Physiological Targets for Orthostatic Hypotension: Improving Nonpharmacological Interventions in Patients with Orthostatic Cerebral Hypoperfusion.

Orthostatic hypotension (OH) is a form of orthostatic intolerance (OI) and a key physiological indicator of autonomic dysfunction that is associated with an increased risk of major cerebrocardiovascular events. Symptoms of cerebral hypoperfusion have been reported in patients with OH, which worsens symptoms and increases the risk of syncope. Since pharmacological interventions increase blood pressure (BP) independent of posture and do not restore normal baroreflex control, nonpharmacological treatments are considered the foundation of OH management. While reductions in cerebral blood flow velocity (CBFv) during orthostatic stress are associated with a decrease in end-tidal CO2 (EtCO2) and hypocapnia in patients with OI, their contribution to the severity of OH is not well understood. These measures have been physiological targets in a wide variety of biofeedback interventions. This study explored the relationship between cardiovascular autonomic control, EtCO2 and cerebral hypoperfusion in patients (N = 72) referred for OI. Patients with systolic OH were more likely to be male, older, demonstrate reduced adrenal and vagal baroreflex sensitivity, and reduced cardiovagal control during head-up tilt (HUT) than patients without systolic OH. Greater reduction in CBFv during HUT was associated with a larger reduction in ETCO2 and systolic BP during HUT. While deficits in cardiovascular autonomic control played a more important role in systolic OH, reduced EtCO2 was a major contributor to orthostatic cerebral hypoperfusion. These findings suggest that biofeedback treatments targeting both the autonomic nervous system and EtCO2 should be part of nonpharmacological interventions complementing the standard of care in OH patients with symptoms of cerebral hypoperfusion.

Cardiovascular Autonomic Regulation, ETCO2 and the Heart Rate Response to the Tilt Table Test in Patients with Orthostatic Intolerance.

Chronic orthostatic intolerance (COI) is defined by changes in heart rate (HR), blood pressure (BP), respiration, symptoms of cerebral hypoperfusion and sympathetic overactivation. Postural tachycardia syndrome (POTS) is the most common form of COI in young adults and is defined by an orthostatic increase in heart rate (HR) of ≥ 30 bpm in the absence of orthostatic hypotension. However, some patients referred for evaluation of COI symptoms do not meet the orthostatic HR response criterion of POTS despite debilitating symptoms. Such patients are ill defined, posing diagnostic and therapeutic challenges. This study explored the relationship among cardiovascular autonomic control, the orthostatic HR response, EtCO2 and the severity of orthostatic symptoms and fatigue in patients referred for evaluation of COI. Patients (N = 108) performed standardized testing protocol of the Autonomic Reflex Screen and completed the Composite Autonomic Symptom Score (COMPASS-31) and the Fatigue Severity Scale (FSS). Greater severity of COI was associated with younger age, larger phase IV amplitude in the Valsalva maneuver and lower adrenal baroreflex sensitivity. Greater fatigue severity was associated with a larger reduction in ETCO2 during 10 min of head-up tilt (HUT) and reduced low-frequency (LF) power of heart rate variability. This study suggests that hemodynamic changes associated with the baroreflex response and changes in EtCO2 show a stronger association with the severity of orthostatic symptoms and fatigue than the overall orthostatic HR response in patients with COI.

Investigation of vagal afferent functioning using the Heartbeat Event Related Potential.

Although there has been much support for HRV Biofeedback as an effective intervention for various disorders, there is a lack of comprehension of the underlying mechanisms. The predominant theories of increased vagal efferents and baroreflex gain are insufficient in explaining the frequent observations that HRV Biofeedback impacts changes in constructs beyond ANS mediation, such as emotion regulation, attentional control, and self-regulatory reserve. It has been suspected that vagal afferent functioning may be the underlying mechanism, but little research has explored this. Previously, researchers measured cortical evoked potentials contingent to the heart, or an indication of vagal afferent functioning (Schandry et al., 1986). Twenty-five participants were randomly stratified to HRV Biofeedback or EMG Biofeedback for four sessions. Repeated measures ANOVAs revealed that the HRV group exhibited statistically significantly increased baseline Heartbeat Event-Related Potentials (updated term for 'evoked potential') while the relaxation control group did not. The results of this study provide initial support to the premise that HRV Biofeedback stimulates changes in the vagal afferent pathway that are longer lasting than simply the short term effects of breathing.

Sensory Gating Deficits in First-Episode Psychosis: Evidence From Neurophysiology, Psychophysiology, and Neuropsychology.

Sensory gating deficits are commonly found in patients with schizophrenia. However, there is still scarce research on this issue. Thirty-eight patients with first-episode psychosis (FEP) were compared to thirty-eight controls. A condition-test paradigm of event-related potentials (ERP), prepulse inhibition (PPI), and some specific tasks of the MATRICS Consensus Cognitive Battery (MCCB) were used (i.e., TMT, BACS-SC, and Fluency for processing speed and CPT-IP for attention and vigilance). The ERP components measured were P50, N1, and P2. The PPI intervals examined were 30, 60, and 120 msec. Regarding the MCCB, processing speed and attention/vigilance cognitive domains were selected. FEP patients showed significant deficits in N1 and P2 components, at 30 and 60 PPI levels and in all the MCCB subtests selected. We obtained significant relationships in N1 with PPI-60, and with one MCCB subtest for processing speed. In addition, this same subtest showed significant association with P2. Therefore, sensory gating functioning is widely impaired since the very early stages of schizophrenia.

Cardiovascular disease risks in adult Native and Mexican Americans with a history of alcohol use disorders: association with cardiovascular autonomic control.

Hypertension and obesity are serious health problems that have been associated with an increased risk of cardiovascular disease (CVD). We recently showed a relationship between hypertension, obesity and cardiovagal control in a sample of Native and Mexican Americans at high risk of alcohol use disorders (AUD). While studies have shown that Native and Mexican Americans exhibit high rates of AUD, the consequences of AUD on CVD risk factors and their relationship with cardiovascular autonomic control is not well understood in these ethnic groups. This study investigated whether an association could be demonstrated between cardiovascular autonomic control and several CVD risk factors in Native and Mexican American men and women (n = 228) who are literate in English and are residing legally in San Diego County. Participants with lifetime history of AUD showed higher rates of systolic and diastolic hypertension and obesity than participants without lifetime AUD. Lifetime AUD was significantly associated with reduced HR response to deep breathing (HRDB) measure of cardiovagal control, higher current drinking quantity, and obesity. Reduced HRDB was also associated with increased systolic pre-hypertension or hypertension (pre-/hypertension) and with higher diastolic blood pressure in a linear regression model that included several diagnostic and demographic variables. HRDB and time- and frequency-domain measures of cardiovagal control were significantly reduced in participants with diastolic pre-/hypertension. These data suggest that lower cardiovagal control may play a role in the prevalence of systolic and diastolic pre-/hypertension in a community sample with a history of alcohol and substance use disorders.

CHRNA5 and CHRNA3 variants and level of neuroticism in young adult Mexican American men and women.

A lifetime history of alcohol dependence has been associated with elevations in neuroticism in Mexican American young adults. The identification of genetic markers associated with neuroticism and their influence on the development of alcohol use disorders (AUD) may contribute to our understanding of the relationship between personality traits and the increased risk of AUD in Mexican Americans. The purpose of this study was to investigate associations between neuroticism and 13 single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine (nAChR) α5-subunit (CHRNA5) and α3-subunit (CHRNA3) genes in young adult Mexican American men and women. Participants were 465 young adult Mexican American men and women who are literate in English and are residing legally in San Diego County. Each participant gave a blood sample and completed a structured diagnostic interview. Neuroticism was assessed using the Maudsley Personality Inventory. The minor alleles of four CHRNA5 polymorphisms (rs588765, rs601079, rs680244 and rs555018) and three CHRNA3 polymorphisms (rs578776, rs6495307 and rs3743078) showed associations with neuroticism. Several of these SNPs also displayed nominal associations with DSM-IV alcohol and nicotine dependence, but tests of mediation suggested that these relations could be partially explained by the presence of co-occurring neuroticism. These findings suggest that genetic variations in nicotinic receptor genes may influence the development of neuroticism, which in turn is involved in the development of AUDs and nicotine dependence in Mexican American young adults.

Obesity in american Indian and mexican american men and women: associations with blood pressure and cardiovascular autonomic control.

Obesity is a serious public health problem, especially in some minority communities, and it has been associated with an increased risk of cardiovascular diseases. While obesity is a serious health concern in both American Indian and Mexican American populations, the relationship between obesity and cardiac autonomic control in these two populations is not well understood. The present study in a selected sample of American Indians and Mexican Americans assessed associations between obesity, blood pressure (BP), and cardiovascular autonomic control. Cardiovascular autonomic control, systolic and diastolic mean BP, and body mass index were obtained from one hundred thirty-two American Indian and Mexican American men and women who are literate in English and are residing legally in San Diego County. Men had a significant greater systolic and diastolic BP and were more likely to develop systolic prehypertension and hypertension than women. Obese participants showed greater mean heart rate (HR) and systolic and diastolic BP than nonobese participants. Obese men also exhibited greater cardiac sympathetic activity and lower cardiovagal control than obese women. These results suggest that obesity and gender differences in cardiovascular autonomic control may contribute to risk for cardiovascular disorders in this sample of American Indians and Mexican Americans.

Effects of adolescent onset voluntary drinking followed by ethanol vapor exposure on subsequent ethanol consumption during protracted withdrawal in adult Wistar rats.

Epidemiological studies have demonstrated that heavy drinking and alcohol abuse and dependence peak during the transition between late adolescence and early adulthood. The objective of the present study was to determine whether a model of early onset adolescent ethanol drinking exposure that is followed by an ethanol vapor regimen during late adolescence and young adulthood leads to an increase in drinking in adulthood. In this model, initiation of voluntary ethanol drinking in adolescence, using a sweetened solution, was followed by an 8-wk intermittent ethanol vapor regimen in Wistar rats. A limited-access two-bottle choice paradigm was then used to measure intake of a 10% (w/v) ethanol solution. No differences in water intake (g/kg), total fluid intake (ml/kg) and body weight (g) were observed between air-exposed and ethanol-vapor exposed groups during the pre-vapor and post-vapor phases. The 8 weeks of ethanol vapor exposure was found to produce only a modest, but statistically significant, elevation of ethanol intake during the protracted withdrawal period, compared to air-exposed rats. A significant increase in ethanol preference ratio was also observed in ethanol-vapor exposed rats during the sucrose-fading phase, but not during the protracted withdrawal period. The findings from the present study suggest that in addition to alcohol exposure, environmental variables that impact appetitive as well as consumptive behaviors may be important in developing robust drinking effects that model, in animals, the increased risk for alcohol dependence seen in some human adolescents who begin drinking at an early age.

Event-related oscillations to affective stimuli: heritability, linkage and relationship to externalizing disorders.

Event-related oscillations (EROs) are heritable electrophysiological measures associated with cognitive activity and have been shown to be particularly informative for the genetic analysis of substance dependence and other psychiatric disorders. In the present study associations between the cortical event-related oscillations (EROs) elicited by affective stimuli, and the diagnosis of ASPD or CD (ASPD/CD) were investigated, and heritability and linkage analyses conducted in 662 individuals residing in an American Indian community. Results from this study found that participants with ASPD/CD showed increased alpha ERO energy in centro-parietal leads in the 0-250 ms time window in response to all three emotional expressions (sad, neutral and happy faces). Participants with ASPD/CD also showed increased alpha ERO energy in centro-parietal leads in the 400-700 ms time window in response to happy and neutral faces. Variance components analysis suggested a significant familial component to each of the described ERO phenotypes. Although a follow-up genome-wide linkage analysis failed to detect significant evidence of genetic linkage for any of these phenotypes, centro-parietal alpha energy in response to happy faces showed suggestive evidence of linkage to chromosome 1p36.31 (LOD = 2.40), in an area found in previous studies to be associated with externalizing phenotypes. Findings from this study suggest greater activation of neural circuits required to perform a facial recognition task in participants with ASPD/CD. The observed increase in alpha ERO energy may represent a heritable endophenotype associated with select externalizing disorders in this population.

Hypermorphic mutation of the voltage-gated sodium channel encoding gene Scn10a causes a dramatic stimulus-dependent neurobehavioral phenotype.

The voltage-gated sodium channel Na(v)1.8 is known to function in the transmission of pain signals induced by cold, heat, and mechanical stimuli. Sequence variants of human Na(v)1.8 have been linked to altered cardiac conduction. We identified an allele of Scn10a encoding the α-subunit of Na(v)1.8 among mice homozygous for N-ethyl-N-nitrosourea-induced mutations. The allele creates a dominant neurobehavioral phenotype termed Possum, characterized by transient whole-body tonic immobility induced by pinching the skin at the back of the neck ("scruffing"). The Possum mutation enhanced Na(v)1.8 sodium currents and neuronal excitability and heightened sensitivity of mutants to cold stimuli. Striking electroencephalographic changes were observed concomitant with the scruffing-induced behavioral change. In addition, electrocardiography demonstrated that Possum mice exhibited marked sinus bradycardia and R-R variability upon scruffing, abrogated by infusion of atropine. However, atropine failed to prevent or mitigate the tonic immobility response. Hyperactive sodium conduction via Na(v)1.8 thus leads to a complex neurobehavioral phenotype, which resembles catatonia in schizophrenic humans and tonic immobility in other mammals upon application of a discrete stimulus; no other form of mechanosensory stimulus could induce the immobility phenotype. Our data confirm the involvement of Na(v)1.8 in transducing pain initiated by cold and additionally implicate Na(v)1.8 in previously unknown functions in the central nervous system and heart.

Prolonged chronic ethanol exposure alters neuropeptide Y and corticotropin-releasing factor levels in the brain of adult Wistar rats.

There is evidence to suggest that alterations in neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) contribute to the escalated voluntary ethanol intake seen following long term chronic ethanol exposure. The present study assessed whether the duration of chronic ethanol exposure and abstinence alters brain levels of NPY and CRF in adult Wistar rats. NPY-like immunoreactivity (NPY-LI) and CRF-LI were determined in the amygdala (AMYG), frontal cortex (FCTX), hippocampus (HPC) and parietal cortex (PCTX) of adult Wistar rats after chronic ethanol exposure, and 24-h and 2-weeks following withdrawal (WD). Chronic ethanol exposure consisted of either a 2-week or an 8-week ethanol vapor regimen. No change in brain levels of NPY-LI, CRF-LI and the NPY-LI/CRF-LI ratio was observed 2-weeks following ethanol exposure, whereas, 8-weeks of ethanol exposure produced a significant effect on NPY-LI expression in the AMYG and FCTX. Moreover, an 8-week ethanol vapor regimen significantly increased CRF-LI levels in the HPC and PCTX. Findings from the present study suggest that a longer duration of ethanol vapor, similar to what is required to enhance voluntary drinking, is required to produce changes in NPY-LI and CRF-LI expression in the adult rat brain.

Sleep quality and alcohol-use disorders in a select population of young-adult Mexican Americans.

OBJECTIVE: Adult male Hispanics, particularly those born in the United States, are more likely to drink frequently and to consume larger quantities of alcohol than Whites or Blacks. Because alcohol and other substance-use disorders are frequently associated with disturbances in sleep, this study investigated measures of sleep quality and substance use disorders in a select sample of young-adult Mexican Americans. METHOD: Diagnoses of alcohol-use disorders and other psychiatric disorders (based on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised), results from the Pittsburgh Sleep Quality Index (PSQI), family history of alcohol dependence, and measures of acculturation stress were obtained from 294 Mexican American young adults, ages 18-30, who were literate in English and were residing legally in San Diego County. RESULTS: Lifetime diagnoses of alcohol-use disorders, family history of alcohol dependence, acculturation stress, and lifetime diagnoses of major depressive disorder were all correlated with significantly poorer quality sleep as indexed by the global score on the PSQI. Regression analyses also revealed that gender was correlated with habitual bedtime, whereas drug dependence (cannabis, stimulants, and/or opiates) was significantly correlated with how long it took to fall asleep, major depressive disorder with the number of hours spent sleeping a night, and anxiety disorders and major depressive disorder with waking up in the early morning or middle of the night. CONCLUSIONS: These data suggest that alcohol-use disorders are significantly associated with poorer quality of sleep in this population of young adults and that substance-use disorders may affect different aspects of sleep than anxiety and depressive disorders do. These findings may be helpful in designing prevention and intervention programs for alcohol-use disorders in this high-risk population.

Event-related oscillations in the parietal cortex of adult alcohol-preferring (P) and alcohol-nonpreferring rats (NP).

The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption and have been demonstrated to exhibit many of the characteristics of human alcohol dependence. Electrophysiologic studies have shown P rats exhibit more electroencephalographic fast frequency activity and reduced P3 amplitude in the parietal cortex than NP rats, findings that are more common in alcohol-dependent individuals. Event-related oscillations (EROs) have been suggested to be good endophenotypes associated with ethanol dependence in clinical studies. Recently EROs have also been demonstrated to occur in rodents in response to stimuli that are similar to that used in human clinical studies. The objective of the present study was to characterize EROs in adult P and NP rats. A time-frequency representation method was used to determine delta, theta, and alpha/beta ERO energy and the degree of phase variation in the parietal cortex of adult P and NP rats. The present results suggest that the decrease in P3 amplitudes previously shown in P rats were not associated with changes in ERO energy but were significantly associated with decreases in evoked delta and alpha/beta phase locking. These studies demonstrate ERO measures may also be good endophenotypes in animal models of alcoholism.

Adolescent ethanol exposure: does it produce long-lasting electrophysiological effects?

This review discusses evidence for long-lasting neurophysiological changes that may occur following exposure to ethanol during adolescent development in animal models. Adolescence is the time that most individuals first experience ethanol exposure, and binge drinking is not uncommon during adolescence. If alcohol exposure is neurotoxic to the developing brain during adolescence, not unlike it is during fetal development, then understanding how ethanol affects the developing adolescent brain becomes a major public health issue. Adolescence is a critical time period when cognitive, emotional, and social maturation occurs and it is likely that ethanol exposure may affect these complex processes. To study the effects of ethanol on adolescent brain, animal models where the dose and time of exposure can be carefully controlled that closely mimic the human condition are needed. The studies reviewed provide evidence that demonstrates that relatively brief exposure to high levels of ethanol, via ethanol vapors, during a period corresponding to parts of adolescence in the rat is sufficient to cause long-lasting changes in functional brain activity. Disturbances in waking electroencephalogram and a reduction in the P3 component of the event-related potential (ERP) have been demonstrated in adult rats that were exposed to ethanol vapor during adolescence. Adolescent ethanol exposure was also found to produce long-lasting reductions in the mean duration of slow-wave sleep (SWS) episodes and the total amount of time spent in SWS, a finding consistent with a premature aging of sleep. Further studies are necessary to confirm these findings, in a range of strains, and to link those findings to the neuroanatomical and neurochemical mechanisms potentially underlying the lasting effects of adolescent ethanol exposure.

Effects of adolescent ethanol exposure on event-related oscillations (EROs) in the hippocampus of adult rats.

Electrophysiological studies have shown that adolescent ethanol (EtOH) exposure can produce long-term changes in hippocampal EEG and ERP activity. Recently, evidence has emerged suggesting that event-related oscillations (EROs) may be good indices of alcoholism risk in humans, however, have not been evaluated for their ability to index the effects of EtOH exposure. The objective of the present study was to characterize EROs generated in hippocampus in adult rats exposed to EtOH during adolescence. Adolescent male Sprague-Dawley rats were exposed to EtOH vapor for 12h/d for 10 days. A time-frequency representation method was used to determine delta, theta, alpha and beta ERO energy and the degree of phase variation in the hippocampus of adult rats exposed to EtOH and age-matched controls. The present results suggest that the decrease in P3 amplitudes, previously observed in adult rats exposed to EtOH during adolescence, is associated with increases in evoked theta ERO energy. These studies suggest that EROs are suitable for characterizing the long-term effects of adolescent EtOH exposure. Further studies are needed to determine the relationship between the mechanisms that regulate these neurophysiological endophenotypes and the consequences of adolescent EtOH exposure.

Milk consumption during adolescence decreases alcohol drinking in adulthood.

Early onset of alcohol consumption increases the risk for the development of dependence. Whether adolescent consumption of other highly palatable solutions may also affect alcohol drinking in adulthood is not known. The purpose of this study was to determine the effects of adolescent consumption of four solutions: water, sucrose, sucrose-milk and milk on ethanol drinking in adult rats. Rats had limited access to one of the four solutions from day PND 29 to PND 51 and were subsequently trained to consume ethanol (E) using a sucrose (S) fade-out procedure. Adolescent consumption of sucrose and sucrose-milk solutions increased intake of 2.5% E when it was combined with 10% S but it had no effect on the drinking of 10% E alone. Adolescent consumption of milk and sucrose-milk significantly decreased the intake of 10% E when it was combined with 10% S, and milk significantly reduced 10% E consumption alone and when it was combined with 5% S. Adolescent exposure to the sucrose-milk and sucrose solutions was also found to increase sucrose and sucrose-milk consumption. Our findings suggest adolescent exposure to sucrose increases, whereas, exposure to milk reduces ethanol consumption in adult rats. Our results may provide a new theoretical approach to the early prevention of alcoholism.

Impairment of memory consolidation by galanin correlates with in vivo inhibition of both LTP and CREB phosphorylation.

Changes in the state of CREB phosphorylation and in LTP in the hippocampus have been associated with learning and memory. Here we show that galanin, the neuropeptide released in the hippocampal formation from cholinergic and noradrenergic fibers, that has been shown to produce impairments in memory consolidation in the Morris water maze task inhibits both LTP and CREB phosphorylation in the rat hippocampus in vivo. While there are many transmitters regulating CREB phosphorylation none has been shown to suppress behaviorally-induced hippocampal CREB phosphorylation as potently as galanin. The in vivo inhibition of dentate gyrus-LTP and of CREB phosphorylation by the agonist occupancy of GalR1 and GalR2-type galanin receptors provides strong in vivo cellular and molecular correlates to galanin-induced learning deficits and designates galanin as a major regulator of the memory consolidation process.

Event-related oscillations in mice: effects of stimulus characteristics.

Event-related oscillations (EROs) are rhythmic changes that are evoked by sensory and/or cognitive processes that influence the dynamics of the EEG. EROs are estimated by a decomposition of the EEG signal into phase and magnitude information for a range of frequencies and then changes in those frequencies are characterized over a millisecond time scale with respect to task events. EROs have been demonstrated to be sensitive measures of both normal and abnormal cognitive functioning in humans but have not been fully described in mice. The results of these studies demonstrate that EROs can be generated in cortical sites in mice in the delta, theta, alpha/beta frequency ranges in response to auditory stimuli. Oscillations in the 7.5-40 Hz frequencies were significantly affected in the 0-50 ms time range in response to differences in tone frequency. Whereas, changes in tone loudness produced changes in oscillations in the 7.5-40 Hz frequencies in the 350-800 ms range. No significant changes in EROs were found to differences in tone probability. These studies suggest that EROs are an electrophysiological assay sensitive to tone characteristics and as such may be suitable for the exploration of the effects of genetic or neuropharmacological manipulations on neurosensory processing in mice.

Contingent and non-contingent effects of low-dose ethanol on GABA neuron activity in the ventral tegmental area.

Ventral tegmental area (VTA) GABA neurons appear to be critical regulators of mesocorticolimbic dopamine (DA) neurotransmission, which has been implicated in alcohol reward. The aim of this study was to evaluate the effects of low-dose "non-contingent" intravenous (IV) ethanol (0.01-0.1 g/kg) on VTA GABA neuron firing rate and synaptic responses, as well as VTA GABA neuron firing rate during low-dose "contingent" IV ethanol self-administration. Intravenous administration of 0.01-0.03 g/kg ethanol significantly increased VTA GABA neuron firing rate and afferent-evoked synaptic responses. In the runway self-administration paradigm, presentation of an olfactory cue (S+; almond extract) or no-cue (S-; no odor) in the Start box was paired with IV administration of low-dose ethanol (0.01 g/kg) or saline in the Target box. Runway excursion times decreased significantly in association during S+, and increased significantly during S- conditions. The firing rate of VTA GABA neurons markedly increased when rats received 0.01 g/kg IV ethanol in the Target box. VTA GABA neuron firing increased in the Start box of the runway in association with S+, but not S-. These findings demonstrate that VTA GABA neurons are activated by low-dose IV ethanol and that their firing rate increases in anticipation of ethanol reward.