axonal injury in CHS is paralleled by reduced cortical tissue and absence of normal developmental patterns.