Mismatch negativity and personality traits in chronic primary insomniacs

The thalamo-(fronto)cortical circuit is involved in sleep regulation, and its dysfunction might contribute to the pathophysiology of chronic primary insomnia. To obtain more evidence of the involvement of the circuit, we studied 23 patients with chronic primary insomnia and 28 healthy volunteers via the assessment of mismatch negativity (MMN) elicited by tone intensity deviance, and of personality traits measured by Zuckerman's Sensation Seeking Scales, and Zuckerman-Kuhlman's Personality Questionnaire. In insomniacs, MMN amplitude at Fz was significantly larger; Depression, which was measured by Plutchik-van Praag's Depression Inventory, and Neuroticism-anxiety and Impulsivity scores were higher, while the Thrill and adventure seeking score was lower; MMN amplitude was positively correlated with Depression and with Impulsivity. In healthy subjects, MMN amplitude at Fz was positively correlated with Neuroticism-anxiety, but negatively with Experience seeking. The larger MMN and distinct personality traits suggest a hyperactivity in the thalamo-(fronto)cortical neuronal circuit in insomniacs, which is probably the result of weak thalamic gating mechanisms, or an imbalance of several neurotransmitter systems.     

Enhanced sympathetic cardiac modulation in bruxism patients

Sleep bruxism, an oral parafunction including teeth clenching and grinding, might be related to increased stress. To evaluate sympathetic cardiac activity in bruxism patients, we monitored cardiac autonomic modulation using spectral analysis of heart rate variability and compared results to those of age-matched healthy volunteers. In bruxism patients, sympathetic cardiac activity was higher than in volunteers. The increased sympathetic tone suggests increased stress and might be related to occlusal disharmonies.     

Nighttime sleep and daytime functioning correlates of the insomnia complaint in young adults

The nighttime and daytime correlates of the insomnia complaint (IC) were assessed in an in-class survey on a sample of 1238 first year university students (18.85 ± 1.45 years) at the Universidad Autónoma of Madrid, Spain. Evidence was found that the likelihood of complaining of insomnia was increased by perceiving difficulties with initiating and maintaining sleep, reporting low quality of nocturnal sleep, having a long sleep onset latency and having an evening circadian preference. The most strongly related daytime variables to IC being perceived difficulties in concentrating, feelings of irritability and fatigue, and symptoms of anxiety and depression. The data, in addition to confirm those of clinical studies on subjects complaining of insomnia, suggest that having an evening chronotype increases the vulnerability of adolescents and young adults to complain of insomnia.     

慢性原发性失眠患者主客观睡眠质量差异及相关因素

背景慢性失眠患者由于警觉性和浅睡比例较高,常判断不清入睡与觉醒的界限,表现为对失眠特别是入睡困难和睡眠时间不足的严重程度常有夸大,即使使用药物改善睡眠后也有同样的表现,而原发性失眠患者伴有明显的心身症状。因此我们观察患者主观与客观睡眠质量的差异与焦虑症状之间的关系,初步了解影响慢性原发性失眠患者主客观睡眠差异的相关因素。方法共收录慢性失眠患者55例,男24例,女31例。符合美国精神障碍诊断与统计手册第4版(DSM-IV)原发性失眠症诊断标准,采用病程超过6个月为慢性失眠。排除患有符合DSM-IV轴I障碍诊断标准的精神障碍者及明显躯体疾病者。收录正常对照组共15名,男8名,女7名。其中性别及年龄与患者组差异无统计学意义,排除有超过1周失眠主诉者及患有符合DSM-IV轴I精神障碍诊断标准的精神障碍者及明显躯体疾病者。所有受试者完成匹兹堡睡眠质量指数表(Pittsburgh sleep quality index,PSQI)、状态-特质焦虑问卷(STAI)、一般情况调查表及在多导睡眠仪监测前3d连续的睡眠日记;并在睡眠监测前晚进行一夜的预睡。结果①分析显示,秩和检验分析显示,慢性原发性失眠患者的无论主观或客观入睡潜伏期、睡眠时间及睡眠效率均小于正常对照组[分别是主观睡眠时间为(157.8±141.7)minv.s(423.4±42.8)min,P<0.001;客观睡眠时间为(332.2±154.7)minv.s(418.1±47.8)min,P=0.009;主观入睡潜伏期为(80.3±73.7)minv.s.(19.2±8.6)min,P<0.001;客观睡眠潜伏期为(23.2±25.4)minv.s.(7.7±4.7)min,P=0.017;主观睡眠效率为(0.52±0.27)v.s.(0.91±0.05),P<0.001;客观睡眠效率为(0.67±0.28)v.s.(0.90±0.07),P<0.001]。②秩和检验分析显示,慢性失眠患者主观睡眠潜伏期大于PSG监测值[(80.3±73.7)minv.s.(23.2±25.4)min,P<0.001],主观睡眠时间、睡眠效率低于PSG监测值[分别为(157.8±141.7)minv.s.(332.2±154.7)min,P<0.001;(0.52±0.27)v.s.(0.67±0.28),P<0.001];而正常对照组除在主、客观睡眠潜伏期存在差异[(19.2±8.6)minv.s.(7.7±4.7)min,P=0.019]外,其他观察值均无明显差异。③患者主观与客观睡眠潜伏期差值与STAI总分、TAI及SAI分呈正相关(r分别为0.402、0.374及0.397,P<0.05),而与病程、性别及年龄无明显相关性;主客观睡眠效率差值与STAI各项目分及病程、性别、年龄无显著相关性。结论慢性原发性失眠患者存在过分夸大失眠严重程度的倾向,主客观睡眠时间、睡眠效率与入睡潜伏期均有明显的差别,其主客观睡眠潜伏期的差异与患者的特质焦虑水平及状态焦虑水平呈正相关。提示焦虑症状在其主客观睡眠质量差异中起到关键的作用。     

Roles of cardiac sympathetic neuroimaging in autonomic medicine

Clinical Autonomic Research - Sympathetic neuroimaging is based on the injection of compounds that either radiolabel sites of the cell membrane norepinephrine transporter (NET) or that are taken up...     

Exploration of cardiac sympathetic adrenergic nerve activity in narcolepsy

ObjectiveTo compare cardiac sympathetic adrenergic nerve activity in patients with narcolepsy type 1 (NT1) and controls using ¹²³I-MIBG myocardial scintigraphy, and to determine the clinical and neurophysiological variables associated with ¹²³I-MIBG scintigraphy results in NT1.MethodsFifty-six NT1 patients and 91 controls without neurological diseases underwent a cardiac scintigraphy. MIBG uptake was quantified by delayed heart/mediastinum (H/M) ratio. Clinical, neurophysiological and biological determinants of a low H/M were assessed in NT1.ResultsMIBG uptake did not differ between NT1 and controls in crude and adjusted associations. Five patients had low MIBG uptake (<1.42, first decile of controls), often with advanced age, cardiovascular (CV) diseases, stimulants intake, and REM sleep behavior disorder. Patients with H/M <1.62 (lowest tertile) were older, with higher BMI, microarousal index and CV comorbidities. A three-fold increase of phasic/tonic REM sleep motor activities was found in those patients, confirmed in a subanalysis of 40 drug-free patients. No association was found with CSF hypocretin levels.ConclusionA direct measure of the heart adrenergic nerve activity revealed no sympathetic denervation in NT1.SignificanceOur results indicate normal cardiac sympathetic innervation in NT1. However, few patients with low MIBG uptake also presented CV comorbidities and REM sleep motor deregulation, potentially at high CV risk, requiring a careful follow-up.     

Progressive loss of cardiac sympathetic innervation in Parkinson's disease

This study addressed whether cardiac sympathetic denervation progresses over time in Parkinson's disease. In 9 patients without orthostatic hypotension, 6-[(18)F]fluorodopamine positron emission tomography scanning was repeated after a mean of 2 years from the first scan. 6-[(18)F]fluorodopamine-derived radioactivity was less in the second scan than in the first scan, by 31% in the left ventricular free wall and 16% in the septum. In Parkinson's disease, loss of cardiac sympathetic denervation progresses in a pattern of loss suggesting a dying-back mechanism.     

Myocardial infarction stimulates galanin expression in cardiac sympathetic neurons

Cardiac ischemia-reperfusion alters sympathetic neurotransmission in the heart, but little is known about its effect on neuropeptide expression in sympathetic neurons. Ischemia followed by reperfusion induces the production of inflammatory cytokines in the heart, including interleukin-6 and cardiotrophin-1. These cytokines and related molecules inhibit the expression of neuropeptide Y (NPY), and stimulate the expression of vasoactive intestinal peptide (VIP), substance P (SubP), and galanin (GAL) in cultured sympathetic neurons. Therefore, we quantified NPY, VIP, SubP, and GAL mRNA in neurons of the stellate ganglia 1 week after ischemia-reperfusion to determine if neuropeptide expression was altered in cardiac sympathetic neurons. NPY, VIP, and SubP mRNAs were unchanged compared to unoperated control animals, but GAL mRNA was increased significantly. The increased GAL mRNA was not accompanied by elevated GAL peptide content in the stellate ganglia. Galanin content was increased significantly in the heart, however, indicating that elevated GAL mRNA led to increased peptide production. GAL content was increased in the left ventricle below the coronary artery ligation, but was not increased significantly in the atria or the base of the heart above the ligation. The buildup of GAL specifically in the damaged left ventricle is consistent with previous reports that GAL is transported to regenerating nerve endings after axon damage.     

Spinal segmental preganglionic outflow to cervical sympathetic trunk and postganglionic cardiac sympathetic nerves

The aim of this study was to verify in which spinal cord segments the preganglionic neurones projecting to the cervical sympathetic trunk or converging onto the somata of the postganglionic cardiac sympathetic neurones are located in cats. The thoracic white rami T1 to T5 were electrically stimulated and the evoked responses were recorded in the cervical sympathetic trunks and postganglionic cardiac nerves. The responses were mostly evoked by electrical stimulation of group B preganglionic fibres. The maximum amplitude of evoked responses in the cervical sympathetic trunk was obtained when the T2 white ramus was stimulated and decreased gradually when followed by the stimulation of T1, T3, T4 and T5 white rami. In most cases the maximum amplitude of evoked responses in the left inferior cardiac nerve, right inferior cardiac nerve and left middle cardiac nerve was obtained when the T3 white ramus was stimulated. The size of the responses decreased when more cranial and caudal white rami were stimulated. It was found that the somata of the postganglionic neurones of the right and left inferior cardiac nerves were placed in the right and left stellate ganglion, respectively. Somata of the postganglionic neurones with axons in the left middle cardiac nerve were mainly located in the left middle cervical ganglion and some in the left stellate ganglion.     

Characteristics of insomnia in a primary care setting: EQUINOX survey of 5293 insomniacs from 10 countries

ObjectiveTo describe the characteristics of insomnia in primary care physicians’ (PCPs’) practices in 10 countries and to understand how the difficulty of maintaining sleep (DMS) was or was not associated with other insomnia symptoms such as difficulty initiating sleep (DIS), early morning awakenings (EMA) or nonrestorative sleep (NRS) in PCPs patients with insomnia.MethodsInternational, noninterventional, cross-sectional, observational survey conducted in a primary care setting in subjects complaining of sleep disturbances in 10 countries. A questionnaire based on DSM-IV and ICSD criteria was administered.ResultsThirteen thousand one hundred twenty-four subjects were enrolled by 647 physicians; 5293 of them (32.6%) had insomnia and were surveyed. The population was predominantly female (63.9%) with a mean age of 47.8 ± 15.3 years; 39.9% of these patients have already been treated for sleep difficulties. Combination of all types of insomnia symptoms (DIS + DMS + EMA + NRS) was the most frequently reported combination (38.6% of the subjects), while the percentage of subjects presenting with only one type of insomnia symptom (DIS, DMS, EMA or NRS) was very low: 3%, 1.8%, 0.9% and 1.4% respectively. DMS was on average the most commonly reported insomnia symptom (80.2%). Multiple logistic regression showed that DMS, EMA and NRS symptoms were significantly linked with each other and also to other insomnia criteria (sleep satisfaction, sleep quality, sleep duration, number of hours of sleep, frequency of insomnia symptoms, wake up rested / unrested and non restorative sleep).ConclusionsPatients visiting PCPs with insomnia are likely to present with severe and poly-symptomatic insomnia.     

Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension

BackgroundDiseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac sympathetic denervation, as reflected by low myocardial concentrations of 6-[¹⁸F]fluorodopamine-derived radioactivity. We studied the impact of such denervation on cardiac chronotropic and inotropic function.MethodsCardiac inotropic function was assessed by the pre-ejection period index and the systolic time ratio index in response to the directly acting beta-adrenoceptor agonist, isoproterenol, and to the indirectly acting sympathomimetic amine, tyramine, in patients with PD + NOH or PAF (PD + NOH/PAF group, N = 13). We compared the results to those in patients with multiple system atrophy, which usually entails NOH with normal cardiac sympathetic innervation (MSA, N = 15), and in normal control subjects (N = 5).ResultsThe innervated and denervated groups did not differ in baseline mean pre-ejection period index or systolic time ratio index. Tyramine increased cardiac contractility in the MSA patients and controls but not in the PD + NOH/PAF group. For similar heart rate responses, the PD + NOH/PAF group required less isoproterenol (p < 0.01) and had lower plasma isoproterenol levels (p < 0.01) than did the MSA group.ConclusionsAmong patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol. This pattern suggests that cardiac denervation is associated with decreased ability to release endogenous norepinephrine from sympathetic nerves and with supersensitivity of cardiac beta-adrenoreceptors.     

Dobutamine stress test unmasks cardiac sympathetic denervation in Parkinson's disease

OBJECTIVE: Cardiac uptake of [(123)I]metaiodobenzyl guanidine (MIBG) is reduced in patients with Parkinson's disease (PD). However, the cardiac sympathetic abnormality associated with this reduction is unclear. To unmask this abnormality in PD patients we examined the functional consequences of cardiac beta-receptor activation. METHODS: Cardiovascular responses to stepwise administration of the beta1-receptor agonist, dobutamine (DOB), were assessed in 25 PD patients and 12 age-matched controls. Changes in blood pressure were compared to determine the optimal dose at which to detect denervation supersensitivity, and cardiac contractility was measured by DOB echocardiography, based on peak aortic flow velocity. The relations of these cardiovascular responses to the ratio of MIBG uptake into the heart vs. that into the mediastinum (H/M ratio) were analyzed. RESULTS: At 4 microg/kg/min DOB, systolic blood pressure increased more in PD patients than in controls (PD, 17.5+/-12.3 mm Hg; control, 7.2+/-6.2 mm Hg, p<0.01), suggesting the presence of denervation supersensitivity. At this DOB dose cardiac contractility also increased more in PD than in controls (PD, 39.0+/-15.7%; control, 23.5+/-5.2%, p<0.005) and this hyperdynamic response was significantly correlated with reduced H/M ratios (early: r=-0.63, p<0.01, delayed: r=-0.66, p<0.01). CONCLUSION: Low-dose DOB unmasks cardiac sympathetic denervation in PD patients, and decreased MIBG uptake indicates the presence of denervation supersensitivity within the heart, resulting in hyperdynamic cardiac contractility in response to a beta 1-stress condition.     

Spinal segmental sympathetic outflow to cervical sympathetic trunk, vertebral nerve, inferior cardiac nerve and sympathetic fibres in the thoracic vagus

The spinal segmental localization of preganglionic neurons which convey activity to the sympathetic nerves, i.e. vertebral nerve, right inferior cardiac nerve, sympathetic fibres in the thoracic vagus and cervical sympathetic trunk, was determined on the right side in chloralose anaesthetized cats. For that purpose the upper thoracic white rami were electrically stimulated with a single pulse, suprathreshold for B and C fibres, and the evoked responses were recorded in the sympathetic nerves. The relative preganglionic input from each segment of the spinal cord to the four sympathetic nerves was determined from the size of the evoked responses. It was found that each sympathetic nerve receives a maximum preganglionic input from one segment of the spinal cord (dominant segment) and that the preganglionic input gradually decreased from neighbouring segments. The spinal segmental preganglionic outflow to the cervical sympathetic trunk, thoracic vagus, right inferior cardiac nerve and vertebral nerve gradually shifted from the most rostral to the most caudal spinal cord segments. In some cases, a marked postganglionic component was found in the cervical sympathetic trunk. It was evoked by preganglionic input from the same spinal cord segments which transmitted activity to the vertebral nerve. These results indicate that there is a fixed relation between the spinal segmental localization of preganglionic neurons and the branch of the stellate ganglion receiving the input from these neurons.     

Sleep architecture in insomniacs with severe benzodiazepine abuse

Objective

Benzodiazepines (BZDs) are the most commonly prescribed compounds in insomnia. A long-term of BZDs use may cause dependence and abuse. The aim of this study was to evaluate sleep architecture and microstructure (in terms of cyclic alternating pattern – CAP – analysis and of sleep EEG power spectral analysis) in a group of long-term users of high doses of BZDs for their primary chronic insomnia.

Preserved cardiac sympathetic nerve accounts for normal cardiac uptake of MIBG in PARK2.

We performed [123I] MIBG myocardial scintigraphy in two of three patients with PARK2 from unrelated families and examined the heart tissues from the three patients immunohistochemically using an antibody against tyrosine hydroxylase (TH) to see whether cardiac sympathetic nerve is involved. Cardiac uptake of MIBG was normal except for a slight decrease in the late phase in one of the patients. Postmortem examination revealed that TH-immunoreactive nerve fibers in the epicardium were well preserved in all three patients. The present study confirmed that cardiac sympathetic nerve is well preserved in PARK2 with a homozygous exon deletion, which accounts for normal cardiac uptake of MIBG. Moreover, normal cardiac uptake of MIBG might be of potential diagnostic value to indicate the absence of Lewy body pathology, even in patients with levodopa-responsive Parkinsonism, as in PARK2.     

Comparison of interwave latencies of brain stem auditory evoked responses in narcoleptics, primary insomniacs and normal controls.

A study of brain stem auditory evoked responses (BAER) was carried out in 10 narcoleptics, 10 primary insomniacs and 10 normal controls to determine if a neurophysiologic abnormality could be detected in these primary sleep disorders. The mean interpeak conduction times of Wave I-III, III-V and Iv were compared between the following groups: normal controls awake and in monitored sleep; narcoleptics awake and in monitored sleep, normal controls awake and narcoleptics awake; normal controls awake and insomniacs awake; narcoleptics awake and insomniacs awake; narcoleptics with cataplexy (n = 6) awake and narcoleptics without cataplexy (n = 4) awake. No significant differences were found which suggests that these sleep disorders represent dysfunctions which do not involve brain stem structures subserving the BAER.     

Sudden withdrawal of carbamazepine increases cardiac sympathetic activity in sleep.

OBJECTIVE: To evaluate the cardiac autonomic effects of abrupt withdrawal of carbamazepine (CBZ) during sleep in patients with epilepsy. BACKGROUND: The pathophysiology of sudden unexpected death in epilepsy (SUDEP) is uncertain, with ictal or peri-ictal cardiorespiratory compromise appearing probable. Risk factors for SUDEP include multiple antiepileptic drugs (AED), poor compliance, and abrupt AED withdrawal. The spectral analysis of the beat-to-beat heart rate variability (HRV) displays two main components: low frequency (LF), representing sympathetic and parasympathetic influence and high frequency (HF), representing parasympathetic influence. The LF/HF ratio is commonly regarded as an indicator of sympathovagal balance. METHOD: Twelve patients with medically intractable seizures underwent abrupt withdrawal of CBZ to facilitate seizure recording during controlled circuit TV-EEG monitoring. Continuous EKG recording was begun 24 hours before CBZ reduction. Spectral analysis of the HRV was performed during selected samples of non-REM sleep before and after CBZ reduction. Analyses were made at least 6 hours after from (complex) partial and 12 hours from generalized seizures. RESULTS: The mean LF/HF ratio before withdrawal of CBZ was 2.15 compared with a ratio of 2.65 on day 4 after withdrawal, an increase of 19% (geometric mean; 95% CI, 2% to 34%; Wilcoxon test, z = 2.36; p = 0.018). The ratio increased in 10 patients compared with a decrease in only one patient. CONCLUSION: Abrupt withdrawal of CBZ leads to enhanced sympathetic activity in sleep as evidenced by increased LF/HF ratios. Increased sympathetic activity in the setting of seizure-induced hypoxia could predispose to SUDEP.     

Renal sympathetic and cardiac changes associated with anaphylactic hypotension

Severe anaphylactic reactions can result in life-threatening hypotension, but little is known about the autonomic changes that accompany the hypotensive response. The aim of this study was to determine the renal sympathetic and cardiac responses to anaphylactic hypotension, and to evaluate the contribution of sinoaortic and vagal afferent inputs in producing these responses. Rats were sensitized with bovine serum albumin (BSA) and, after 10-14 days, were anaesthesized with sodium pentobarbitone and arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded. In about two thirds of the rats, injection of BSA evoked a severe and sustained hypotension, while in the remainder, there was either a more transient hypotension or else no significant change in arterial pressure. In control unsensitized rats, BSA injection had no significant effect on arterial pressure, heart rate, or RSNA. The BSA-induced hypotension in sensitized rats was associated with increases in HR and RSNA, the magnitudes of which were correlated with the magnitude of the hypotension. There were two components to the cardiac and renal sympathoexcitatory response: (1) an initial increase in HR and RSNA, which immediately followed the onset of hypotension and which was abolished by sinoaortic denervation and vagotomy, and (2) a delayed and gradual increase in HR and RSNA, which continued even while the arterial pressure was recovering and was reduced but not abolished by sinoaortic denervation and vagotomy. Thus, BSA-induced anaphylactic hypotension causes prolonged tachycardia and renal sympathoexcitation, which is only partly due to reflex effects arising from sinoaortic baroreceptors and cardiopulmonary receptors.     

Involvement of alpha4 integrins in maintenance of cardiac sympathetic axons

Sympathetic neurons extend and maintain axons that innervate the myocardium, and proper innervation is important for cardiac function. However, the molecular basis for axon outgrowth and maintenance is not well understood. We have shown previously that the integrin alpha4beta1 is expressed on developing axons, and the alpha4 function is important for the development of innervation in vivo [Wingerd, K.L., Goodman, N.L., Tresser, J.W., Smail, M.M., Leu, S.T., Rohan, S.J., Pring, J.L., Jackson, D.Y., and Clegg, D.O., 2002. Alpha 4 integrins and vascular cell adhesion molecule-1 play a role in sympathetic innervation of the heart. J. Neurosci. 22,10772-10780]. Here we examine the function of alpha4beta1 integrins in the maintenance of cardiac sympathetic innervation in vitro and in vivo, and investigate integrin expression and function after myocardial infarction and in hypertensive rats. On substrates of vascular cell adhesion molecule-1 (VCAM-1), alpha4beta1 was required for both initial outgrowth and maintenance of neurites in vitro. On fibronectin substrates, initial outgrowth requires only alpha4 integrins, but maintenance requires both alpha4 integrins and RGD-dependent integrins. In vivo, in adult Long Evans rats, inhibition of alpha4 integrins resulted in decreased maintenance of sympathetic fibers innervating the apex of the heart. However, alpha4 integrins were not detected on most sympathetic axons that sprout after myocardial infarction, and alpha4 function was not required for sprouting. Spontaneously hypertensive rats (SHR) have increased numbers of cardiac sympathetic fibers compared to the parental Wistar strain, but many of these lack alpha4 expression, and alpha4 function is not required for maintenance of these fibers in the heart. These results suggest that developing sympathetic axons and sprouting sympathetic axons use different mechanisms of outgrowth, and that maintenance of cardiac sympathetic innervation involves alpha4 integrins in some rat strains.