Isolating the independent effects of hypoxia and hyperventilation-induced hypocapnia on cerebral haemodynamics and cognitive function.

NEW FINDINGS: What is the central question of this study? What are the independent effects of hypoxia and hypocapnia on cerebral haemodynamics and cognitive function? What is the main finding and its importance? Exposure to hyperventilation-induced hypocapnia causes cognitive impairment in both normoxia and hypoxia. In addition, supplementation of carbon dioxide during hypoxia alleviates the cognitive impairment and reverses hypocapnia-induced vasoconstriction of the cerebrovasculature. These data provide new evidence for the independent effect of hypocapnia on the cognitive impairment associated with hypoxia. ABSTRACT: Hypoxia, which is accompanied by hypocapnia at altitude, is associated with cognitive impairment. This study examined the independent effects of hypoxia and hypocapnia on cognitive function and assessed how changes in cerebral haemodynamics may underpin cognitive performance outcomes. Single reaction time (SRT), five-choice reaction time (CRT) and spatial working memory (SWM) tasks were completed in 20 participants at rest and after 1 h of isocapnic hypoxia (IH, end-tidal oxygen partial pressure ( PETO2 ) = 45 mmHg, end-tidal carbon dioxide partial pressure ( PETCO2 ) clamped at normal) and poikilocapnic hypoxia (PH, PETO2  = 45 mmHg, PETCO2 not clamped). A subgroup of 10 participants were also exposed to euoxic hypocapnia (EH, PETO2  = 100 mmHg, PETCO2 clamped 8 mmHg below normal). Middle cerebral artery velocity (MCAv) and prefrontal cerebral haemodynamics were measured with transcranial Doppler and near infrared spectroscopy, respectively. IH did not affect SRT and CRT performance from rest (566 ± 50 and 594 ± 70 ms), whereas PH (721 ± 51 and 765 ± 48 ms) and EH (718 ± 55 and 755 ± 34 ms) slowed response times (P < 0.001 vs. IH). Performance on the SWM task was not altered by condition. MCAv increased during IH compared to PH (P < 0.05), which was unchanged from rest. EH caused a significant fall in MCAv and prefrontal cerebral oxygenation (P < 0.05 vs. baseline). MCAv was moderately correlated to cognitive performance (R2  = 0.266-0.289), whereas prefrontal cerebral tissue perfusion and saturation were not (P > 0.05). These findings reveal a role of hyperventilation-induced hypocapnia per se on the development of cognitive impairment during normoxic and hypoxic exposures.

Investigating links between habitual physical activity, cerebrovascular function, and cognitive control in healthy older adults.

A growing body of evidence indicates regular physical activity benefits older adults' cognitive functioning, particularly when a high level of cognitive control is required. Recent research has pointed to improved cerebrovascular function as one mechanism through which such benefits might arise. This study built on previous research by investigating in 51 healthy older adults aged 60-72 years relationships between habitual physical activity, cerebrovascular function (indicated by resting cerebral blood flow velocity in the middle cerebral artery [n = 42], and its responsiveness to hypercapnia [n = 26] and hypocapnia [n = 25]), and cognitive control (inhibition and switching). Linear regression analyses showed moderate positive associations between physical activity and inhibitory control, but not cerebrovascular function. There were also no significant relationships between the cerebrovascular measures and cognitive control. These results indicate that regular engagement in physical activity is associated with superior inhibitory control in older adulthood, but cerebrovascular function was not found to explain those relationships. Taken together, the current findings reinforce reports of positive links between habitual physical activity and cognition in healthy older adults, but also signal that interrelationships with cerebrovascular function may be more complex than currently indicated by the literature, necessitating further research to elucidate the role cerebrovascular function might play in accounting for physical activity-cognition links in healthy older adults.

Low pre-treatment end-tidal CO2 predicts dropout from cognitive-behavioral therapy for anxiety and related disorders.

Recent clinical trial research suggests that baseline low end-tidal CO2 (ETCO2, the biological marker of hyperventilation) may predict poorer response to cognitive-behavioral therapy (CBT) for anxiety-related disorders. The present study examined the predictive value of baseline ETCO2 among patients treated for such disorders in a naturalistic clinical setting. Sixty-nine adults with a primary diagnosis of a DSM-5 anxiety disorder, obsessive-compulsive disorder, or posttraumatic stress disorder completed a 4-min assessment of resting ETCO2, and respiration rate (the first minute was analyzed). Lower ETCO2 was not associated with a diagnosis of panic disorder, and was associated with lower subjective distress ratings on certain measures. Baseline ETCO2 significantly predicted treatment dropout: those meeting cutoff criteria for hypocapnia were more than twice as likely to drop out of treatment, and ETCO2 significantly predicted dropout beyond other pre-treatment variables. Weekly measurement suggested that the lower-ETCO2 patients who dropped out were not responding well to treatment prior to dropout. The present results, along with previous clinical trial data, suggest that lower pre-treatment ETCO2 is a negative prognostic indicator for CBT for anxiety-related disorders. It is suggested that patients with lower ETCO2 might benefit from additional intervention that targets respiratory abnormality.

Anxiety, pCO2 and cerebral blood flow.

This study examined the effect of anxiety on cerebral blood flow at different levels of pCO2 in healthy participants (N=29). Three types of breathing were used to manipulate pCO2 in a within-subject threat-of-shock paradigm: spontaneous breathing, CO2-inhalation and hyperventilation resulting in normo-, hyper- and hypocapnia. Transcranial Doppler ultrasonography was used to measure CBF velocity (CBFv) in the right middle cerebral artery, while breathing behavior and end-tidal pCO2 were monitored. During normocapnia, elevated anxiety was clearly associated with increased CBFv. Consistent with the cerebral vasoconstrictive and vasodilating effects of, respectively, hypo- and hypercapnia, we observed a positive linear association between CBFv and pCO2. The slope of this association became steeper with increasing anxiety, indicating that anxiety enhances the sensitivity of CBFv to changes in pCO2. The findings may elucidate conflicting findings in the literature and are relevant for brain imaging relying on regional cerebral blood flow.

Hyperventilation in panic disorder and asthma: empirical evidence and clinical strategies.

Sustained or spontaneous hyperventilation has been associated with a variety of physical symptoms and has been linked to a number of organic illnesses and mental disorders. Theories of panic disorder hold that hyperventilation either produces feared symptoms of hypocapnia or protects against feared suffocation symptoms of hypercapnia. Although the evidence for both theories is inconclusive, findings from observational, experimental, and therapeutic studies suggest an important role of low carbon dioxide (CO2) levels in this disorder. Similarly, hypocapnia and associated hyperpnia are linked to bronchoconstriction, symptom exacerbation, and lower quality of life in patients with asthma. Raising CO2 levels by means of therapeutic capnometry has proven beneficial effects in both disorders, and the reversing of hyperventilation has emerged as a potent mediator for reductions in panic symptom severity and treatment success.

Effects of hypocapnia on spontaneous burst activity in the piriform-amygdala complex of newborn rat brain preparations in vitro.

We examined effects of hypocapnia on burst activity in the piriform-amygdala complex and C(4) inspiratory activity in limbic-brainstem-spinal cord preparations from 0- to 1-day-old rats. Hypocapnia (2% CO(2)) increased the burst rate in the piriform-amygdala complex but decreased the C(4) inspiratory burst rate. Since hyperventilation induces hypocapnia, and enhanced amygdala activity may be involved in induction of a sense of anxiety, our findings might explain the neuronal mechanism of a vicious circle between hyperventilation and an increased sense of anxiety.

The role of hyperventilation: hypocapnia in the pathomechanism of panic disorder

OBJECTIVE: The authors present a profile of panic disorder based on and generalized from the effects of acute and chronic hyperventilation that are characteristic of the respiratory panic disorder subtype. The review presented attempts to integrate three premises: hyperventilation is a physiological response to hypercapnia; hyperventilation can induce panic attacks; chronic hyperventilation is a protective mechanism against panic attacks. METHOD: A selective review of the literature was made using the Medline database. Reports of the interrelationships among panic disorder, hyperventilation, acidosis, and alkalosis, as well as catecholamine release and sensitivity, were selected. The findings were structured into an integrated model. DISCUSSION: The panic attacks experienced by individuals with panic disorder develop on the basis of metabolic acidosis, which is a compensatory response to chronic hyperventilation. The attacks are triggered by a sudden increase in (pCO2) when the latent (metabolic) acidosis manifests as hypercapnic acidosis. The acidotic condition induces catecholamine release. Sympathicotonia cannot arise during the hypercapnic phase, since low pH decreases catecholamine sensitivity. Catecholamines can provoke panic when hyperventilation causes the hypercapnia to switch to hypocapnic alkalosis (overcompensation) and catecholamine sensitivity begins to increase. CONCLUSION: Therapeutic approaches should address long-term regulation of the respiratory pattern and elimination of metabolic acidosis.

OBJETIVO: Os autores apresentam um modelo de transtorno do pânico que se baseia nos efeitos da hiperventilação aguda e crônica, característicos do subtipo respiratório de transtorno do pânico. O modelo é generalizado a partir desses efeitos. Ele integra três características da hiperventilação: a hiperventilação é uma resposta fisiológica à hipercapnia; a hiperventilação pode induzir ataques de pânico; a hiperventilação crônica representa um mecanismo protetor contra os ataques de pânico. MÉTODO: Revisão seletiva da literatura a partir da base de dados Medline. Foram selecionados relatos referentes à inter-relação entre transtorno do pânico, hiperventilação, acidose, alcalose, liberação de catecolaminas e sensibilidade a catecolaminas, sendo os achados estruturados de modo a formar um modelo integrado. DISCUSSÃO: Os ataques de pânico do transtorno do pânico desenvolvem-se com base numa acidose metabólica, que é uma resposta compensatória à hiperventilação crônica. Os ataques são desencadeados por um súbito aumento da pressão parcial de dióxido de carbono (pCO2), quando a acidose (metabólica) latente se manifesta pela acidose hipercápnica. A condição acidótica induz liberação de catecolaminas. A simpaticotonia não pode manifestar-se durante a fase de hipercapnia, pois o baixo pH diminui a sensibilidade às catecolaminas. As catecolaminas podem provocar pânico quando a hipercapnia comuta para uma alcalose hipocápnica devido à supercompensação pela hiperventilação, situação na qual a sensibilidade às catecolaminas liberadas começa a aumentar. CONCLUSÃO: As abordagens terapêuticas deveriam voltar-se para a regulação em longo prazo do padrão respiratório e a eliminação da acidose metabólica.

Autonomic and respiratory characteristics of posttraumatic stress disorder and panic disorder.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and panic disorder (PD) are two anxiety disorders with prominent psychophysiological symptoms. The PTSD criterion of persistent hyperarousal suggests autonomic dysregulation, and the disorder has been associated with elevated heart rate. In contrast, PD has been associated with respiratory abnormalities such as low end-tidal Pco(2). An integrated analysis of automatic and respiratory function in a direct comparison of these anxiety disorders is currently lacking. METHODS: Electrodermal, cardiovascular, and respiratory psychophysiology was examined in 23 PTSD patients, 26 PD patients, and 32 healthy individuals at baseline and during threat of shock. RESULTS: At baseline, the PTSD patients, in contrast to the other two groups, were characterized by attenuated parasympathetic and elevated sympathetic control, as evidenced by low respiratory sinus arrhythmia (a measure of cardiac vagal control) and high electrodermal activity. They also displayed elevated heart rate and cardiovascular sympathetic activation in comparison with healthy controls. PD patients exhibited lower Pco(2) (hypocapnia) and higher cardiovascular sympathetic activation compared with healthy controls. PTSD patients, but not PD patients, sighed more frequently than controls. During the threat of shock phase, the PTSD group demonstrated blunted electrodermal responses. CONCLUSIONS: Persistent hyperarousal symptoms in PTSD seem to be due to high sympathetic activity coupled with low parasympathetic cardiac control. Respiratory abnormalities were also present in PTSD. Several psychophysiological measures exhibited group-comparison effect sizes in the order of 1.0, supporting their potential for enhancing differential diagnosis and possibly suggesting utility as endophenotypes in genetic studies of anxiety disorders.

The role of hyperventilation: hypocapnia in the pathomechanism of panic disorder.

OBJECTIVE: The authors present a profile of panic disorder based on and generalized from the effects of acute and chronic hyperventilation that are characteristic of the respiratory panic disorder subtype. The review presented attempts to integrate three premises: hyperventilation is a physiological response to hypercapnia; hyperventilation can induce panic attacks; chronic hyperventilation is a protective mechanism against panic attacks. METHOD: A selective review of the literature was made using the Medline database. Reports of the interrelationships among panic disorder, hyperventilation, acidosis, and alkalosis, as well as catecholamine release and sensitivity, were selected. The findings were structured into an integrated model. DISCUSSION: The panic attacks experienced by individuals with panic disorder develop on the basis of metabolic acidosis, which is a compensatory response to chronic hyperventilation. The attacks are triggered by a sudden increase in (pCO2) when the latent (metabolic) acidosis manifests as hypercapnic acidosis. The acidotic condition induces catecholamine release. Sympathicotonia cannot arise during the hypercapnic phase, since low pH decreases catecholamine sensitivity. Catecholamines can provoke panic when hyperventilation causes the hypercapnia to switch to hypocapnic alkalosis (overcompensation) and catecholamine sensitivity begins to increase. CONCLUSION: Therapeutic approaches should address long-term regulation of the respiratory pattern and elimination of metabolic acidosis.

Voluntary hyperventilation in the treatment of panic disorder--functions of hyperventilation, their implications for breathing training, and recommendations for standardization.

Hyperventilation has numerous theoretical and empirical links to anxiety and panic. Voluntary hyperventilation (VH) tests have been applied experimentally to understand psychological and physiological mechanisms that produce and maintain anxiety, and therapeutically in the treatment of anxiety disorders. From the theoretical perspective of hyperventilation theories of anxiety, VH is useful diagnostically to the clinician and educationally to the patient. From the theoretical perspective of cognitive-behavior therapy, VH is a way to expose patients with panic disorder to sensations associated with panic and to activate catastrophic cognitions that need restructuring. Here we review panic disorder treatment studies using breathing training that have included VH. We differentiate the roles of VH in diagnosis, education about symptoms, training of breathing strategies, interoceptive exposure, and outcome measurement--discussing methodological issues specific to these roles and VH test reliability and validity. We propose how VH procedures might be standardized in future studies.

Hypocapnia and its relation to fear of falling.

OBJECTIVE: To determine if hypocapnia occurs in patients with fear of falling and to explore potential causes of hypocapnia. DESIGN: Observational study in patients who fall with and without fear of falling. SETTING: Rehabilitation wards of an elderly care unit. PATIENTS: Consecutive fallers with (n = 20) and without (n = 10) fear of falling. MAIN OUTCOME MEASURES: End-tidal CO2 (PETCO2) and respiratory rate (RR) responses were measured during sustained isometric muscle contraction (SIMC) (40% of maximum voluntary contraction of quadriceps for 2 min) and during a 5-meter walk. Falls efficacy scale (FES) and Hospital anxiety and depression scale (HAD). RESULTS: Patients with fear of falling had significantly higher FES and HAD scores (p < .01). During SIMC, baseline and nadir PETCO2 levels were significantly lower in patients with a fear of falling (p < .01). During the 5-meter walk, PETCO2 was lower at baseline, at nadir, and at the end of the walk in the fear of falling group than in controls (p < .01). RR was higher at nadir and end of the walk in the fear of falling group than in controls (p < .02). CONCLUSIONS: Hypocapnia may occur in patients with a fear of falling during SIMC and walking. Anxiety seems to be the main cause, but muscle weakness may contribute. Breathing or relaxation techniques and reconditioning may have a role in treating fear of falling in the rehabilitation setting.

Respiratory learning and somatic complaints: a conditioning approach using CO2-enriched air inhalation.

In a differential respiratory conditioning paradigm with normal Ss two odors (fresh smelling niaouli and bad smelling ammonia) were used as conditioned stimuli (CS+ or CS-) and 7.4% CO2-enriched air was used as the unconditioned stimulus (US). Three CS+ and three CS- trials were run during acquisition, followed on the next day by the same number of CS+ and CS- only trials. Respiratory frequency, minute ventilation, end-tidal fractional concentration of CO2 and subjective complaints were measured throughout the experiment. While during acquisition all measures were affected, the conditioning effects included only respiratory frequency and subjective complaints. A selective association effect appeared in that the conditioning effects were confined to ammonia as CS+: respiratory frequency increased and more somatic complaints were presented when compared to the CS- condition. The conditioning effect on complaints was not confined to complaints of general arousal, but included respiratory complaints as well. Correlational analyses showed that increases in complaints as caused by the conditioning procedure were predicted by changes in somatic variables, but not by individual differences in Negative Affectivity.

Effect of mild hypocapnia on fetal breathing and behavior in unanesthetized normoxic fetal lambs.

We hypothesized that the level of arterial PCO2 (PaCO2) affects the incidence of fetal breathing movements and electrocorticographic (ECoG) states in chronically instrumented fetal sheep. Six fetuses of 128-132 days gestational age were instrumented for recording fetal behavior and for later connection to an extracorporeal membrane oxygenation (ECMO) system to change fetal blood gases. Before ECMO fetal arterial pH and blood gases were pH 7.40 +/- 0.01, PaCO2 42.9 +/- 1.5 Torr, and arterial PO2 (PaCO2) 19.2 +/- 1.7 Torr; during ECMO in normocapnia they were pH 7.37 +/- 0.01, PaCO2 46.1 +/- 0.7 Torr, and PaCO2 27.6 +/- 3.0 Torr; and during ECMO in mild hypocapnia they were pH 7.47 +/- 0.01, PaCO2 35.3 +/- 1.7 Torr, and PaCO2 26.6 +/- 1.7 Torr. The overall incidence of breathing movements, the incidence of breathing movements during low-voltage (LV) ECoG activity, and the mean duration of periods of breathing decreased significantly during hypocapnia. Fetal ECoG activity showed normal cycling during the periods of mild hypocapnia, and the mean duration of LV ECoG periods did not change. During mild hypocapnia, eye movements remained associated with LV ECoG activity and nuchal electromyographic activity remained associated with high-voltage ECoG activity. These results suggest that the presence of breathing movements in fetal life is not only dependent on the behavioral state but also on the level of fetal PaCO2.

Behavioral effects of carbon monoxide: meta analyses and extrapolations.

In the absence of reliable data, this work was performed to estimate the dose-effects function of carboxyhemoglobin (HbCO) on behavior in humans. Meta analysis is the quantitative analysis of the combined findings of a number of research reports. By meta analysis, an HbCO-behavior dose-effects function was estimated for rats and corrected for effects of hypothermia (which accompanies acute HbCO increases in rats but not in humans). By use of pulmonary function models and blood gas equations, equivalent HbCO values were calculated for data in the literature on hypoxic hypoxia and behavior. Another meta analysis was performed to fit a dose-effects function to the equivalent HbCO data and to correct for the behavioral effects of hypocapnia (which usually occurs during hypoxic hypoxia but not with HbCO elevation). The two extrapolations agreed closely and indicated that, for healthy sedentary persons, 18-25% HbCO would be required to produce a 10% decrement in behavior. Confidence intervals are computed to characterize the uncertainty. Frequent reports of lower-level effects are discussed.