Vincenza Castronovo

Obstructive Sleep Apnea: Brain Structural Changes and Neurocognitive Function before and after Treatment

RATIONALE Obstructive sleep apnea (OSA) is commonly associated with neurocognitive impairments that have not been consistently related to specific brain structure abnormalities. Knowledge of the brain structures involved in OSA and the corresponding functional implications could provide clues to the pathogenesis of cognitive impairment and its reversibility in this disorder. OBJECTIVES To investigate the cognitive deficits and the corresponding brain morphology changes in OSA, and the modifications after treatment, using combined neuropsychologic testing and voxel-based morphometry. METHODS A total of 17 patients treatment-naive to sleep apnea and 15 age-matched healthy control subjects underwent a sleep study, cognitive tests, and magnetic resonance imaging. After 3 months of treatment, cognitive and imaging data were collected to assess therapy efficacy. MEASUREMENTS AND MAIN RESULTS Neuropsychologic results in pretreatment OSA showed impairments in most cognitive areas, and in mood and sleepiness. These impairments were associated with focal reductions of gray-matter volume in the left hippocampus (entorhinal cortex), left posterior parietal cortex, and right superior frontal gyrus. After treatment, we observed significant improvements involving memory, attention, and executive-functioning that paralleled gray-matter volume increases in hippocampal and frontal structures. CONCLUSIONS The cognitive and structural deficits in OSA may be secondary to sleep deprivation and repetitive nocturnal intermittent hypoxemia. These negative effects may be recovered by consistent and thorough treatment. Our findings highlight the importance of early diagnosis and successful treatment of this disorder.

Measuring the error in sleep estimation in normal subjects and in patients with insomnia

The aims of this study were to measure the error in sleep estimation in normal controls and subjects with primary insomnia to establish the minimum amount of sleep needed for reliable subjective estimation and to depict the distribution of the error in sleep estimation in both groups. A two‐step retrospective (study 1) and prospective (study 2) validation study was carried out. Study 1 included 288 normal subjects [176 females and 112 males, mean age 58.5 years, standard deviation (SD) 7.23]. Study 2 included 159 patients (98 females and 61 males; mean age 49.1 years, SD 12.71) with primary insomnia. Participants underwent a full‐night polysomnographic study, followed by a morning assessment of subjective sleep parameters. A misperception index (MI) was computed using the following formula: MI = [objective total sleep time (oTST)−subjective total sleep time (sTST)]/oTST. The statistical properties of this index were analysed in detail in both groups. In controls, the Bland–Altman test demonstrated the reliability of this index for values of oTST >120 min. Healthy subjects estimated their sleep time correctly, while insomniacs largely underestimated their sleep time. Statistical analysis of the distribution of MI in insomnia patients disclosed the presence of two subgroups, one with moderate sleep misperception (132 patients) and the other with high sleep misperception (27 patients). The latter presented MI values ≥0.9, exhibiting statistical properties different from those with MI <0.9 and from normal subjects. The MI gives a reliable and immediate description of sleep misperception in healthy and insomnia subjects. Its application supports the existence of the high misperception of insomnia as a separate pathological entity.

Sleep staging from Heart Rate Variability: time-varying spectral features and Hidden Markov Models

An alternative DSS which models the behaviour of the Heart Rate Variability (HRV) signal linked to stable (NREM) and instable (REM) cerebral waves during sleep and a probabilistic model of the sleep stages transitions for decision was developed. Time-Varying Autoregressive Models (TVAMs) were used as feature extractor while Hidden Markov Models (HMM) was used as time series classifier. 24 full polysomnography recordings from healthy sleepers were used for the analysis and those were separated in two sets of

Sleep and upper airway obstruction in children with achondroplasia

OBJECTIVE The features of achondroplasia, the most common form of dwarfism, includes short cranial base and midface hypoplasia; both abnormalities increased the risk of upper airway obstruction during sleep. The aim of our study was to evaluate sleep and respiratory function of children with achondroplasia and to differentiate central from obstructive apnea. We also wanted to correlate apneic events with foramen magnum stenosis. STUDY DESIGN Sixteen children with achondroplasia (mean age, 4.7 years) were studied by noctumal polysomnography and brain computed tomography or magnetic resonance imaging. A comparison of sleep and respiratory findings was made between the study group and 25 children with adenotonsillar hypertrophy. RESULTS The study revealed no significant difference between groups with respect to sleep architecture. We also found no relationship between apnea type and foramen magnum stenosis. Twelve children (75%) with achondroplasia had significant upper airway obstruction during sleep, with symptoms of continuous snoring and periods of brief obstructive apnea, hypopnea, or both. The mean apneahypopnea index (per hour of sleep) did not differ significantly between the two groups. However, the breathing rate during sleep was increased in children with achondroplasia. These findings indicate that the most important breathing disorder during sleep in children with achondroplasia is upper airway obstruction. CONCLUSION We conclude that polysomnography with detailed scoring of breathing abnormalities is a useful tool in evaluating sleep-disordered breathing in children with achondroplasia.

An unattended device for sleep-related breathing disorders: validation study in suspected obstructive sleep apnoea syndrome

Portable devices for the diagnosis of obstructive sleep apnoea (OSA) are considered to be an acceptable alternative to polysomnography (PSG), but their validation is essential. The aim of our study was to validate a device specifically designed for OSA diagnosis. Twenty nine suspected OSA patients were studied with simultaneous nocturnal PSG and an unattended recording device (MicroDigitrapper-S) (M-S). The device measured body position, snoring sound, oronasal flow, thoracic and abdominal effort, heart rate and percentage arterial oxygen saturation (Sa,O2%). We compared the apnoea plus hypopnoea index (AHI) and Sa,O2% results of PSG with that of the systems automatic analysis (M-SA). We also performed a semiautomatic analysis (M-SS) with visual editing of the raw data. Results at different AHI cut-off levels were analysed to obtain an indication of accuracy in diagnosis and severity. Both M-SA and M-SS showed a sensitivity and specificity of 100% at the cut-off level of AHI > 10. When increasing the cut-off levels, M-SA sensitivity decreased (55% for AHI > 40), while specificity remained high (95%). This was improved to a clinically acceptable level of agreement by M-SS analysis (sensitivity 91% and specificity 94%). In conclusion, the MicroDigitrapper-S device showed a good sensitivity and specificity for the diagnosis of OSA. However, the device could not predict the severity of OSA precisely enough. In severe cases (apnoea plus hypopnoea index > 40), semi-automatic scoring was necessary to obtain a more accurate detection of the severity of the disease.

Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives.

Narcolepsy is a rare neurological sleep disorder affecting around 0.05% of the general population. Genetic factors are known to have an important role in narcolepsy. However, because of its very low prevalence, it is difficult to have groups of comparison between first‐degree relatives and general population subjects in order to identify a specific spectrum of disorders in these families. Consequently, from 157 Italian patients with narcolepsy, 263 first‐degree relatives were recruited, two refused to participate. These family members were compared with a matched group of 1071 subjects selected from a sample of 3970 subjects representative of the general population of Italy (46 million inhabitants). Finally, 68 spouses of narcoleptic patients were used to assess for possible role of environmental factors. All subjects were interviewed by telephone using the Sleep‐EVAL system. Nineteen cases of narcolepsy were discovered among the first‐degree relatives of 17 probands (10.8%). Compared with the general population subjects, the relative risk of narcolepsy among female first‐degree relatives was of 54.4 and of 105.1 among male first‐degree relatives. First‐degree relatives were also at higher risk for idiopatic hypersomnia (OR: 23.0), obstructive sleep apnea syndrome (OR: 6.8), adjustment sleep disorder (OR: 4.0), insufficient sleep syndrome (OR: 7.0), circadian rhythm disorders (OR: 2.5), REM behavior disorder (OR: 4.4), and sleep talking (OR: 2.0). The vulnerability to sleep disorders is very high in first‐degree relatives and the link with different expressivity and severity of hypersomnia can be confirmed.

REM sleep behaviour disorder.

REM sleep behaviour disorder (RBD) is a parasomnia characterised by nocturnal complex motor activity associated with dream mentation. RBD, which affects mainly older men, may be idiopathic or associated with other neurological disorders. A strong association between RBD and alpha-synucleinopathies has been recently observed, with the parasomnia often heralding the clinical onset of the neurodegenerative disease. The idiopathic form accounts for up to 60% of the cases reported in the three largest series of RBD patients. Follow-up studies in small samples revealed that a proportion of RBD patients will eventually develop Parkinson’s disease and/or a dementia of Lewy bodies type in the years following the RBD diagnosis. Recently, neurophysiological and neuropsychological studies in idiopathic RBD have found evidence of central nervous system dysfunction. An impairment of cortical activity, specific neuropsychological deficits, signs of autonomic dysfunction and olfactory impairment have been observed in these patients, challenging the concept of idiopathic RBD. The detection of early markers of neurodegenerative disorders in idiopathic RBD, and the evaluation of their value by the combined application in prospective studies may be crucial for developing early intervention strategies.

‘Nocturnal groaning’: just a sound or parasomnia?

We describe the clinical and polysomnographic characteristics of 12 patients complaining of expiratory groaning during sleep. Groaning occurred almost exclusively during rapid eye movement sleep. We reviewed all the literature cases, obtaining a total sample of 27 patients. There is no evident association with any predisposing factors or underlying disease. The results obtained from empirical treatment, including drugs and CPAP, are unsatisfactory. The origins of nocturnal groaning, as well as the long‐term prognosis, remained unexplained.

Effects of reboxetine on sleep and nocturnal cardiac autonomic activity in patients with dysthymia

Antidepressants may have sleep and autonomic side-effects. The acute and long-term effect of reboxetine (2 mg b.i.d.) on sleep and cardiac autonomic activity was compared with that of placebo in a single-blind study. Twelve patients affected by dysthymia underwent four polysomnographic studies at baseline (placebo); at night 3 (reboxetine; acute effect); at night 9 (reboxetine; intermediate-term effect); and at night 122 (reboxetine; chronic effect). After the first administration, reboxetine increased time awake after sleep onset, number of awakenings, percentage of stages 1 and 2 non-rapid eye movement (REM), and reduced the amount of stages 3–4 non-REM, but all these effects disappeared by continuing treatment. However, reboxetine caused a persistent suppression of REM sleep, which was accompanied by an increase of REM sleep latency. The spectral analysis of heart ratevariability showed a trend towards an increase in sympathetic activity with both acute and intermediate reboxetine use. Long-term treatment with 4 mg reboxetine does not cause significant changes in cardiac autonomic function.

Sleep apnea: Altered brain connectivity underlying a working-memory challenge

Obstructive sleep apnea (OSA) is characterized by the frequent presence of neuro-cognitive impairment. Recent studies associate cognitive dysfunction with altered resting-state brain connectivity between key nodes of the executive and default-mode networks, two anti-correlated functional networks whose strength of activation increases or decreases with cognitive activity, respectively. To date no study has investigated a relationship between cognitive impairment in OSA and brain connectivity during an active working-memory challenge. We thus investigated the effect of OSA on working-memory performance and underlying brain connectivity. OSA patients and matched healthy controls underwent functional magnetic resonance imaging (fMRI) scanning while performing a 2-back working-memory task. Standard fMRI analyses highlighted the brain regions activated at increasing levels of working-memory load, which were used as seeds in connectivity analyses. The latter were based on a multiregional Psycho-Physiological-Interaction (PPI) approach, to unveil group differences in effective connectivity underlying working-memory performance. Compared with controls, in OSA patients normal working-memory performance reflected in: a) reduced interhemispheric effective connectivity between the frontal “executive” nodes of the working-memory network, and b) increased right-hemispheric connectivity among regions mediating the “salience-based” switch from the default resting-state mode to the effortful cognitive activity associated with the executive network. The strength of such connections was correlated, at increasing task-demands, with executive (Stroop test) and memory (Digit Span test) performance in neuro-cognitive evaluations. The analysis of effective connectivity changes during a working-memory challenge provides a complementary window, compared with resting-state studies, on the mechanisms supporting preserved performance despite functional and structural brain modifications in OSA.