Efficacy of transcranial photobiomodulation in the treatment for major depressive disorder: A TMS-EEG and pilot study.

BACKGROUND: Major depressive disorder (MDD) was a prevalent mental condition that may be accompanied by decreased excitability of left frontal pole (FP) and abnormal brain connections. An 820 nm tPBM can induce an increase in stimulated cortical excitability. The purpose of our study was to establish how clinical symptoms and time-varying brain network connectivity of MDD were affected by transcranial photobiomodulation (tPBM). METHODS: A total of 11 patients with MDD received 820 nm tPBM targeting the left FP for 14 consecutive days. The severity of symptoms was evaluated by neuropsychological assessments at baseline, after treatment, 4-week and 8-week follow-up; 8-min transcranial magnetic stimulation combined electroencephalography (TMS-EEG) was performed for five healthy controls and five patients with MDD before and after treatment, and time-varying EEG network was analyzed using the adaptive-directed transfer function. RESULTS: All of scales scores in the 11 patients decreased significantly after 14-day tPBM (p < .01) and remained at 8-week follow-up. The time-varying brain network analysis suggested that the brain regions with enhanced connection information outflow in MDD became gradually more similar to healthy controls after treatment. CONCLUSIONS: This study showed that tPBM of the left FP could improve symptoms of patients with MDD and normalize the abnormal network connections.

An Exploration of Anti-Inflammatory Therapy in Acute/Subacute Severe Cerebral Venous Thrombosis with Hereditary Protein C/S Deficiency: Case Series.

Background: Inflammation was associated with the severity of severe cerebral venous thrombosis (CVT) on admission and poor prognosis at discharge. Hereditary protein C/S deficiency (hereditary PCD/PSD) not only promotes thrombosis but also activates the inflammatory response, further inducing venous thrombosis. However, conventional treatments such as standard anticoagulant/endovascular therapy (EVT) do not seem to improve prognosis. Anti-inflammatory therapy may be a new way to treat the disease. Methods: We enrolled five patients with acute/subacute severe CVT with hereditary PCD/PSD from January 2020 to July 2022. In addition to standard anticoagulant therapy, all of them were given short-term methylprednisolone pulse therapy. Neurological deficit, increased intracranial pressure, venous recanalization, serum and cerebrospinal fluid (CSF) inflammatory markers and adverse events were retrospectively described before and after treatment and at 6 months after discharge. Results: Inflammatory indexes of all patients were significantly elevated on admission. After methylprednisolone pulse therapy, serum inflammatory indexes including neutrophil-to-lymphocyte ratio (P=0.043); platelet-to-lymphocyte ratio (P=0.043); systemic immune inflammatory index (P=0.043); interleukin-6 (P=0.043) and hypersensitive C-reactive protein (P=0.022) reduced dramatically compared with baseline. CSF inflammatory indexes had a decreasing trend compared with baseline (P>0.05). In terms of venous recanalization, one patient achieved complete recanalization, four patients obtained partial recanalization. Compared with baseline on admission, the NIH Stroke Scale (NIHSS), modified Rankin Scale (mRS) and intracranial pressure were all considerably lower at discharge (P=0.029, P=0.041 and P=0.017). At 6-month follow-up, NIHSS and mRS further declined. During hospitalization and 6-month follow-up, none of the five patients experienced severe steroid-related adverse effects such as recurrence of venous thrombosis, spontaneous fracture or osteonecrosis, and gastroduodenal ulcer. Conclusion: Acute/subacute severe CVT with hereditary PCD/PSD has high levels of inflammation. In addition to conventional anticoagulant therapy, early anti-inflammatory therapy using steroids may be necessary. Nevertheless, substantial randomized controlled trials with larger sample sizes are required for further investigation.

820-nm Transcranial near-infrared stimulation on the left DLPFC relieved anxiety: A randomized, double-blind, sham-controlled study.

OBJECTIVE: Generalized anxiety disorder (GAD) is a chronic mood disease associated with abnormal brain network connections, including decreased activity in the left dorsolateral prefrontal cortex (DLPFC). Cortical excitability can be increased with 820-nm transcranial near-infrared stimulation (tNIRS), while transcranial magnetic stimulation with electroencephalography (TMS-EEG) can help evaluate time-varying brain network connectivity. A randomized, double-blind, sham-controlled trial was conducted to assess the efficacy of tNIRS on the left DLPFC and the impact on time-varying brain network connections in GAD patients. METHODS: A total of 36 GAD patients were randomized to receive active or sham tNIRS for 2 weeks. Clinical psychological scales were assessed before, after, and at the 2-, 4-, and 8-week follow-ups. TMS-EEG was performed for 20 min before and immediately after tNIRS treatment. The healthy controls did not receive tNIRS and only had TMS-EEG data collected once in the resting state. RESULTS: The Hamilton Anxiety Scale (HAMA) scores of the active stimulation group decreased post-treatment compared with the sham group (P = 0.021). The HAMA scores of the active stimulation group at the 2-, 4-, and 8-week follow-up assessments were lower than those before treatment (P < 0.05). The time-varying EEG network pattern showed an information outflow from the left DLPFC and the left posterior temporal region after active treatment. CONCLUSION: Herein, 820-nm tNIRS targeting the left DLPFC had significant positive effects on therapy for GAD that lasted at least 2 months. tNIRS may reverse the abnormality of time-varying brain network connections in GAD.

Seasonal Adaptation: Geographic Photoperiod-Temperature Patterns Explain Genetic Variation in the Common Vole Tsh Receptor.

The vertebrate photoperiodic neuroendocrine system uses the photoperiod as a proxy to time the annual rhythms in reproduction. The thyrotropin receptor (TSHR) is a key protein in the mammalian seasonal reproduction pathway. Its abundance and function can tune sensitivity to the photoperiod. To investigate seasonal adaptation in mammals, the hinge region and the first part of the transmembrane domain of the Tshr gene were sequenced for 278 common vole (Microtus arvalis) specimens from 15 localities in Western Europe and 28 localities in Eastern Europe. Forty-nine single nucleotide polymorphisms (SNPs; twenty-two intronic and twenty-seven exonic) were found, with a weak or lack of correlation with pairwise geographical distance, latitude, longitude, and altitude. By applying a temperature threshold to the local photoperiod-temperature ellipsoid, we obtained a predicted critical photoperiod (pCPP) as a proxy for the spring onset of local primary food production (grass). The obtained pCPP explains the distribution of the genetic variation in Tshr in Western Europe through highly significant correlations with five intronic and seven exonic SNPs. The relationship between pCPP and SNPs was lacking in Eastern Europe. Thus, Tshr, which plays a pivotal role in the sensitivity of the mammalian photoperiodic neuroendocrine system, was targeted by natural selection in Western European vole populations, resulting in the optimized timing of seasonal reproduction.

Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression.

Mood disorders are associated with elevated inflammation, and the reduction of symptoms after multiple treatments is often accompanied by pro-inflammation restoration. A variety of neuromodulation techniques that regulate regional brain activities have been used to treat refractory mood disorders. However, their efficacy varies from person to person and lack reliable indicator. This review summarizes clinical and animal studies on inflammation in neural circuits related to anxiety and depression and the evidence that neuromodulation therapies regulate neuroinflammation in the treatment of neurological diseases. Neuromodulation therapies, including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), electroconvulsive therapy (ECT), photobiomodulation (PBM), transcranial ultrasound stimulation (TUS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS), all have been reported to attenuate neuroinflammation and reduce the release of pro-inflammatory factors, which may be one of the reasons for mood improvement. This review provides a better understanding of the effective mechanism of neuromodulation therapies and indicates that inflammatory biomarkers may serve as a reference for the assessment of pathological conditions and treatment options in anxiety and depression.

Corticospinal excitability enhancement with simultaneous transcranial near-infrared stimulation and anodal direct current stimulation of motor cortex.

OBJECTIVES: Non-invasive brain stimulation (NIBS) is beneficial to many neurological and psychiatric disorders by modulating neuroplasticity and cortical excitability. However, recent studies evidence that single type of NIBS such as transcranial direct current stimulation (tDCS) does not have meaningful clinical therapeutic responses due to their small effect size. Transcranial near-infrared stimulation (tNIRS) is a novel form of NIBS. Both tNIRS and tDCS implement its therapeutic effects by modulating cortical excitability but with different mechanisms. We hypothesized that simultaneous tNIRS and tDCS is superior to single stimulation, leading to a greater cortical excitability. METHODS: Sixteen healthy subjects participated in a double-blind, sham-controlled, cross-over designed study. Motor evoked potentials (MEPs) were used to measure motor cortex excitability. The changes of MEP were calculated and compared in the sham condition, tDCS stimulation condition, tNIRS condition and the simultaneous tNIRS and anodal tDCS condition. RESULTS: tDCS alone and tNIRS alone both elicited higher MEP after stimulation, while the MEP amplitude in the simultaneous tNIRS and tDCS condition was significantly higher than either tNIRS alone or tDCS alone. The enhancement lasted up to at least 30 minutes after stimulation, indicating simultaneous 820 nm tNIRS with 2 mA anodal tDCS have a synergistic effect on cortical plasticity. CONCLUSIONS: Simultaneous application of tNIRS with tDCS produces a stronger cortical excitability effect. SIGNIFICANCE: The simultaneous tNIRS and tDCS is a promising technology with exciting potential as a means of treatment, neuro-enhancement, or neuro-protection.

Repetitive Transcranial Magnetic Stimulation Modulates Frontal and Temporal Time-Varying EEG Network in Generalized Anxiety Disorder: A Pilot Study.

Generalized Anxiety Disorder (GAD) is a highly prevalent yet poorly understood chronic mental disorder. Previous studies have associated GAD with excessive activation of the right dorsolateral prefrontal cortex (DLPFC). This study aimed to investigate the effect of low-frequency repetitive transcranial magnetic stimulation (repetitive TMS, rTMS) targeting the right DLPFC on clinical symptoms and TMS-evoked time-varying brain network connectivity in patients with GAD. Eleven patients with GAD received 1 Hz rTMS treatment targeting the right DLPFC for 10 days. The severity of the clinical symptoms was evaluated using the Hamilton Anxiety Scale (HAMA) and the Hamilton Depression Scale (HAMD) at baseline, right after treatment, and at the one-month follow-up. Co-registration of single-pulse TMS (targeting the right DLPFC) and electroencephalography (TMS-EEG) was performed pre- and post-treatment in these patients and 11 healthy controls. Time-varying brain network connectivity was analyzed using the adaptive directed transfer function. The scores of HAMA and HAMD significantly decreased after low-frequency rTMS treatment, and these improvements in ratings remained at the one-month follow-up. Analyses of the time-varying EEG network in the healthy controls showed a continuous weakened connection information outflow in the left frontal and mid-temporal regions. Compared with the healthy controls, the patients with GAD showed weakened connection information outflow in the left frontal pole and the posterior temporal pole at baseline. After 10-day rTMS treatment, the network patterns showed weakened connection information outflow in the left frontal and temporal regions. The time-varying EEG network changes induced by TMS perturbation targeting right DLPFC in patients with GAD were characterized by insufficient information outflow in the left frontal and temporal regions. Low-frequency rTMS targeting the right DLPFC reversed these abnormalities and improved the clinical symptoms of GAD.

Population recovery changes population composition at a major southern Caribbean juvenile developmental habitat for the green turtle, Chelonia mydas.

Understanding the population composition and dynamics of migratory megafauna at key developmental habitats is critical for conservation and management. The present study investigated whether differential recovery of Caribbean green turtle (Chelonia mydas) rookeries influenced population composition at a major juvenile feeding ground in the southern Caribbean (Lac Bay, Bonaire, Caribbean Netherlands) using genetic and demographic analyses. Genetic divergence indicated a strong temporal shift in population composition between 2006-2007 and 2015-2016 (ϕST = 0.101, P < 0.001). Juvenile recruitment (<75.0 cm straight carapace length; SCL) from the north-western Caribbean increased from 12% to 38% while recruitment from the eastern Caribbean region decreased from 46% to 20% between 2006-2007 and 2015-2016. Furthermore, the product of the population growth rate and adult female abundance was a significant predictor for population composition in 2015-2016. Our results may reflect early warning signals of declining reproductive output at eastern Caribbean rookeries, potential displacement effects of smaller rookeries by larger rookeries, and advocate for genetic monitoring as a useful method for monitoring trends in juvenile megafauna. Furthermore, these findings underline the need for adequate conservation of juvenile developmental habitats and a deeper understanding of the interactions between megafaunal population dynamics in different habitats.

Long-term isolation at a low effective population size greatly reduced genetic diversity in Gulf of California fin whales.

The Gulf of California, Mexico is home to many cetacean species, including a presumed resident population of fin whales, Balaenoptera physalus. Past studies reported very low levels of genetic diversity among Gulf of California fin whales and a significant level of genetic differentiation from con-specifics in the eastern North Pacific. The aim of the present study was to assess the degree and timing of the isolation of Gulf of California fin whales in a population genetic analysis of 18 nuclear microsatellite genotypes from 402 samples and 565 mitochondrial control region DNA sequences (including mitochondrial sequences retrieved from NCBI). The analyses revealed that the Gulf of California fin whale population was founded ~2.3 thousand years ago and has since remained at a low effective population size (~360) and isolated from the eastern North Pacific (Nem between 0.89-1.4). The low effective population size and high degree of isolation implied that Gulf of California fin whales are vulnerable to the negative effects of genetic drift, human-caused mortality and habitat change.

Fin whale (Balaenoptera physalus) mitogenomics: A cautionary tale of defining sub-species from mitochondrial sequence monophyly.

The advent of massive parallel sequencing technologies has resulted in an increase of studies based upon complete mitochondrial genome DNA sequences that revisit the taxonomic status within and among species. Spatially distinct monophyly in such mitogenomic genealogies, i.e., the sharing of a recent common ancestor among con-specific samples collected in the same region has been viewed as evidence for subspecies. Several recent studies in cetaceans have employed this criterion to suggest subsequent intraspecific taxonomic revisions. We reason that employing intra-specific, spatially distinct monophyly at non-recombining, clonally inherited genomes is an unsatisfactory criterion for defining subspecies based upon theoretical (genetic drift) and practical (sampling effort) arguments. This point was illustrated by a re-analysis of a global mitogenomic assessment of fin whales, Balaenoptera physalus spp., published by Archer et al. (2013), which proposed to further subdivide the Northern Hemisphere fin whale subspecies, B. p. physalus. The proposed revision was based upon the detection of spatially distinct monophyly among North Atlantic and North Pacific fin whales in a genealogy based upon complete mitochondrial genome DNA sequences. The extended analysis conducted in this study (1676 mitochondrial control region, 162 complete mitochondrial genome DNA sequences and 20 microsatellite loci genotyped in 380 samples) revealed that the apparent monophyly among North Atlantic fin whales reported by Archer et al. (2013) to be due to low sample sizes. In conclusion, defining sub-species from monophyly (i.e., the absence of para- or polyphyly) can lead to erroneous conclusions due to relatively "trivial" aspects, such as sampling. Basic population genetic processes (i.e., genetic drift and migration) also affect the time to the most recent common ancestor and hence the probability that individuals in a sample are monophyletic.

Spatial variation in the accumulation of POPs and mercury in bottlenose dolphins of the Lower Florida Keys and the coastal Everglades (South Florida).

The bottlenose dolphin (Tursiops truncatus) is an upper trophic level predator and the most common cetacean species found in nearshore waters of southern Florida, including the Lower Florida Keys (LFK) and the Florida Coastal Everglades (FCE). The objective of this study was to assess contamination levels of total mercury (T-Hg) in skin and persistent organic pollutants (PCBs, PBDEs, DDXs, HCHs, HCB, Σ PCDD/Fs and Σ DL-PCBs) in blubber samples of bottlenose dolphins from LFK (n = 27) and FCE (n = 24). PCBs were the major class of compounds found in bottlenose dolphin blubber and were higher in individuals from LFK (Σ 6 PCBs LFK males: 13,421 ± 7730 ng g-1 lipids, Σ 6 PCBs LFK females: 9683 ± 19,007 ng g-1 lipids) than from FCE (Σ 6 PCBs FCE males: 5638 ng g-1 ± 3627 lipids, Σ 6 PCBs FCE females: 1427 ± 908 ng g-1 lipids). These levels were lower than previously published data from the southeastern USA. The Σ DL-PCBs were the most prevalent pollutants of dioxin and dioxin like compounds (Σ DL-PCBs LFK: 739 ng g-1 lipids, Σ DL-PCBs FCE: 183 ng g-1 lipids) since PCDD/F concentrations were low for both locations (mean 0.1 ng g-1 lipids for LFK and FCE dolphins). The toxicity equivalences of PCDD/Fs and DL-PCBs expressed as TEQ in LFK and FCE dolphins is mainly expressed by DL-PCBs (81% LFK - 65% FCE). T-Hg concentrations in skin were significantly higher in FCE (FCE median 9314 ng g-1 dw) compared to LFK dolphins (LFK median 2941 ng g-1 dw). These concentrations are the highest recorded in bottlenose dolphins in the southeastern USA, and may be explained, at least partially, by the biogeochemistry of the Everglades and mangrove sedimentary habitats that create favourable conditions for the retention of mercury and make it available at high concentrations for aquatic predators.

Genomic and functional overlap between somatic and germline chromosomal rearrangements.

Genomic rearrangements are a common cause of human congenital abnormalities. However, their origin and consequences are poorly understood. We performed molecular analysis of two patients with congenital disease who carried de novo genomic rearrangements. We found that the rearrangements in both patients hit genes that are recurrently rearranged in cancer (ETV1, FOXP1, and microRNA cluster C19MC) and drive formation of fusion genes similar to those described in cancer. Subsequent analysis of a large set of 552 de novo germline genomic rearrangements underlying congenital disorders revealed enrichment for genes rearranged in cancer and overlap with somatic cancer breakpoints. Breakpoints of common (inherited) germline structural variations also overlap with cancer breakpoints but are depleted for cancer genes. We propose that the same genomic positions are prone to genomic rearrangements in germline and soma but that timing and context of breakage determines whether developmental defects or cancer are promoted.

Extensive localization of long noncoding RNAs to the cytosol and mono- and polyribosomal complexes.

BACKGROUND: Long noncoding RNAs (lncRNAs) form an abundant class of transcripts, but the function of the majority of them remains elusive. While it has been shown that some lncRNAs are bound by ribosomes, it has also been convincingly demonstrated that these transcripts do not code for proteins. To obtain a comprehensive understanding of the extent to which lncRNAs bind ribosomes, we performed systematic RNA sequencing on ribosome-associated RNA pools obtained through ribosomal fractionation and compared the RNA content with nuclear and (non-ribosome bound) cytosolic RNA pools. RESULTS: The RNA composition of the subcellular fractions differs significantly from each other, but lncRNAs are found in all locations. A subset of specific lncRNAs is enriched in the nucleus but surprisingly the majority is enriched in the cytosol and in ribosomal fractions. The ribosomal enriched lncRNAs include H19 and TUG1. CONCLUSIONS: Most studies on lncRNAs have focused on the regulatory function of these transcripts in the nucleus. We demonstrate that only a minority of all lncRNAs are nuclear enriched. Our findings suggest that many lncRNAs may have a function in cytoplasmic processes, and in particular in ribosome complexes.

Extraction and structural analysis of glycosaminoglycans from formalin-fixed, paraffin-embedded tissues.

Glycosaminoglycans (GAGs) are long, anionic polysaccharides involved in many basic aspects of mammalian physiology and pathology. Here we describe a method to extract GAGs from formalin-fixed, paraffin-embedded tissues and found that they are structurally comparable with GAGs extracted from frozen tissues. We employed this method to structurally characterize GAGs in tissues, including laser-dissected layers of skin and pathological specimens. This method enables the use of the archival paraffin-embedded material for detailed (structural) analysis of GAGs.