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.

Cerebral impairment in heart failure.

Patients with heart failure (HF) exhibit a wide range of symptoms, including dyspnea, sleep-disordered breathing, autonomic abnormalities, cognitive dysfunction, and neuropsychological disturbances. These symptoms, which affect quality of life and morbidity and mortality in the condition, are largely related to structural and functional changes in the brain. There are increasing reports of brain abnormalities in HF, but often the linkages between brain injury and common HF clinical symptomatology are not clearly described. In this review, we will discuss the current evidence of brain injury and the associated clinical symptoms in HF, focusing on those brain regions that are commonly damaged in the condition. We will also provide a brief exploration of some potential mechanisms for brain injury in HF.

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.

Volumetric and microstructural abnormalities of the amygdala in focal epilepsy with varied levels of SUDEP risk.

Although the mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet well understood, generalised- or focal-to-bilateral tonic-clonic seizures (TCS) are a major risk factor. Previous studies highlighted alterations in structures linked to cardio-respiratory regulation; one structure, the amygdala, was enlarged in people at high risk of SUDEP and those who subsequently died. We investigated volume changes and the microstructure of the amygdala in people with epilepsy at varied risk for SUDEP since that structure can play a key role in triggering apnea and mediating blood pressure. The study included 53 healthy subjects and 143 patients with epilepsy, the latter separated into two groups according to whether TCS occur in years before scan. We used amygdala volumetry, derived from structural MRI, and tissue microstructure, derived from diffusion MRI, to identify differences between the groups. The diffusion metrics were obtained by fitting diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. The analyses were performed at the whole amygdala level and at the scale of amygdaloid nuclei. Patients with epilepsy showed larger amygdala volumes and lower neurite density indices (NDI) than healthy subjects; the left amygdala volumes were especially enhanced. Microstructural changes, reflected by NDI differences, were more prominent on the left side and localized in the lateral, basal, central, accessory basal and paralaminar amygdala nuclei; basolateral NDI lowering appeared bilaterally. No significant microstructural differences appeared between epilepsy patients with and without current TCS. The central amygdala nuclei, with prominent interactions from surrounding nuclei of that structure, project to cardiovascular regions and respiratory phase switching areas of the parabrachial pons, as well as to the periaqueductal gray. Consequently, they have the potential to modify blood pressure and heart rate, and induce sustained apnea or apneusis. The findings here suggest that lowered NDI, indicative of reduced dendritic density, could reflect an impaired structural organization influencing descending inputs that modulate vital respiratory timing and drive sites and areas critical for blood pressure control.

Volumetric and microstructural abnormalities of the amygdala in focal epilepsy with varied levels of SUDEP risk.

Although the mechanisms of sudden unexpected death in epilepsy (SUDEP) are not yet well understood, generalised- or focal-to-bilateral tonic-clonic seizures (TCS) are a major risk factor. Previous studies highlighted alterations in structures linked to cardio-respiratory regulation; one structure, the amygdala, was enlarged in people at high risk of SUDEP and those who subsequently died. We investigated volume changes and the microstructure of the amygdala in people with epilepsy at varied risk for SUDEP since that structure can play a key role in triggering apnea and mediating blood pressure. The study included 53 healthy subjects and 143 patients with epilepsy, the latter separated into two groups according to whether TCS occur in years before scan. We used amygdala volumetry, derived from structural MRI, and tissue microstructure, derived from diffusion MRI, to identify differences between the groups. The diffusion metrics were obtained by fitting diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) models. The analyses were performed at the whole amygdala level and at the scale of amygdaloid nuclei. Patients with epilepsy showed larger amygdala volumes and lower neurite density indices (NDI) than healthy subjects; the left amygdala volumes were especially enhanced. Microstructural changes, reflected by NDI differences, were more prominent on the left side and localized in the lateral, basal, central, accessory basal and paralaminar amygdala nuclei; basolateral NDI lowering appeared bilaterally. No significant microstructural differences appeared between epilepsy patients with and without current TCS. The central amygdala nuclei, with prominent interactions from surrounding nuclei of that structure, project to cardiovascular regions and respiratory phase switching areas of the parabrachial pons, as well as to the periaqueductal gray. Consequently, they have the potential to modify blood pressure and heart rate, and induce sustained apnea or apneusis. The findings here suggest that lowered NDI, indicative of reduced dendritic density, could reflect an impaired structural organization influencing descending inputs that modulate vital respiratory timing and drive sites and areas critical for blood pressure control.

Impaired cerebellar and limbic responses to the valsalva maneuver in heart failure.

Heart failure (HF) patients show an inability to regulate autonomic functions, a characteristic which is associated with increased mortality. These autonomic deficits may stem from earlier demonstrated injury to central autonomic regulatory areas, providing a structural basis for the autonomic abnormalities. However, knowledge of structural injury provides insufficient insights into timing and magnitude of signal patterns within affected areas which lead to impaired autonomic outflow. Among damaged brain areas, cerebellar sites are key for timely coordination of sympathetic and parasympathetic attributes, and for dampening extremes of hypotension and hypertension induced by other injured sites, including hypothalamic and limbic areas. We collected functional magnetic resonance imaging (fMRI) signals in cerebellar and limbic areas to characterize amplitude and timing patterns of neural responses to the Valsalva maneuver, an autonomic challenge that elicits sequential sympathetic and parasympathetic responses, in 16 HF patients and 33 control subjects. HF patients showed distorted fMRI signal patterns during the challenge period in the cerebellar vermis, left cerebellar crus II, and left insula, whereas the right crus II and insula, and bilateral amygdalae showed normal patterns. However, all structures, except the left crus II, showed altered responses in HF during the recovery period. Crus II patterns reflected a failure of HF subjects to demonstrate the normal lateralized responses, while in the insula, HF subjects exhibited abnormal left-right patterns, relative to controls. The abnormal timing and response patterns in these injured areas critical for autonomic regulation likely contribute to the enhanced sympathetic outflow and autonomic dysfunction characteristic of HF.

Regional variation in brain tissue texture in patients with tonic-clonic seizures.

Patients with epilepsy, who later succumb to sudden unexpected death, show altered brain tissue volumes in selected regions. It is unclear whether the alterations in brain tissue volume represent changes in neurons or glial properties, since volumetric procedures have limited sensitivity to assess the source of volume changes (e.g., neuronal loss or glial cell swelling). We assessed a measure, entropy, which can determine tissue homogeneity by evaluating tissue randomness, and thus, shows tissue integrity; the measure is easily calculated from T1-weighted images. T1-weighted images were collected with a 3.0-Tesla MRI from 53 patients with tonic-clonic (TC) seizures and 53 healthy controls; images were bias-corrected, entropy maps calculated, normalized to a common space, smoothed, and compared between groups (TC patients and controls using ANCOVA; covariates, age and sex; SPM12, family-wise error correction for multiple comparisons, p<0.01). Decreased entropy, indicative of increased tissue homogeneity, appeared in major autonomic (ventromedial prefrontal cortex, hippocampus, dorsal and ventral medulla, deep cerebellar nuclei), motor (sensory and motor cortex), or both motor and autonomic regulatory sites (basal-ganglia, ventral-basal cerebellum), and external surfaces of the pons. The anterior and posterior thalamus and midbrain also showed entropy declines. Only a few isolated regions showed increased entropy. Among the spared autonomic regions was the anterior cingulate and anterior insula; the posterior insula and cingulate were, however, affected. The entropy alterations overlapped areas of tissue changes found earlier with volumetric measures, but were more extensive, and indicate widespread injury to tissue within critical autonomic and breathing regulatory areas, as well as prominent damage to more-rostral sites that exert influences on both breathing and cardiovascular regulation. The entropy measures provide easily-collected supplementary information using only T1-weighted images, showing aspects of tissue integrity other than volume change that are important for assessing function.

Insular functional organization during handgrip in females and males with obstructive sleep apnea.

STUDY OBJECTIVES: Brain regulation of autonomic function in obstructive sleep apnea (OSA) is disrupted in a sex-specific manner, including in the insula, which may contribute to several comorbidities. The insular gyri have anatomically distinct functions with respect to autonomic nervous system regulation; yet, OSA exerts little effect on the organization of insular gyral responses to sympathetic components of an autonomic challenge, the Valsalva. We further assessed neural responses of insular gyri in people with OSA to a static handgrip task, which principally involves parasympathetic withdrawal. METHODS: We measured insular function with blood oxygen level dependent functional MRI. We studied 48 newly-diagnosed OSA (age mean±std:46.5±9 years; AHI±std:32.6±21.1 events/hour; 36 male) and 63 healthy (47.2±8.8 years;40 male) participants. Subjects performed four 16s handgrips (1 min intervals, 80% subjective maximum strength) during scanning. fMRI time trends from five insular gyri-anterior short (ASG); mid short (MSG); posterior short (PSG); anterior long (ALG); and posterior long (PLG)-were assessed for within-group responses and between-group differences with repeated measures ANOVA (p<0.05) in combined and separate female-male models; age and resting heart-rate (HR) influences were also assessed. RESULTS: Females showed greater right anterior dominance at the ASG, but no differences emerged between OSA and controls in relation to functional organization of the insula in response to handgrip. Males showed greater left anterior dominance at the ASG, but there were also no differences between OSA and controls. The males showed a group difference between OSA and controls only in the ALG. OSA males had lower left activation at the ALG compared to control males. Responses were mostly influenced by HR and age; however, age did not impact the response for right anterior dominance in females. CONCLUSIONS: Insular gyri functional responses to handgrip differ in OSA vs controls in a sex-based manner, but only in laterality of one gyrus, suggesting anterior and right-side insular dominance during sympathetic activation but parasympathetic withdrawal is largely intact, despite morphologic injury to the overall structure.

Functional organization of the insula in men and women with obstructive sleep apnea during Valsalva.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) patients show impaired autonomic regulation, perhaps related to functional reorganization of the insula, which in healthy individuals shows sex-specific anterior and right dominance during sympathetic activation. We examined insular organization of responses to a Valsalva maneuver in OSA with functional magnetic resonance imaging (fMRI). METHODS: We studied 43 newly diagnosed OSA (age mean ± SD: 46.8 ± 8.7 years; apnea-hypopnea index (AHI) ± SD: 32.1 ± 20.1 events/hour; 34 males) and 63 healthy (47.2 ± 8.8 years; 40 males) participants. Participants performed four 18-second Valsalva maneuvers (1-minute intervals, pressure ≥ 30 mmHg) during scanning. fMRI time trends from five insular gyri-anterior short (ASG); mid short (MSG); posterior short (PSG); anterior long (ALG); and posterior long (PLG)-were assessed for within-group responses and between-group differences with repeated measures ANOVA (p < 0.05); age and resting heart rate (HR) influences were also assessed. RESULTS: Right and anterior fMRI signal dominance appeared in OSA and controls, with no between-group differences. Separation by sex revealed group differences. Left ASG anterior signal dominance was lower in OSA versus control males. Left ASG and ALG anterior dominance was higher in OSA versus control females. In all right gyri, only OSA females showed greater anterior dominance than controls. Right dominance was apparent in PSG and ALG in all groups; females showed right dominance in MSG and PLG. OSA males did not show PLG right dominance. Responses were influenced substantially by HR but modestly by age. CONCLUSIONS: Anterior and right insular fMRI dominance appears similar in OSA versus control participants during the sympathetic phase of the Valsalva maneuver. OSA and control similarities were present in just males, but not necessarily females, which may reflect sex-specific neural injury.

Three-dimensional surface maps link local atrophy and fast ripples in human epileptic hippocampus.

OBJECTIVES: There is compelling evidence that pathological high-frequency oscillations (HFOs), called fast ripples (FR, 150-500Hz), reflect abnormal synchronous neuronal discharges in areas responsible for seizure genesis in patients with mesial temporal lobe epilepsy (MTLE). It is hypothesized that morphological changes associated with hippocampal atrophy (HA) contribute to the generation of FR, yet there is limited evidence that hippocampal FR-generating sites correspond with local areas of atrophy. METHODS: Interictal HFOs were recorded from hippocampal microelectrodes in 10 patients with MTLE. Rates of FR and ripple discharge from each microelectrode were evaluated in relation to local measures of HA obtained using 3-dimensional magnetic resonance imaging (MRI) hippocampal modeling. RESULTS: Rates of FR discharge were 3 times higher in areas of significant local HA compared with rates in nonatrophic areas. Furthermore, FR occurrence correlated directly with the severity of damage in these local atrophic regions. In contrast, we found no difference in rates of ripple discharge between local atrophic and nonatrophic areas. INTERPRETATION: The proximity between local HA and microelectrode-recorded FR suggests that morphological changes such as neuron loss and synaptic reorganization may contribute to the generation of FR. Pathological HFOs, such as FR, may provide a reliable surrogate marker of abnormal neuronal excitability in hippocampal areas responsible for the generation of spontaneous seizures in patients with MTLE. Based on these data, it is possible that MRI-based measures of local HA could identify FR-generating regions, and thus provide a noninvasive means to localize epileptogenic regions in hippocampus.

Three-dimensional hippocampal atrophy maps distinguish two common temporal lobe seizure-onset patterns.

PURPOSE: Current evidence suggests that the mechanisms underlying depth electrode-recorded seizures beginning with hypersynchronous (HYP) onset patterns are functionally distinct from those giving rise to low-voltage fast (LVF) onset seizures. However, both groups have been associated with hippocampal atrophy (HA), indicating a need to clarify the anatomic correlates of each ictal onset type. We used three-dimensional (3D) hippocampal mapping to quantify HA and determine whether each onset group exhibited a unique distribution of atrophy consistent with the functional differences that distinguish the two onset morphologies. METHODS: Sixteen nonconsecutive patients with medically refractory epilepsy were assigned to HYP or LVF groups according to ictal onset patterns recorded with intracranial depth electrodes. Using preimplant magnetic resonance imaging (MRI), levels of volumetrically defined HA were determined by comparison with matched controls, and the distribution of local atrophy was mapped onto 3D hippocampal surface models. RESULTS: HYP and LVF groups exhibited significant and equivalent levels of HA ipsilateral to seizure onset. Patients with LVF onset seizures also showed significant contralateral volume reductions. On ipsilateral contour maps HYP patients exhibited an atrophy pattern consistent with classical hippocampal sclerosis (HS), whereas LVF atrophy was distributed more laterally and diffusely. Contralateral LVF maps also showed regions of subicular atrophy. DISCUSSION: The HS-like distribution of atrophy and the restriction of HA to the ipsilateral hippocampus in HYP patients are consistent with focal hippocampal onsets, and suggest a mechanism utilizing intrahippocampal circuitry. In contrast, the bilateral distribution of nonspecific atrophy in the LVF group may reflect mechanisms involving both hippocampal and extrahippocampal networks.

Sex-specific hippocampus volume changes in obstructive sleep apnea.

Introduction: Obstructive sleep apnea (OSA) patients show hippocampal-related autonomic and neurological symptoms, including impaired memory and depression, which differ by sex, and are mediated in distinct hippocampal subfields. Determining sites and extent of hippocampal sub-regional injury in OSA could reveal localized structural damage linked with OSA symptoms. Methods: High-resolution T1-weighted images were collected from 66 newly-diagnosed, untreated OSA (mean age ±â€¯SD: 46.3 ±â€¯8.8 years; mean AHI ±â€¯SD: 34.1 ±â€¯21.5 events/h;50 male) and 59 healthy age-matched control (46.8 ±â€¯9.0 years;38 male) participants. We added age-matched controls with T1-weighted scans from two datasets (IXI, OASIS-MRI), for 979 controls total (426 male/46.5 ±â€¯9.9 years). We segmented the hippocampus and analyzed surface structure with "FSL FIRST" software, scaling volumes for brain size, and evaluated group differences with ANCOVA (covariates: total-intracranial-volume, sex; P < .05, corrected). Results: In OSA relative to controls, the hippocampus showed small areas larger volume bilaterally in CA1 (surface displacement ≤0.56 mm), subiculum, and uncus, and smaller volume in right posterior CA3/dentate (≥ - 0.23 mm). OSA vs. control males showed higher bilateral volume (≤0.61 mm) throughout CA1 and subiculum, extending to head and tail, with greater right-sided increases; lower bilateral volumes (≥ - 0.45 mm) appeared in mid- and posterior-CA3/dentate. OSA vs control females showed only right-sided effects, with increased CA1 and subiculum/uncus volumes (≤0.67 mm), and decreased posterior CA3/dentate volumes (≥ - 0.52 mm). Unlike males, OSA females showed volume decreases in the right hippocampus head and tail. Conclusions: The hippocampus shows lateralized and sex-specific, OSA-related regional volume differences, which may contribute to sex-related expression of symptoms in the sleep disorder. Volume increases suggest inflammation and glial activation, whereas volume decreases suggest long-lasting neuronal injury; both processes may contribute to dysfunction in OSA.

Regional cortical thickness changes accompanying generalized tonic-clonic seizures.

Objective: Generalized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms. Methods: High-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ±â€¯SD: 37.1 ±â€¯12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ±â€¯12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations (P < 0.05 corrected). Results: Increased cortical thickness appeared in post-central gyri, insula, and subgenual, anterior, posterior, and isthmus cingulate cortices. Post-central gyri increases were greater in females, while males showed more extensive cingulate increases. Frontal and temporal cortex, lateral orbitofrontal, frontal pole, and lateral parietal and occipital cortices showed thinning. The extents of thickness changes were sex- and hemisphere-dependent, with only males exhibiting right-sided and posterior cingulate thickening, while females showed only left lateral orbitofrontal thinning. Regional cortical thickness showed modest correlations with seizure frequency, but not epilepsy duration. Significance: Cortical thickening and thinning occur in patients with generalized tonic-clonic seizures, in cardiovascular and somatosensory areas, with extent of changes sex- and hemisphere-dependent. The data show injury in key autonomic and respiratory cortical areas, which may contribute to dysfunctional cardiorespiratory patterns during seizures, as well as to longer-term SUDEP risk.

Sex differences in insular cortex gyri responses to a brief static handgrip challenge.

BACKGROUND: Cardiovascular disease varies between sexes, suggesting male-female autonomic control differences. Insular gyri help coordinate autonomic regulation and show a sex-dependent response to a sympathetic challenge. METHODS: We examined sex-related insular gyral responses to a short static handgrip exercise challenge eliciting parasympathetic withdrawal with functional magnetic resonance imaging (fMRI) during four 16-s challenges (80% maximum strength) in 23 healthy females (age; mean ± std 50 ± 8 years) and 40 males (46 ± 9 years). Heart rate (HR) and fMRI signals were compared with repeated measures ANOVA (P < 0.05). Additional analyses were performed with age and age interactions, as well as right-handed only subjects. RESULTS: Females showed higher resting HR than males, but smaller percent HR change increases to the challenges. All gyri showed fMRI patterns concurrent with an HR peak and decline to baseline. fMRI signals followed an anterior-posterior organization in both sexes, but lateralization varied by gyri and sex. All subjects showed greater signals in the anterior vs. posterior gyri (females 0.3%, males 0.15%). The middle gyri showed no lateralization in females but left-sided dominance in males (0.1%). The posterior gyri showed greater left than right activation in both sexes. The anterior-most gyri exhibited a prominent sex difference, with females showing a greater right-sided activation (0.2%) vs. males displaying a greater left-sided activation (0.15%). Age and handedness affected a minority of findings but did not alter the overall pattern of results. CONCLUSIONS: The anterior insula plays a greater role in cardiovascular regulation than posterior areas during a predominantly parasympathetic withdrawal challenge, with opposite lateralization between sexes. In females, the left anterior-most gyrus responded distinctly from other regions than males. Those sex-specific structural and functional brain patterns may contribute over time to variations in cardiovascular disease between the sexes.

Dysfunctional Brain Networking among Autonomic Regulatory Structures in Temporal Lobe Epilepsy Patients at High Risk of Sudden Unexpected Death in Epilepsy.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is common among young people with epilepsy. Individuals who are at high risk of SUDEP exhibit regional brain structural and functional connectivity (FC) alterations compared with low-risk patients. However, less is known about network-based FC differences among critical cortical and subcortical autonomic regulatory brain structures in temporal lobe epilepsy (TLE) patients at high risk of SUDEP. METHODS: 32 TLE patients were risk-stratified according to the following clinical criteria: age of epilepsy onset, duration of epilepsy, frequency of generalized tonic-clonic seizures, and presence of nocturnal seizures, resulting in 14 high-risk and 18 low-risk cases. Resting-state functional magnetic resonance imaging (rs-fMRI) signal time courses were extracted from 11 bilateral cortical and subcortical brain regions involved in autonomic and other regulatory processes. After computing all pairwise correlations, FC matrices were analyzed using the network-based statistic. FC strength among the 11 brain regions was compared between the high- and low-risk patients. Increases and decreases in FC were sought, using high-risk > low-risk and low-risk > high-risk contrasts (with covariates age, gender, lateralization of epilepsy, and presence of hippocampal sclerosis). RESULTS: High-risk TLE patients showed a subnetwork with significantly reduced FC (t = 2.5, p = 0.029) involving the thalamus, brain stem, anterior cingulate, putamen and amygdala, and a second subnetwork with significantly elevated FC (t = 2.1, p = 0.031), which extended to medial/orbital frontal cortex, insula, hippocampus, amygdala, subcallosal cortex, brain stem, thalamus, caudate, and putamen. CONCLUSION: TLE patients at high risk of SUDEP showed widespread FC differences between key autonomic regulatory brain regions compared to those at low risk. The altered FC revealed here may help to shed light on the functional correlates of autonomic disturbances in epilepsy and mechanisms involved in SUDEP. Furthermore, these findings represent possible objective biomarkers which could help to identify high-risk patients and enhance SUDEP risk stratification via the use of non-invasive neuroimaging, which would require validation in larger cohorts, with extension to patients with other epilepsies and subjects who succumb to SUDEP.

Obstructive sleep apnea is associated with altered midbrain chemical concentrations.

Obstructive sleep apnea (OSA) is accompanied by altered structure and function in cortical, limbic, brainstem, and cerebellar regions. The midbrain is relatively unexamined, but contains many integrative nuclei which mediate physiological functions that are disrupted in OSA. We therefore assessed the chemistry of the midbrain in OSA in this exploratory study. We used a recently developed accelerated 2D magnetic resonance spectroscopy (2D-MRS) technique, compressed sensing-based 4D echo-planar J-resolved spectroscopic imaging (4D-EP-JRESI), to measure metabolites in the midbrain of 14 OSA (mean age±SD:54.6±10.6years; AHI:35.0±19.4; SAO2 min:83±7%) and 26 healthy control (50.7±8.5years) subjects. High-resolution T1-weighted scans allowed voxel localization. MRS data were processed with custom MATLAB-based software, and metabolite ratios calculated with respect to the creatine peak using a prior knowledge fitting (ProFit) algorithm. The midbrain in OSA showed decreased N-acetylaspartate (NAA; OSA:1.24±0.43, Control:1.47±0.41; p=0.03; independent samples t-test), a marker of neuronal viability. Increased levels in OSA over control subjects appeared in glutamate (Glu; OSA:1.23±0.57, Control:0.98±0.33; p=0.03), ascorbate (Asc; OSA:0.56±0.28, Control:0.42±0.20; (50.7±8.5years; p=0.03), and myo-inositol (mI; OSA:0.96±0.48, Control:0.72±0.35; p=0.03). No differences between groups appeared in γ-aminobutyric acid (GABA) or taurine. The midbrain in OSA patients shows decreased NAA, indicating neuronal injury or dysfunction. Higher Glu levels may reflect excitotoxic processes and astrocyte activation, and higher mI is also consistent with glial activation. Higher Asc levels may result from oxidative stress induced by intermittent hypoxia in OSA. Additionally, Asc and Glu are involved with glutamatergic processes, which are likely upregulated in the midbrain nuclei of OSA patients. The altered metabolite levels help explain dysfunction and structural deficits in the midbrain of OSA patients.

Sex Differences in Insular Cortex Gyri Responses to the Valsalva Maneuver.

Sex differences in autonomic regulation may underlie cardiovascular disease variations between females and males. One key autonomic brain region is the insular cortex, which typically consists of five main gyri in each hemisphere, and shows a topographical organization of autonomic function across those gyri. The present study aims to identify possible sex differences in organization of autonomic function in the insula. We studied brain functional magnetic resonance imaging (fMRI) responses to a series of four 18-s Valsalva maneuvers in 22 healthy females (age ± SD: 50.0 ± 7.9 years) and 36 healthy males (45.3 ± 9.2 years). Comparisons of heart rate (HR) and fMRI signals were performed with repeated measures ANOVA (threshold P < 0.05 for all findings). All subjects achieved the target 30 mmHg expiratory pressure for all challenges. Typical HR responses were elicited by the maneuver, including HR increases from ~4 s into the strain period (Phase II) and rapid declines to below baseline 5-10 s, following strain release (Phase IV). Small, but significant, sex differences in HR percent change occurred during the sympathetic-dominant Phase II (female < male) and parasympathetic-dominant Phase IV (female > male, i.e., greater undershoot in males). The insular cortices showed similar patterns in all gyri, with greater signal decreases in males than females. Both sexes exhibited an anterior-posterior topographical organization of insular responses during Phase II, with anterior gyri showing higher responses than more posterior gyri. The exception was the right anterior-most gyrus in females, which had lower responses than the four other right gyri. Responses were lateralized, with right-sided dominance during Phase II in both sexes, except the right anterior-most gyrus in females, which showed lower responses than the left. The findings confirm the anterior and right-sided sympathetic dominance of the insula. Although sex differences were prominent in response magnitude, organization differences between males and females were limited to the right anterior-most gyrus, which showed a lower fMRI response in females vs. males (and vs. other gyri in females). The sex differences suggest a possible differing baseline state of brain physiology or tonic functional activity between females and males, especially in the right anterior-most gyrus.

Functional Imaging of Autonomic Regulation: Methods and Key Findings.

Central nervous system processing of autonomic function involves a network of regions throughout the brain which can be visualized and measured with neuroimaging techniques, notably functional magnetic resonance imaging (fMRI). The development of fMRI procedures has both confirmed and extended earlier findings from animal models, and human stroke and lesion studies. Assessments with fMRI can elucidate interactions between different central sites in regulating normal autonomic patterning, and demonstrate how disturbed systems can interact to produce aberrant regulation during autonomic challenges. Understanding autonomic dysfunction in various illnesses reveals mechanisms that potentially lead to interventions in the impairments. The objectives here are to: (1) describe the fMRI neuroimaging methodology for assessment of autonomic neural control, (2) outline the widespread, lateralized distribution of function in autonomic sites in the normal brain which includes structures from the neocortex through the medulla and cerebellum, (3) illustrate the importance of the time course of neural changes when coordinating responses, and how those patterns are impacted in conditions of sleep-disordered breathing, and (4) highlight opportunities for future research studies with emerging methodologies. Methodological considerations specific to autonomic testing include timing of challenges relative to the underlying fMRI signal, spatial resolution sufficient to identify autonomic brainstem nuclei, blood pressure, and blood oxygenation influences on the fMRI signal, and the sustained timing, often measured in minutes of challenge periods and recovery. Key findings include the lateralized nature of autonomic organization, which is reminiscent of asymmetric motor, sensory, and language pathways. Testing brain function during autonomic challenges demonstrate closely-integrated timing of responses in connected brain areas during autonomic challenges, and the involvement with brain regions mediating postural and motoric actions, including respiration, and cardiac output. The study of pathological processes associated with autonomic disruption shows susceptibilities of different brain structures to altered timing of neural function, notably in sleep disordered breathing, such as obstructive sleep apnea and congenital central hypoventilation syndrome. The cerebellum, in particular, serves coordination roles for vestibular stimuli and blood pressure changes, and shows both injury and substantially altered timing of responses to pressor challenges in sleep-disordered breathing conditions. The insights into central autonomic processing provided by neuroimaging have assisted understanding of such regulation, and may lead to new treatment options for conditions with disrupted autonomic function.

Impaired neural structure and function contributing to autonomic symptoms in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show major autonomic alterations in addition to their better-known breathing deficiencies. The processes underlying CCHS, mutations in the PHOX2B gene, target autonomic neuronal development, with frame shift extent contributing to symptom severity. Many autonomic characteristics, such as impaired pupillary constriction and poor temperature regulation, reflect parasympathetic alterations, and can include disturbed alimentary processes, with malabsorption and intestinal motility dyscontrol. The sympathetic nervous system changes can exert life-threatening outcomes, with dysregulation of sympathetic outflow leading to high blood pressure, time-altered and dampened heart rate and breathing responses to challenges, cardiac arrhythmia, profuse sweating, and poor fluid regulation. The central mechanisms contributing to failed autonomic processes are readily apparent from structural and functional magnetic resonance imaging studies, which reveal substantial cortical thinning, tissue injury, and disrupted functional responses in hypothalamic, hippocampal, posterior thalamic, and basal ganglia sites and their descending projections, as well as insular, cingulate, and medial frontal cortices, which influence subcortical autonomic structures. Midbrain structures are also compromised, including the raphe system and its projections to cerebellar and medullary sites, the locus coeruleus, and medullary reflex integrating sites, including the dorsal and ventrolateral medullary nuclei. The damage to rostral autonomic sites overlaps metabolic, affective and cognitive regulatory regions, leading to hormonal disruption, anxiety, depression, behavioral control, and sudden death concerns. The injuries suggest that interventions for mitigating hypoxic exposure and nutrient loss may provide cellular protection, in the same fashion as interventions in other conditions with similar malabsorption, fluid turnover, or hypoxic exposure.