A Critical Review of the Pathophysiology of Dysautonomia Following Traumatic Brain Injury

The management of Dysautonomia following severe traumatic brain injury (TBI) remains problematic, primarily due to an inadequate understanding of the pathophysiology of the condition. While the original theories inferred an epileptogenic source, there is greater support for disconnection theories in the literature. Disconnection theories suggest that Dysautonomia follows the release of one or more excitatory centres from higher centre control. Conventional disconnection theories suggest excitatory centre/s located in the upper brainstem and diencephalon drive paroxysms. Another disconnection theory, the Excitatory:Inhibitory Ratio (EIR) Model, suggests the causative brainstem/diencephalic centres are inhibitory in nature, with damage releasing excitatory spinal cord processes. Review of the available data suggests that Dysautonomia follows structural and/or functional (for example raised intracerebral pressure or neurotransmitter blockade) abnormalities, with the tendency to develop Dysautonomic paroxysms being more closely associated with mesencephalic rather than diencephalic damage. Many reports suggest that paroxysmal episodes can be triggered by environmental events and minimised by various but predictable neurotransmitter effects. This article presents a critical review of the competing theories against the available observational, clinical and neurotransmitter evidence. Following this process, it is suggested that the EIR Model more readily explains pathophysiological and treatment data compared to conventional disconnection models. In particular, the EIR Model provides an explanatory model that encompasses other acute autonomic emergency syndromes, accommodates ‘triggering’ of paroxysms and provides a rationale for all known medication effects.     

Designed Trpzip-3 β-Hairpin Inhibits Amyloid Formation in Two Different Amyloid Systems

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Cardiac autonomic modulation during methadone therapy among heroin users: A pilot study

Background

Methadone therapy benefits heroin users in both the medical and psychosocial dimensions. However, both heroin and methadone have cardiac toxicity. Only limited information is available describing the changes in cardiac autonomic function of heroin users and effects of methadone therapy. We conduct the current study to explore the cardiac vagal function in heroin users as well as the impact of lapse and methadone therapy.

Methods

80 heroin users from a methadone therapy clinic were distributed into 31 compliant and 49 incompliant patients according to whether they lapsed into heroin use within 10 days. 40 healthy control subjects were recruited from the community. Participants underwent electrocardiographic recordings and the heroin users were further investigated before and after methadone therapy. Spectral analysis of heart rate variability (HRV) was computed for cardiac parasympathetic modulation (high-frequency power, HF) and cardiac sympathetic modulation (normalized low-frequency power, LF%).

Results

The baseline HRV parameters found lower HF values for heroin users and lower RR interval values for patients with a recent lapse compared with the healthy control subjects. After 1 h of methadone administration, heroin users who had lapsed showed a significant increase in HF but the heroin users who had not lapsed did not.

Conclusion

Our findings suggest that heroin users show decreased cardiac vagal activity and that methadone therapy immediately facilitates vagal regulation in patients with a recent lapse. The differential patterns of autonomic alteration under methadone between those with and without lapse might offer an objective measure of lapse.     

EEG AND AUTONOMIC RESPONSE PATTERN DURING WAKING AND SLEEP STAGES

The response hierarchy of EEG and autonomic variables to tones of increasing intensity was studied during waking and sleep stages 2, REM, and SW (3 & 4 combined). Tones of 1000 Hz (5 sec duration, 55 sec ISI) were presented to 35 young adult male subjects. During waking, the tones began below awake auditory threshold and increased by 5 db until a motor response (button press) was made. During sleep, tones began at awake threshold and went to arousal threshold, i.e., motor response and/or an EEG change indicative of arousal. Changes in EEG, finger pulse amplitude, heart rate, skin potential, skin resistance, and respiration period were measured for each stimulus and were compared to a pseudostimulus response scored 25 sec prior to the actual stimulus. In the awake state, statistically significant responses (p < .05) were found for EEG, finger pulse, heart rate early deceleration, skin potential, and skin resistance to the tone at awake threshold, but not to tones at lesser db levels. During sleep, significant EEG responses were present to tones 30–25 db below arousal threshold, finger pulse 20–15 db below, and heart rate acceleration 20–5 db below. Significant skin potential, skin resistance, and motor responses were seen only at arousal threshold. Thus, in sleep, in contrast to waking, there were clear responses to stimuli below the arousal threshold, and there was definite ordering of the appearance of the various responses: EEG preceded the cardiovascular, with electrodermal and motor occurring only at arousal. This order was constant over sleep stages. Arousal thresholds were very similar across sleep stages in day sleepers (approximately 35 db above awake threshold). The threshold during stage 2 for night sleepers was about 15 db lower than that for day sleepers.     

Kinetic analysis of the dose-dependent hepatic handling of 1-anilino-8-naphthalene sulfonate in rats

The dose dependency in the hepatic transport of an anionic fluorescent dye, 1-anilino-8-naphthalene sulfonate (ANS), was investigated by measuring the plasma disappearance and biliary excretion in rats. Bulk of the administered ANS distributed into the liver at 10 min after iv bolus injection. The plasma disappearance curves of ANS were then kinetically analyzed based on a two-compartment model, in which the ligand is eliminated only from the peripheral compartment (liver compartment). The total body clearance (CL_tot) decreased with increasing dose of ANS. That is, the values of CL_tot were 4.06 and 1.98 ml/min/per kg at the doses of 3 and 100 mol/kg, respectively. The clearances of the uptake and sequestration processes (CL_up and CL_seq, respectively) for a total ligand were constant irrespective of dose, while the efflux clearance (CL_eff) for a total ligand was increased by twofold with increasing dose. A mechanism for the increase in the CL_eff value might be explained by a saturation of the ANS binding to the intracellular proteins. The hepatocellular distribution and the binding of ANS to cytosolic proteins were then determined. ANS mainly distributed to the cytosol fraction, and the unbound fraction in the cytosol increased from approximately 0.04 to 0.09 when the cytosolic concentrations of ANS increased from 40 to 900 M, respectively. In,spite of such increase in the unbound fraction in the cytosol, the CL_seq values remained unchanged with increasing dose, suggesting that the saturation of sequestration clearance for unbound ANS might occur. Furthermore, the plasma disappearance curves of ANS at various doses were simultaneously analyzed based on three nonlinear kinetic models: Model I is a model incorporating both saturable intracellular binding and saturable sequestration; Model II is a model incorporating only saturable intracellular binding; Model III is the model incorporating only saturable sequestration. Goodness- of- fit evaluated by AIC value was best for Model I. Taken together, the nonlinearity in the plasma clearance of ANS was confirmed to be attributed to saturation of both its binding to cytosolic proteins and sequestration process.     

Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in obsessive–compulsive disorder patients

Salivary α-amylase (sAA) serves as a marker of sympathoadrenal medullary system (SAM) activity. Salivary AA has not been extensively studied in obsessive–compulsive disorder (OCD) patients. In the current study, 45 OCD patients and 75 healthy volunteers were assessed with the Yale–Brown Obsessive–Compulsive Scale (Y–BOCS), the Profile of Mood State (POMS), and the State-Trait Anxiety Inventory (STAI). Measures of heart rate variability (HRV), sAA, and salivary cortisol were also obtained following the application of electrical stimulation stress. The Y–BOCS and POMS Tension–Anxiety, Depression–Dejection, Anger–Hostility, Fatigue, and Confusion scores were significantly increased in patients with OCD compared with healthy controls. In contrast, Vigor scores were significantly decreased in patients with OCD relative to scores in healthy controls. There was no difference in HRV between the patients and the controls. Salivary AA levels in female and male OCD patients were significantly elevated relative to controls both before and after electrical stimulation. In contrast, there were no differences in salivary cortisol levels between OCD patients and controls. The elevated secretion of sAA before and after stimulation may suggest an increased responsiveness to novel and uncontrollable situations in patients with OCD. An increase in sAA might be a characteristic change of OCD.     

Heart rate variability parameters and ventricular arrhythmia correlate with pulmonary arterial pressure in adult patients with idiopathic pulmonary arterial hypertension

ObjectiveThis aim of this study was to correlate heart rate variability (HRV) parameters to pulmonary arterial pressure (PAP) in patients with purely idiopathic pulmonary arterial hypertension (IPAH).BackgroundHRV is decreased in patients with PAH. Whether HRV indices can be used to assess PAP in IPAH patients remains unclear.MethodsHRV parameters obtained by 24-h ECG were evaluated in 26 IPAH patients and 51 controls.ResultsTime-domain HRV parameters (SDNN, p < 0.0001; SDANN, p < 0.0001; RMSSD, p = 0.006) were lower in IPAH patients. Frequency-domain indices (high-frequency power, HFP, p = 0.001; low-frequency power, LFP, p = 0.003; total power, TP, p = 0.001) were also decreased in IPAH patients. In IPAH patients, RMSSD (p = 0.001), HFP (p = 0.015), and LFP (p = 0.027) were significantly correlated with PAP. IPAH patients had longer QTc intervals (p < 0.0001) and more premature ventricular contractions (p < 0.0001) than controls.ConclusionsIPAH is associated with autonomic dysfunction. RMSSD, HFP, and LFP may be used as a supplemental tool to assess PAP in IPAH patients. IPAH patients with autonomic dysfunction are at high risk for ventricular arrhythmia.     

Autonomic correlates of children's concern and disregard for others

Psychophysiological research on empathy and prosociality in children has focused most often on cardiac activity, heart rate (HR), and HR deceleration in particular. We examined these processes in 7-year-old children during two empathy mood inductions. We independently assessed children's responses to others' distress in two different contexts: structured probes (simulated pain) and maternal interviews. We identified three groups of children who showed either (1) concern for others in distress (i.e., empathy and prosocial behaviors), (2) active disregard (i.e., anger/hostility and antisocial behavior), or (3) passive disregard (i.e., little or no concern). We compared groups on HR and HR deceleration. The active disregard group consistently showed the lowest HR both when groups were based on structured probes and on mothers' reports. Children who showed passive disregard displayed little self-distress during other's distress and different patterns of association of self-distress and HR than the other two groups. Active and passive disregard thus may reflect two different aspects of lack of concern for others. HR deceleration was seen for all three groups, suggesting it is not necessarily a cardiac index of concern for others. Interdisciplinary approaches and multiple-systems analysis are needed to better understand psychobiological substrates.     

Irritable bowel syndrome and symptom severity: Evidence of negative attention bias,diminished vigour,and autonomic dysregulation

Objective

To determine if cognitive processing, and subjective and physiological responses to stress and relaxation differed between an irritable bowel syndrome (IBS) group and control group. How these variables relate to the severity of IBS symptoms was also determined.

Methods

Twenty-one IBS participants and 20 controls provided cognitive (attention and processing), subjective (perceived stress and vigour), and physiological (heart rate, blood pressure, and skin conductance) data during a relaxation and stress phase. Logistic regression analyses determined which variables are related to the IBS group and hierarchical linear regression assessed how the variables are related to the severity of IBS symptoms.

Results

Subjective and cognitive factors (drowsiness at baseline, total vigour, and reduced Stroop colour-naming accuracy for negative words) are significantly related to IBS, χ² (3, N = 41) = 23.67, p < .001, accurately categorising 85% of participants. IBS symptom severity was associated with both subjective (drowsiness at baseline and a smaller reduction in tiredness from relaxation to stress) and physiological (smaller increase in systolic blood pressure from baseline to stress phase and lower skin conductance at baseline) variables. This model predicted IBS severity, F (4, 16) = 11.20, p < .001, and accounted for 74% of the variability in scores.

Conclusions

A negative attention bias, which may be related to a negative self-schema, as well as perceived low vigour were important in categorising IBS. Low subjective vigour and reduced physiological reactivity to both relaxation and stress conditions were associated with IBS severity, suggestive of illness-related allostatic load.