Recent advances in the treatment of narcolepsy.

OPINION STATEMENT: A diagnosis of narcolepsy requires pharmacologic treatment in more than 90% of patients. Wake-promoting compounds are used to treat excessive daytime sleepiness (EDS), and anticataplectics are used for cataplexy. The treatment of EDS includes the use of amphetamine-like CNS stimulants (such as dextroamphetamine and methylphenidate), modafinil, and its R-enantiomer, armodafinil. Because of its high safety and low side-effect profiles, modafinil has become the first-line treatment of choice for EDS associated with narcolepsy. However, wake-promoting compounds do not improve cataplexy and dissociated manifestation of REM sleep, and so antidepressants (monoamine uptake inhibitors) are additionally used for the treatment of cataplexy and REM sleep abnormalities. Tricyclic antidepressants potently reduce REM sleep and thus have been used for the treatment of cataplexy and REM sleep abnormalities, but these have recently been replaced by more selective serotonin and/or noradrenaline uptake inhibitors with better side-effect profiles. As sodium oxybate (the approved formula of γ-hydroxybutyrate in the United States), given at night, improves both EDS and cataplexy, the number of US patients treated with sodium oxybate is increasing, while much progress has been made in understanding the modes of action of amphetamine-like CNS stimulants.

Local and Transient Changes of Sleep Spindle Density During Series of Prefrontal Repetitive Transcranial Magnetic Stimulation in Patients With a Major Depressive Episode.

The neuromodulatory effects of brain stimulation therapies notably involving repetitive transcranial magnetic stimulation (rTMS) on nocturnal sleep, which is critically disturbed in major depression and other neuropsychiatric disorders, remain largely undetermined. We have previously reported in major depression patients that prefrontal rTMS sessions enhanced their slow wave activity (SWA) power, but not their sigma power which is related to sleep spindle activity, for electrodes located nearby the stimulation site. In the present study, we focused on measuring the spindle density to investigate cumulative effects of prefrontal rTMS sessions on the sleep spindle activity. Fourteen male inpatients diagnosed with medication-resistant unipolar or bipolar depression were recruited and subjected to 10 daily rTMS sessions targeting the left dorsolateral prefrontal cortex (DLPFC). All-night polysomnography (PSG) data was acquired at four time points: Adaptation, Baseline, Post-1 (follow-up after the fifth rTMS session), and Post-2 (follow-up after the tenth rTMS session). Clinical and cognitive evaluations were longitudinally performed at Baseline, Post-1, and Post-2 time points to explore associations with the spindle density changes. The PSG data from 12 of 14 patients was analyzed to identify sleep spindles across the sleep stages II-IV at four electrode sites: F3 (frontal spindle near the stimulation site), F4 (contralateral homologous frontal region), P3 (parietal spindle in the hemisphere ipsilateral to the stimulation site), and P4 (contralateral parietal region). Statistical analysis by two-way ANOVA revealed that spindle density at F3 increased at Post-1 but decreased at Post-2 time points. Moreover, the local and transient increase of spindle density at F3 was associated with the previously reported SWA power increase at F3, possibly reflecting a shared mechanism of thalamocortical synchronization locally enhanced by diurnal prefrontal rTMS sessions. Clinical and cognitive correlations were not observed in this dataset. These findings suggest that diurnal rTMS sessions transiently modulate nocturnal sleep spindle activity at the stimulation site, although clinical and cognitive effects of the local changes warrant further investigation.

Factors affecting mental illness and social stress in hospital workers treating COVID-19: Paradoxical distress during pandemic era.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has affected all countries in the world. Hospital workers are at high risk of mental illness, such as anxiety and depression. Furthermore, they also face many social stresses, such as deterioration of human relations and income reduction. Apart from mental illness, these social stresses can reduce motivation and lead to voluntary absenteeism, which contribute to a collapse of medical systems. Thus, for maintaining medical systems, it is crucial to clarify risk factors for both mental illness and increased social stress among hospital workers. However, little attention has been paid to factors affecting social stress, and thus, we aimed to address this gap. METHODS: In this cross-sectional survey of 588 hospital workers, the levels of anxiety, depression, and social stress were assessed using the 7-item Generalized Anxiety Disorder scale (GAD-7), 9-item Patient Health Questionnaire (PHQ-9), and Tokyo Metropolitan Distress Scale for Pandemic (TMDP). Multiple regression analyses were conducted to identify the demographic variables affecting these problems. RESULTS: Older age and female sex were common risk factors for anxiety, depression, and social stress. Moreover, occupational exposure to COVID-19 and hospital staff other than doctors/fewer non-work days were risk factors for increased anxiety and depression, respectively. Furthermore, living with families/others was a risk factor for increased social stress during this pandemic. CONCLUSION: Our findings could be useful for developing policies and practices to minimize the risk of mental illness and increased social stress among hospital workers, highlighting that attention should be paid to social factors, such as an individual's household situation.

[Foreign accent syndrome in a case of dissociative (conversion) disorder].

Psychiatric symptoms are often manifested in verbal expression. Generally, the contents of such expression are pathological. The formal abnormalities of speech are also observed in various mental disorders, as far as quantitative abnormalities are concerned. However, disturbance of intonation, namely disprosody, is more commonly observed in organic disorders of the brain. When the accent of words and the intonation of sentences changes from that of a native speaker, the speech sounds like the broken language of untrained foreigners. Such foreign accent syndrome is usually an issue of neuropsychology. In this paper, the authors report a case of foreign accent syndrome without organic brain syndrome. The patient was a 44-year-old woman, who developed panic disorder about year after her father's death. Then she developed aphonia. After aphonia was resolved, she began to speak haltingly as if a Chinese woman was trying to speak Japanese. Organic brain diseases were subsequently excluded. She had complicated familial conflicts, including a divorce from a violent and faithless husband, interpersonal difficulties with her husband's parents, and her pubertal daughter. We diagnosed her with dissociative (conversion) disorder of ICD-10. Our patient is clinically interesting, because case reports of dysprosody are unusual and often involve organic brain diseases. We suppose that foreign accent syndrome in our patient is a variant of aphonia, and the patient unconsciously assigned the symptom two ambivalent rolls: to snow that she cannot speak well, and to express her meaning. In addition, she had a Chinese-speaking aunt-in-law who was her ideal role model. We surmise that her symptom signifies identification with her aunt-in-law.

High frequency activities in the human orbitofrontal cortex in sleep-wake cycle.

We recorded human orbitofrontal electrocorticogram during wakefulness and sleep in epileptic patients using subdural electrodes. During wakefulness and rapid eye movement (REM) sleep, we observed beta activity in the raw orbitofrontal signals. Power spectral analysis demonstrated beta enhancement during wakefulness and REM sleep when compared to slow wave sleep (SWS). During the phasic REM periods, the beta power was significantly lower than during the tonic REM periods. Gamma enhancement manifested itself in four out of six subjects during the phasic periods. This study is the first that has focused on electrical activity in the human orbitofrontal cortex. Although the role of the orbitofrontal cortex during sleep still remains unclear, high frequency activities give us important suggestions in elucidating the human sleep mechanism.

[Remarkably low blood pressure induced by combination of SSRI and a small dose of TCA].

Recently, selective serotonin reuptake inhibitors (SSRI) have been frequently used as the first choice of antidepressants because of their safety in comparison with tricyclic antidepressive agents (TCA). On the other hand, when SSRIs are not effective, they are frequently replaced with another antidepressant. In that case, a small dose of a TCA is often added without cross tapering. We report two elderly patients with depression who exhibited markedly low blood pressure when a small dose of a TCA was added to a SSRI. The combination of a SSRI and a TCA can be hazardous because it can cause unexpected adverse effects especially in elderly patients.

Theta oscillation in the human anterior cingulate cortex during all-night sleep: an electrocorticographic study.

Ten epileptic patients each with subdural electrodes surgically attached to the anterior cingulate cortex (ACC; two cases), the orbitofrontal cortex (OFC; seven cases), or both (one case) were included in this study. We recorded each patient's ACC or OFC electrocorticogram (ECoG) during the time period that the patient was awake and naturally asleep. We performed a Fast Fourier Transformation (FFT) power spectral analysis on each ECoG to examine its frequency component. We found that the ACC showed regular and continuous theta oscillation (5-7Hz) during wakefulness and rapid eye movement (REM) sleep, but not during slow wave sleep. Theta waves observed in REM sleep were not as distinct as those found in wakefulness. We also discovered that the orbitofrontal signals represented spectral peaks in the theta band only during wakefulness. This suggests the coexistence of theta oscillation in the ACC. Considering our previous observations of gamma and beta oscillations in the human hippocampus, we hypothesize that the human limbic system manifests two oscillatory activities. The results obtained in this study suggest that electrophysiological activity in the ACC could be related to particular psychological functions in wakefulness and in REM sleep. These results are useful in elucidating the human brain mechanism.

Sleep spindles in human prefrontal cortex: an electrocorticographic study.

To investigate the sleep spindle activity of the human prefrontal cortex (PFC), we simultaneously recorded whole nights of polysomnographic and electrocorticographic (ECoG) activities during the natural sleep of epileptic patients. Subjects were nine patients with intractable epilepsy who had subdural electrodes surgically attached to the orbital (seven cases), medial (three cases), or dorsolateral (two cases) PFC, and in one case to the frontal pole. To examine spindle frequencies, fast Fourier transformation (FFT) and auto-correlation analyses were performed on the PFC ECoG and Cz EEG data, primarily on epochs of stage 2 sleep. Lower sigma band ECoG oscillations of about 12 Hz were widely distributed across all prefrontal cortical areas including the frontal limbic regions, but none of the PFC sigma frequency peaks coincided with the faster (about 14 Hz) Cz EEG sleep spindles. Combining our results with anatomical and electrophysiological facts, it is suggested that the thalamofrontal circuit involving the rostral reticular and the mediodorsal nucleus of the thalamus is responsible for the generation of 12 Hz frontal spindles in humans.

Impulse response function based on multivariate AR model can differentiate focal hemisphere in temporal lobe epilepsy.

The purpose of this study is to propose and investigate a new approach for discriminating between focal and non-focal hemispheres in intractable temporal lobe epilepsy, based on applying multivariate time series analysis to the discharge-free background brain activity observed in nocturnal electrocorticogram (ECoG) time series. Five unilateral focal patients and one bilateral focal patient were studied. In order to detect the location of epileptic foci, linear multivariate autoregressive (MAR) models were fitted to the ECoG data; as a new approach for the purpose of summarizing these models in a single relevant parameter, the behavior of the corresponding impulse response functions was studied and described by an attenuation coefficient. In the majority of unilateral focal patients, the averaged attenuation coefficient was found to be almost always significantly larger in the focal hemisphere, as compared to the non-focal hemisphere. Also the amplitude of the fluctuations of the attenuation coefficient was significantly larger in the focal hemisphere. Moreover, in one patient showing a typical regular sleep cycle, the attenuation coefficient in the focal hemisphere tended to be larger during REM sleep and smaller during Non-REM sleep. In the bilateral focal patient, no statistically significant distinction between the hemispheres was found. This study provides encouraging results for new investigations of brain dynamics by multivariate parametric modeling. It opens up the possibility of relating diseases like epilepsy to the properties of inconspicuous background brain dynamics, without the need to record and analyze epileptic seizures or other evidently pathological waveforms.

Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset.

Sleep and behavioral monitoring of young mice is necessary for understating the progress of symptoms in congenital and acquired diseases associated with sleep and movement disorders. In the current study, we have developed a non-invasive sleep monitoring system that identifies wake and sleep patterns of newborn mice using a simple piezoelectric transducer (PZT). Using this system, we have succeeded in detecting age-dependent occurrences and changes in sleep fragmentation of orexin/ataxin-3 narcoleptic mice (a narcoleptic mouse model with postnatal hypocretin/orexin cell death) across the disease onset. We also detected REM sleep/cataplexy patterns (i.e., immobility with clear heartbeat [IMHB] signals due to the flaccid posture) by the PZT system, and found that sudden onset of REM sleep-like episodes specifically occur in narcoleptic, but not in wild type mice, suggesting that these episodes are likely cataplexy. In contrast, gradual onset of IMHB likely reflects occurrence of REM sleep. In summary, we have shown that the PZT system is useful as a non-invasive sleep and behavior monitoring system to analyze the developmental aspects of sleep and movement disorders in mice models.

Localized potentiation of sleep slow-wave activity induced by prefrontal repetitive transcranial magnetic stimulation in patients with a major depressive episode.

BACKGROUND: The effects of repetitive transcranial magnetic stimulation (rTMS) on sleep structure in major depression are currently unknown. OBJECTIVE: To determine the effects of prefrontal rTMS on sleep electroencephalography (EEG) in major depression. METHODS: In this open-label pilot study, twelve male patients with relatively mild depression, who had been medication-resistant, underwent 10 daily rTMS sessions over the left dorsolateral prefrontal cortex (DLPFC). Polysomnographic (PSG) data were recorded over four nights: Adaptation, Baseline, Post-1 (after the fifth rTMS session), and Post-2 (after the tenth rTMS session). Discrete Fourier Transform (DFT) band power analyses were performed to quantify delta and sigma band activities during Stages II-IV, and determine time courses of these activities between Baseline and Post-1 (first five sessions) and between Post-1 and Post-2 (last five sessions). RESULTS: Post-hoc tests based on a three-way ANOVA model indicated significant delta power increase at F3 (t11 = -2.762, P = 0.018) during the first five sessions; however, sigma power was unchanged. No significant band power changes were observed during the second half. Stages II-IV (percent total sleep time) increased significantly during the first half (t12 = -2.43, P = 0.033). No other significant changes in sleep parameters or clinical correlations were observed. CONCLUSIONS: The first five sessions of high frequency rTMS to the left DLPFC increase slow-wave activity (SWA) at F3, possibly reflecting locally enhanced synaptic plasticity induced by rTMS. This increased activity was not observed during the last half, possibly due to a homeostatic regulation mechanism intrinsic to SWA.

Theta oscillation in the anterior cingulate and beta-1 oscillation in the medial temporal cortices: a human case report.

In previous studies we observed gamma (30-150 Hz) and beta-1 (10-20 Hz) oscillations in the medial temporal lobe (MTL) using subdural electrodes. The beta-1 was present during wake and REM sleep while gamma was present in all states. Recently we studied a patient (35 years M) with electrodes attached to the anterior cingulate cortex (ACC). This structure showed regular theta (5-6 Hz) oscillations. In the first recording, electrodes were attached to the MTL, that demonstrated the beta-1 and gamma oscillations. Two months later, electrodes were placed on orbitofrontal and ACC and an all night sleep recording was carried out. The ACC exhibited a highly regular and continuous theta oscillation during wakefulness and REM sleep, but not during NREM sleep. Since this same subject showed beta-1 oscillations in the MTL, it is probable that the theta in the ACC is independent of beta-1 in the MTL. This single case suggests the existence of two different frequency oscillators in the human limbic system. Elucidating their functional roles will be an interesting challenge for future studies.

Electroencephalogram-triggered functional magnetic resonance imaging in focal epilepsy.

The high spatial resolution and cost performance of functional magnetic resonance imaging (fMRI) is useful for estimating focus localization in epilepsy, but this is difficult in the case of ictal fMRI because this is susceptible to motion artifacts. Electroencephalogram (EEG)-triggered fMRI, which is interictal, can be performed without marked movement and is thought to be useful, but requires further investigation in order to establish a methodology. The authors studied EEG-triggered fMRI in partial epileptic patients. Six patients were examined using a Nihon Kohden digital EEG recorder and Signa Horizon High Speed LX 1.5 T MRI scanner. Six electrodes were attached in the vicinity of the focus detected by scalp EEG. The fMRI scans were recorded after the discharges (activation) and scans without spikes (baseline). Equal numbers of activation and baseline scans were collected and analyzed using SPM99. In three of the six patients, an activated area was observed near the focus, but no activated areas were found in the other three subjects who tended to have a low number of spikes and low spike amplitude. Although various approaches focusing on improvement of the activation/non-activation ratio are required, EEG-triggered fMRI is a promising technique for detecting focal epileptic brain activity.