Altered thalamic functional connectivity and cerebral blood flow in insomnia disorder: a resting-state functional magnetic resonance imaging study.

BACKGROUND AND PURPOSE: The thalamus plays a crucial role in sleep regulation, but few studies have examined functional connectivity of the thalamus in insomnia disorder. This study aimed to investigate the connectivity patterns and perfusion of the thalamus in patients with insomnia disorder using resting-state functional connectivity and three-dimensional arterial spin labeling (3D ASL). MATERIALS AND METHODS: In total, 56 patients with insomnia disorder and 59 healthy control participants with a similar age-, gender-, and education lever distribution underwent resting-state functional magnetic resonance imaging (rs-fMRI) and 3D-ASL. The thalamus was selected as the seed region. Whole-brain connectivity was assessed using rs-fMRI. Cerebral blood flow (CBF) of the bilateral thalamus was measured with 3D-ASL using region-of-interest (ROI) analysis. All participants completed a series of neuropsychological assessments. Sleep parameters were assessed via polysomnography (PSG). The relationships between imaging parameters and clinical variables were assessed with Pearson correlation analysis. RESULTS: Compared with healthy controls, patients with insomnia disorder exhibited increased connectivity between the left thalamus and right precentral gyrus, and right thalamus and left middle frontal gyrus (MFG), right superior parietal lobule (SPL) and right superior frontal gyrus (SFG). Whereas decreased connectivity was noted between the right thalamus and left posterior cerebellar lobe including Crus I, Crus II, and VII b/VII. Connectivity between the right thalamus and left Crus I was positively correlated with MoCA scores (r = 0.286, P = 0.036) in insomnia disorder. CONCLUSIONS: Our findings illustrate functional abnormalities in brain connectivity and their relationship with cognitive impairments in insomnia disorder, providing novel insight into the neural mechanisms of insomnia disorder.

Effects of a group-based lifestyle medicine for depression: A pilot randomized controlled trial.

Given the growing evidence that a range of lifestyle factors are involved in the etiology of depression, a 'lifestyle medicine' approach can be potentially safe and cost-effective to prevent or treat depression. To examine the effects and acceptability of a group-based, integrative lifestyle medicine intervention as a standalone treatment for managing depressive symptoms, a pilot randomized controlled trial (RCT) was conducted in a Chinese adult population in 2018. Participants (n = 31) with PHQ-9 score above the cut-off of ≥ 10, which was indicative of moderate to severe depression, were recruited from the general community in Hong Kong and randomly assigned to lifestyle medicine group (LM group) or care-as-usual group (CAU group) in a ratio of 1:1. Participants in the LM group received 2-hour group sessions once per week for six consecutive weeks, which covered diet, exercise, mindfulness, psychoeducation, and sleep management. Linear mixed-effects model analyses showed that the LM group had a significant reduction in PHQ-9 scores compared to the CAU group at immediate posttreatment and 12-week posttreatment follow-up (d = 0.69 and 0.73, respectively). Moreover, there were significantly greater improvements in anxiety, stress, and insomnia symptoms (measured by DASS-21 and ISI) at all time points in the LM group (d = 0.42-1.16). The results suggests that our 6-week group-based, integrative lifestyle intervention program is effective in lowering depressive, anxiety, stress, and insomnia symptoms in the Chinese population. Further studies in clinical populations with a larger sample size and longer follow-up are warranted.

Variations of Oral Microbiome in Chronic Insomnia Patients with Different Tongue Features.

Chronic insomnia is a disease which brings intense mental pain and disturbing complications to patients worldwide. The oral microbiome exhibits a mechanistic influence on human health. Therefore, it is crucial to understand the oral microbial diversity in insomnia. Tongue diagnosis has been considered a critical basic procedure in insomnia therapeutic decision-making in Traditional Chinese Medicine (TCM). Hence, it is significant to elucidate the various oral microbiome differences in chronic insomnia patients with different tongue features. In this paper, we used 16S rRNA gene sequencing and bioinformatics analysis to investigate dynamic changes in oral bacterial profile and correlations between chronic insomnia patients and healthy individuals, as well as in patients with different tongue coatings. Moreover, the relationship between the severity of insomnia and oral microbiota was explored. Our findings showed that chronic insomnia patients harbored a significantly higher diversity of oral bacteria when compared to healthy controls. More importantly, the results revealed that the diversity and relative abundance of the bacterial community was significantly altered among different tongue coatings in patients but not in healthy individuals. Oral bacteria with a relative abundance [Formula: see text]1% and [Formula: see text] among different tongue groups were considered remarkable bacteria, which included three phyla Proteobacteria, Bacteroidetes, Gracilibacteria, and four genera, Streptococcus, Prevotella_7, Rothia, and Neisseria. Our findings indicate that changes in oral microbiome correlate with tongue coatings in patients with chronic insomnia. Thus, the remarkable microbiome may provide inspiration for further studies on the correlation between tongue diagnosis and oral microbiome in chronic insomnia patients.

iTRAQ-based proteomics analysis on insomnia rats treated with Mongolian medical warm acupuncture.

OBJECTIVE: To explore the proteomic changes in the hypothalamus of rats treated with Mongolian medical warm acupuncture for insomnia therapy based proteomics. METHOD: We used an iTRAQ-based quantitative proteomic approach to identify proteins that potential molecular mechanisms involved in the treatment of insomnia by Mongolian medical warm acupuncture. RESULT: In total, 7477 proteins were identified, of which 36 proteins showed increased levels and 45 proteins showed decreased levels in insomnia model group (M) compared with healthy control group (C), 72 proteins showed increased levels and 44 proteins showed decreased levels from the warm acupuncture treated insomnia group (W) compared with healthy controls (C), 28 proteins showed increased levels and 17 proteins showed decreased levels from the warm acupuncture-treated insomnia group (W) compared with insomnia model group (M). Compared with healthy control groups, warm acupuncture-treated insomnia group showed obvious recovered. Bioinformatics analysis indicated that up-regulation of neuroactive ligand-receptor interaction and oxytocin signaling was the most significantly elevated regulate process of Mongolian medical warm acupuncture treatment for insomnia. Proteins showed that increased/decreased expression in the warm acupuncture-treated insomnia group included Prolargin (PRELP), NMDA receptor synaptonuclear-signaling and neuronal migration factor (NSMF), Transmembrane protein 41B (TMEM41B) and Microtubule-associated protein 1B (MAP1B) to adjust insomnia. CONCLUSION: A combination of findings in the present study suggest that warm acupuncture treatment is efficacious in improving sleep by regulating the protein expression process in an experimental rat model and may be of potential benefit in treating insomnia patients with the added advantage with no adverse effects.

Pinelliae Rhizoma Praeparatum Cum Alumine Extract: Sedative and Hypnotic Effects in Mice and Component Compounds.

Pinelliae Rhizoma Praeparatum Cum Alumine (PRPCA) is useful for eliminating dampness and phlegm in clinical settings, targeting the main mechanisms of insomnia as defined in traditional Chinese medicine. However, little is known regarding the sedative and hypnotic effects of PRPCA. In the present study, we examined the sedative effects of PRPCA via a locomotor activity test and aimed to determine the most appropriate concentration of PRPCA for achieving these effects. The strongest sedative effects were observed at a PRPCA concentration of 0.45 g/ml. In addition, we investigated the hypnotic effects of PRPCA and its role in promoting sleep via sleep monitoring and vigilance state analysis. PRPCA increased rapid eye movement (REM) sleep and non-REM (NREM) sleep while decreasing wakefulness. In addition, PRPCA decreased the number of bouts of wakefulness (16-32 s and 32-64 s) and increased the number of bouts of NREM sleep (128-256 s). Furthermore, we identified a total of 32 component compounds via chromatography and mass spectrometry. Hence, the current work provides valuable information regarding the sedative and hypnotic effects of PRPCA and its regulatory mechanisms in promoting sleep.

Effects of acupuncture on the hypothalamus-pituitary-adrenal axis in chronic insomnia patients: a study protocol for a randomized controlled trial.

BACKGROUND: Acupuncture, as an important component of traditional Chinese medicine (TCM), has been widely applied in the treatment of chronic insomnia in China, while there is no clinical study related to its therapeutic mechanism. METHODS/DESIGN: A single-center, single-blind, randomized, placebo-controlled trial will be conducted at Jiangsu Hospital of Traditional Chinese Medicine. A total of 60 patients will be registered. Eligible participants will be randomly divided into acupuncture group and sham acupuncture group (n = 30 cases in each group). Patients in both groups will be treated once every other day, three times per week for 4 weeks. The primary outcome measures are Pittsburgh Sleep Quality Index (PSQI) and concentrations of adrenocorticotropic hormone (ATCH), corticotrophin-releasing hormone (CRH), and cortisol (CORT). Secondary outcome measures are Insomnia Severity Index (ISI) and Fatigue Severity Scale (FSS). DISCUSSION: This study aims to evaluate the therapeutic effects of acupuncture on chronic insomnia by using PSQI, ISI, and FSS. The mechanism of acupuncture on CIPs will be preliminarily discussed by analyzing the changes in concentrations of CRH, ACTH, and CORT before and after treatment. TRIAL REGISTRATION: Chinese Clinical Trials Register, ChiCTR1800020298.

Factors that shape preference for acupuncture or cognitive behavioral therapy for the treatment of insomnia in cancer patients.

PURPOSE: Patient preference is an essential component of patient-centered supportive cancer care; however, little is known about the factors that shape preference for treatment. This study sought to understand what factors may contribute to patient preference for two non-pharmacological interventions, acupuncture or cognitive behavioral therapy for insomnia (CBT-I). METHODS: We conducted individual, open-ended, semi-structured interviews among cancer survivors who had completed active treatment and met the diagnostic criteria for insomnia disorder. Two forms of codes were used for analysis: a priori set of codes derived from the key ideas and a set of codes that emerged from the data. RESULTS: Among 53 participants, the median age was 60.7 (range 27-83), 30 participants (56.6%) were female, and 18 (34%) were non-white. We identified three themes that contributed to an individual's treatment preference: perception of the treatment's evidence base, experience with the treatment, and consideration of personal factors. Participants gave preference to the treatment perceived as having stronger evidence. Participants also reflected on positive or negative experiences with both of the interventions, counting their own experiences, as well as those of trusted sources. Lastly, participants considered their own unique circumstances and factors such as the amount of work involved, fit with personality, or fit with their "type" of insomnia. CONCLUSIONS: Knowledge of the evidence base, past experience, and personal factors shaped patient preference regardless of whether they accurately represent the evidence. Acknowledging these salient factors may help inform patient-centered decision-making and care.

Pharmacology of a traditional Chinese herb, Shuangren-Anshen capsule, in a hemorrhage mouse model by using an orthogonal array design.

Shuangren-Anshen capsule (SAC) is a traditional Chinese herb that was improved in our laboratory. An orthogonal experiment [L9(3)(4)] was used to optimize the extraction conditions. In vivo, a hemorrhage mouse model was established and the hemoglobin contents of normal control, model control, and treated mice were measured. Additionally, the sedative and hypnotic effects of SACs were assessed based on pharmacological parameters such as changes in locomotive activity, forelimb raising, sleep latency, sleep duration, and number of mice that fell asleep. Brain tissue was sectioned and stained to detect changes in cell morphology by microscopy. The optimum extraction was achieved with 3 cycles of decoction for 120 min each with a 10-fold volume of water added. In the model control group, hemoglobin content significantly decreased and pharmacological parameters increased (P < 0.01) relative to that in the normal control group. Compared to the model control group, the group treated with 0.9 g/kg SAC showed significant (P < 0.05) increase or decrease in hemoglobin content and all pharmacological parameters except sleep duration. The groups treated with 1.8 or 3.6 g/kg SAC and the positive control group also showed significant alterations in hemoglobin content and pharmacological parameters (P < 0.05). In addition, SAC exhibited a protective effect on the morphological structures of the damaged nerve cells in the mouse model. Thus, an optimal extraction process was successfully identified. The pharmacological data also suggests that the drug can improve sleep quality. SAC treatment was shown to cause changes in hemoglobin content and cell morphology in a mouse model.

[Pathological mechanisms of chronic insomnia: Evidence from neuro-electrophysiology and neuroimaging research].

As a widely recognized public health problem as well as prevalent and challenging to modern society, chronic insomnia is involved in wide brain areas (such as prefrontal cortex, anterior cingulate cortex, amygdala, hippocampus, and thalamus) and emotion-cognition neuro-circuit. It is closely related to the conditioned hyperarousal and the increased information process and/or the impaired inhibitory ability to withdraw from awaking state. Thus, some specific abnormal mode may exist in the emotion-cognition circuit, which is associated with abnormal cognition load, such as repeated retrieval/intrusion of aversive memories during night. Studies through the combination of multiple techniques including psychology, electrophysiology and neuroimaging methods are needed to further enhance the understanding of chronic insomnia.

Neurofeedback in ADHD and insomnia: vigilance stabilization through sleep spindles and circadian networks.

In this review article an overview of the history and current status of neurofeedback for the treatment of ADHD and insomnia is provided. Recent insights suggest a central role of circadian phase delay, resulting in sleep onset insomnia (SOI) in a sub-group of ADHD patients. Chronobiological treatments, such as melatonin and early morning bright light, affect the suprachiasmatic nucleus. This nucleus has been shown to project to the noradrenergic locus coeruleus (LC) thereby explaining the vigilance stabilizing effects of such treatments in ADHD. It is hypothesized that both Sensori-Motor Rhythm (SMR) and Slow-Cortical Potential (SCP) neurofeedback impact on the sleep spindle circuitry resulting in increased sleep spindle density, normalization of SOI and thereby affect the noradrenergic LC, resulting in vigilance stabilization. After SOI is normalized, improvements on ADHD symptoms will occur with a delayed onset of effect. Therefore, clinical trials investigating new treatments in ADHD should include assessments at follow-up as their primary endpoint rather than assessments at outtake. Furthermore, an implication requiring further study is that neurofeedback could be stopped when SOI is normalized, which might result in fewer sessions.

Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.

[Effect of Tianwang Buxin decoction or Tianwang Buxin without Radix platycodi decoction on brain neurotransmitter of rats hyposomnia model].

OBJECTIVE: To understand the action mechanism of Tianwang Buxin decoction that is the whole prescription included all drugs from Tianwang Buxin honeyed pill and Tianwang Buxin without radix platycodi decoction on the nerves-calming and hyposomnia-curing. METHOD: The influence of Tianwang Buxin decoction and Tianwang Buxin without radix platycodi decoction on somnus utilizing the mice' s somnus in coordination with Pentobarbital sodium was observed. Investigation whether the compatibility of radix platycodi affect the concentration of brain neurotransmitter, 5-HT, NA and DA, correlated sleep-awareness by HPLC-ECD detection was carried out after rats' hyposomnia model were founded. RESULT: The falling asleep rates of mice given subthreshold dose raised (P<0.05), remarkably because of Tianwang Buxin decoction. But there is significant difference with Tianwang Buxin lack of radix platycodi decoction despite the heightening tendency. All groups were discovered that the level of 5-HT and 5-HIAA, the monoamine transmitter, heighten obviously after the whole prescription and the prescription without radix platycodi were administered in nuclei raphae medullae oblongatae (P<0.05), but it is only the whole prescription group that emerged same phenomenon in the Ammon's horn and striatum area. Furthermore significant difference exist as comparing Tianwang Buxin whole prescription decoction with Tianwang Buxin without radix platycodi decoction. The level of another monoamine transmitter DA stepped up notably in the whole prescription and the prescription without radix platycodi groups following administration in corpora striata (P<0.05). CONCLUSION: The mechanism of hypnosis action lie in enhancement of releasing 5-HT in encephalic regions for the Tianwang Buxin whole prescription decoction, but it's possible that radix platycodi may be the key point that adjusts the additional quantity.

Insomnia associated with thalamic involvement in E200K Creutzfeldt-Jakob disease.

BACKGROUND: Insomnia with predominant thalamic involvement and minor cortical and cerebellar pathologic changes is not characteristic of familial Creutzfeldt-Jakob disease (CJD) but is a hallmark of fatal familial insomnia. OBJECTIVE: To report a 53-year-old woman with intractable insomnia as her initial symptom of disease. METHODS: The authors characterized clinical, pathologic, and molecular features of the disease using EEG, polysomnography, neurohistology, Western blotting, protein sequencing, and prion protein (PrP) gene (PRNP) analysis. RESULTS: The patient developed dysgraphia, dysarthria, bulimia, myoclonus, memory loss, visual hallucinations, and opisthotonos, as well as pyramidal, extrapyramidal, and cerebellar signs. Polysomnographic studies showed an absence of stages 3 and 4, and REM. She died 8 months after onset. On neuropathologic examination, there was major thalamic involvement characterized by neuronal loss, spongiform changes, and prominent gliosis. The inferior olivary nuclei exhibited chromatolysis, neuronal loss, and gliosis. Spongiform changes were mild in the neocortex and not evident in the cerebellum. PrP immunopositivity was present in these areas as well as in the thalamus. PRNP analysis showed the haplotype E200K-129M. Western blot analysis showed the presence of proteinase K (PK)-resistant PrP (PrP(sc)) with the nonglycosylated isoform of approximately 21 kd, corresponding in size to that of type 1 PrP(sc). N-terminal protein sequencing demonstrated PK cleavage sites at glycine (G) 82 and G78, as previously reported in CJD with the E200K-129 M haplotype. CONCLUSIONS: Insomnia may be a prominent early symptom in cases of CJD linked to the E200K-129M haplotype in which the thalamus is severely affected.

Fatal familial insomnia: genetic, neuropathologic, and biochemical study of a patient from a new Italian kindred.

Fatal familial insomnia (FFI) is an inherited prion disease linked to a mutation at codon 178 of the PRNP gene that results in aspartic acid to asparagine substitution, in coupling phase with methionine at position 129. The disease is characterized clinically by insomnia with disturbances of the autonomic, endocrine, and motor systems and neuropathologically by selective degeneration of the thalamus. Phenotypic variability is well known and has been linked to homozygosity or heterozygosity at PRNP codon 129. We report the clinical, neuropathologic, and biochemical findings and genomic analysis of a patient with FFI from a new Italian kindred. Although homozygous for methionine at codon 129, this patient showed some clinical and pathologic features most commonly found in heterozygotes.

Thalamic form of Creutzfeldt-Jakob disease or fatal insomnia? Report of a sporadic case with normal prion protein genotype.

We describe a 68-year-old man with a 53-month history of progressive dementia and clinical features of a progressive supranuclear palsy-like syndrome and dysautonomia. In the late stage of his illness, the patient also developed generalized myoclonic seizures. There was no family history of similar disorders. Histological examination revealed neuronal loss and gliosis with spongiosis in the cerebral cortex. In addition, more severe neuronal loss and gliosis without spongiosis were observed in the thalamus, especially in the anterior ventral and mediodorsal nuclei, and the inferior olivary nucleus. There was also obvious loss of Purkinje cells. Immunohistochemically, no protease-resistant prion protein (PrPres)-positive structures were demonstrated. However, Western blotting revealed the presence of PrPres in the cerebral cortex. This patient had a wild type of PrP genotype. We initially considered this to be a case of the thalamic form of Creutzfeldt-Jakob disease (CJD) with a long duration. However, it is noteworthy that essentially similar pathology, albeit with less severe cerebral cortical changes, has also been reported in fatal familial insomnia, a newly identified phenotypically different prion disease with a mutation in the PrP gene. On the basis of clinicopathological features, we eventually felt that this patient was more likely to have been a sporadic case of fatal insomnia (FI) of long duration. The present case appears to draw further attention to the possible relationship between CJD and FI.

[The spectrum of prion pathology broadens: fatal familial insomnia]. / El espectro de la patología prion se amplía: el insomnio familiar fatal.

INTRODUCTION: The small group of prion diseases, caused by accumulation in the brain of an abnormal protein characterized by its aggregation and relative resistance to proteases (the PrPSc) in man is comprised of Creutzfeldt-Jacob disease (CJE), the Gerstmann-Straussler-Scheinker syndrome, kuru and the newest addition which is fatal familial insomnia (FFI). DEVELOPMENT: FFI is a hereditary condition with dominant autosomal transmission, characterized clinically by progressive insomnia, dysautonomy, changes in the circadian rhythm of hormone secretion, motor signs and slight to moderate deterioration of cognition. The usual age of onset is between 40 and 60 years, and the course of the illness lasts between 7 and 18 months. The histopathological changes, involving neurone loss and reactive gliosis, particularly affect the anteroventral and dorsomedial thalamic nuclei. These lesions lead to insomnia and to autonomic and endocrine disorders. To a lesser extent and degree, lesions are seen in other thalamic nuclei, the cerebral cortex, inferior olives and the cerebellum. FFI and some families with CJE have the same mutation of the codon 178 of the protein prion gene (gene PRNP) with substitution of aspartic acid by asparagine. Polymorphism of codon 129, which codifies methionine or valine determines the development of the clinical and neuropathological phenotype of FFI or CJE respectively. CONCLUSIONS: The description of FFI and the detection of PrPSe in familial cases of diffuse subcortical gliosis has indicated the possibility that there may be other familial or non-familial neurodegenerative diseases caused by prions.

Fatal familial insomnia and familial Creutzfeldt-Jakob disease: clinical, pathological and molecular features.

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD178) are two prion diseases that have different clinical and pathological features, the same aspartic acid to asparagine mutation (D178N) at codon 178 of the prion protein (PrP) gene, but distinct genotypes generated by the methionine-valine polymorphism at codon 129 (129M or 129V) in the mutant allele of the PrP gene. The D178N, 129M allele segregates with FFI while the D178N, 129V allele segregates with CJD178. The proteinase K resistant PrP (PrPres) isoforms present in FFI and CJD178 differ in degree of glycosylation and size. Thus, the amino acid, methionine or valine, at position 129 of the mutant allele, in conjunction with D178N mutation results in significant alterations of PrPres in FFI and CJD178. The 129 polymorphic site also exerts influence through the normal allele: the course of the disease is shorter in the patients homozygous at codon 129 and other minor but consistent phenotypic differences occur between homozygous and heterozygous FFI patients. The comparative study of PrPres distribution in FFI homozygotes and heterozygotes at codon 129 has lead to the conclusion that the phenotypic differences observed between these two FFI patient populations may be the result of different rates of conversion of normal PrP into PrPres, at least in some brain regions.

"Fatal familial insomnia": neuropsychological study of a disease with thalamic degeneration.

Fatal Familial Insomnia (FFI) is an inherited disease characterized clinically by sleep, autonomic and motor disturbances and pathologically by marked atrophy of the anterior and dorsomedial nuclei of the thalamus. The neuropsychological study of three cases of FFI showed: (1) a progressive disturbance of attention and vigilance, (2) a memory deficit with lability of mnesic traces and difficulty in manipulation and ordering of events, suggesting an alteration of working memory and (3) a deficit of frontal abilities with impairment in planning and prevision of events but preservation of general intelligence.

A pathologic basis for Kleine-Levin syndrome.

A patient with Kleine-Levin syndrome, typical except that onset was at 39 years of age, died during a symptomatic period. Autopsy disclosed recent and old lesions in the medial thalamus involving intralaminar, medial, and some dorsal nuclei as well as the pulvinar. Despite massive microglial infiltration, there was minimal neuronal loss. The hypothalamus was not involved. The findings suggest a viral cause for Kleine-Levin syndrome.