Personalized, parcel-guided non-invasive transcranial magnetic stimulation for the treatment of post-concussive syndrome: safety and proof of concept.

OBJECTIVE: To determine the safety and proof of concept of a parcel-guided, repetitive Transcranial Magnetic Stimulation (rTMS) in patients who develop a heterogeneous array of symptoms, known collectively as post-concussive syndrome (PCS), following traumatic brain injury (TBI). METHODS: We performed a retrospective review of off-label, individualized, parcel-guided rTMS in 19 patients from December 2020 to May 2023. Patients had at least one instance of mild, moderate, or severe TBI and developed symptoms not present prior to injury. rTMS targets were identified based on machine learning connectomic software using functional connectivity anomaly matrices compared to healthy controls. EuroQol (EQ-5D), as a measurement of quality of life, and additional questionnaires dependent on individual's symptoms were submitted prior to, after, and during follow-up from rTMS. RESULTS: Nineteen patients showed improvement in EQ-5D and Rivermead Post Concussion Symptoms Questionnaires - 3 after treatment and follow-up. For nine patients who developed depression, five (55%) attained response and remission based on the Beck Depression Inventory after treatment. Eight of ten patients with anxiety had a clinically significant reduction in Generalized Anxiety Disorder-7 scores during follow-up. CONCLUSION: Parcel-guided rTMS is safe and may be effective in reducing PCS symptoms following TBI and should incite further controlled studies.

Discernible interindividual patterns of global efficiency decline during theoretical brain surgery.

The concept of functional localization within the brain and the associated risk of resecting these areas during removal of infiltrating tumors, such as diffuse gliomas, are well established in neurosurgery. Global efficiency (GE) is a graph theory concept that can be used to simulate connectome disruption following tumor resection. Structural connectivity graphs were created from diffusion tractography obtained from the brains of 80 healthy adults. These graphs were then used to simulate parcellation resection in every gross anatomical region of the cerebrum by identifying every possible combination of adjacent nodes in a graph and then measuring the drop in GE following nodal deletion. Progressive removal of brain parcellations led to patterns of GE decline that were reasonably predictable but had inter-subject differences. Additionally, as expected, there were deletion of some nodes that were worse than others. However, in each lobe examined in every subject, some deletion combinations were worse for GE than removing a greater number of nodes in a different region of the brain. Among certain patients, patterns of common nodes which exhibited worst GE upon removal were identified as "connectotypes". Given some evidence in the literature linking GE to certain aspects of neuro-cognitive abilities, investigating these connectotypes could potentially mitigate the impact of brain surgery on cognition.

The influence of sleep disorders on perioperative neurocognitive disorders among the elderly: A narrative review.

This review comprehensively assesses the epidemiology, interaction, and impact on patient outcomes of perioperative sleep disorders (SD) and perioperative neurocognitive disorders (PND) in the elderly. The incidence of SD and PND during the perioperative period in older adults is alarmingly high, with SD significantly contributing to the occurrence of postoperative delirium. However, the clinical evidence linking SD to PND remains insufficient, despite substantial preclinical data. Therefore, this study focuses on the underlying mechanisms between SD and PND, underscoring that potential mechanisms driving SD-induced PND include uncontrolled central nervous inflammation, blood-brain barrier disruption, circadian rhythm disturbances, glial cell dysfunction, neuronal and synaptic abnormalities, impaired central metabolic waste clearance, gut microbiome dysbiosis, hippocampal oxidative stress, and altered brain network connectivity. Additionally, the review also evaluates the effectiveness of various sleep interventions, both pharmacological and nonpharmacological, in mitigating PND. Strategies such as earplugs, eye masks, restoring circadian rhythms, physical exercise, noninvasive brain stimulation, dexmedetomidine, and melatonin receptor agonists have shown efficacy in reducing PND incidence. The impact of other sleep-improvement drugs (e.g., orexin receptor antagonists) and methods (e.g., cognitive-behavioral therapy for insomnia) on PND is still unclear. However, certain drugs used for treating SD (e.g., antidepressants and first-generation antihistamines) may potentially aggravate PND. By providing valuable insights and references, this review aimed to enhance the understanding and management of PND in older adults based on SD.

Post-traumatic hyperoxia after pediatric TBI.

OBJECTIVE: Hyperoxia has been suggested as a mechanism for secondary injury following adult traumatic brain injury (TBI), but its effects have not been well described in pediatric patients. METHODS: Pediatric (≤18yo) TBI patients were identified in a prospective institutional registry from October 2008 to April 2022. The first, highest, and the Area Under the Curve (AUC) PaO2 in the first 24 hours were collected and calculated for each patient from arterial blood gas reports after admission to the ICU. Neurological outcome after 6 months was measured using dichotomized modified Rankin Scale (mRS) and Glasgow Outcome Scale - Extended (GOS-E). Multivariable logistic regression models were used to determine if the three measurements for hyperoxia predicted an unfavorable outcome after controlling for well-established clinical and imaging predictors of outcome. RESULTS: We identified 98 pediatric patients with severe accidental TBI during the study period. Hyperoxia (PaO2 > 300 mmHg) occurred in 33% of the patients. The presence of elevated PaO2 values, determined by all three evaluations of hyperoxia, was not associated with unfavorable outcome after 6 months. CONCLUSION: Utilizing multiple methods to assess exposure, hyperoxia was present in a substantial number of patients with severe TBI but was not associated with an unfavorable outcome.

Effect of maternal age on foetal chromosomal defects: an investigation based on non-invasive prenatal testing.

BACKGROUND: This study aimed to evaluate the value of non-invasive prenatal testing (NIPT) in the prenatal screening of foetal aneuploidy-associated diseases at different gestational ages. METHODS: Briefly, cell-free foetal DNAs were extracted from plasma first, followed by DNA sequencing and bioinformatics analyses for chromosome aneuploidy (T21, T18, and T13), sex chromosome aneuploidy (SCA), and microdeletion/microduplication. Subsequently, the positive results were subject to karyotype analyses. RESULTS: The pregnant women included in this study were divided into six groups, and the results, such as chromosome diagnoses, and clinical phenotypes, were collected for data analyses. According to the results of the data analysis, the positivity rates of foetal chromosomal abnormalities in pregnant women under 20, 20-24, 25-29, 30-34, 35-39, and >40 years old were 0%, 0.17%, 0.25%, 0.27%, 0.60%, and 1.66%, respectively. The positive predictive value (PPV) in the 20-24 years group was 41.67%, that in the 25-29 years group was 62.5%, that in the 30-34 years group was 66.67%, that in the 35-39 years group was 90.74%, and that in the >40 years group was 90.32%. CONCLUSION: Overall, NIPT detection in elderly pregnant women has excellent clinical application value in reducing the incidence of either birth defects or abortion caused by invasive chromosome examination.

It is critical to diagnose foetal chromosome aneuploidy in time through prenatal screening to prevent birth defects. This study aimed to evaluate the value of non-invasive prenatal testing (NIPT) in prenatal screening of foetal aneuploidy-associated diseases at different gestational ages. A retrospective analysis based on NIPT screening data at a medical laboratory was performed. The results showed that the total positivity rate and total positive predictive value of trisomy 21, trisomy 18, and trisomy 13 in older pregnant women (≥35 years old) were significantly higher than those in younger pregnant women, and there was an increasing trend with increasing maternal ages. This study indicated that NIPT detection in elderly pregnant women has an excellent application value in clinical practice to reduce the incidence of birth defects and abortion caused by invasive chromosome examination.

Open-Label Sulforaphane Trial in FMR1 Premutation Carriers with Fragile-X-Associated Tremor and Ataxia Syndrome (FXTAS).

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60-88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.

Personalized, parcel-guided rTMS for the treatment of major depressive disorder: Safety and proof of concept.

BACKGROUND: Not all patients with major depressive disorder (MDD) benefit from the US Food and Drug Administration-approved use of repetitive transcranial magnetic stimulation (rTMS) at the dorsolateral prefrontal cortex. We may be undertreating depression with this one-size-fits-all rTMS strategy. METHODS: We present a retrospective review of targeted and connectome-guided rTMS in 26 patients from Cingulum Health from 2020 to 2023 with MDD or MDD with associated symptoms. rTMS was conducted by identifying multiple cortical targets based on anomalies in individual functional connectivity networks as determined by machine learning connectomic software. Quality of life assessed by the EuroQol (EQ-5D) score and depression symptoms assessed by the Beck Depression Inventory (BDI) were administered prior to treatment, directly after, and at a follow-up consultation. RESULTS: Of the 26 patients treated with rTMS, 16 (62%) attained remission after treatment. Of the 19 patients who completed follow-up assessments after an average interval of 2.6 months, 11 (58%) responded to treatment and 13 (68%) showed significant remission. Between patients classified with or without treatment-resistant depression, there was no difference in BDI improvement. Additionally, there was significant improvement in quality of life after treatment and during follow-up compared to baseline. LIMITATIONS: This review is retrospective in nature, so there is no control group to assess the placebo effect on patient outcomes. CONCLUSION: The personalized, connectome-guided approach of rTMS is safe and may be effective for depression. This personalized rTMS treatment allows for co-treatment of multiple disorders, such as the comorbidity of depression and anxiety.

Parcellation-Based Connectivity Model of the Judgement Core.

Judgement is a higher-order brain function utilized in the evaluation process of problem solving. However, heterogeneity in the task methodology based on the many definitions of judgement and its expansive and nuanced applications have prevented the identification of a unified cortical model at a level of granularity necessary for clinical translation. Forty-six task-based fMRI studies were used to generate activation-likelihood estimations (ALE) across moral, social, risky, and interpersonal judgement paradigms. Cortical parcellations overlapping these ALEs were used to delineate patterns in neurocognitive network engagement for the four judgement tasks. Moral judgement involved the bilateral superior frontal gyri, right temporal gyri, and left parietal lobe. Social judgement demonstrated a left-dominant frontoparietal network with engagement of right-sided temporal limbic regions. Moral and social judgement tasks evoked mutual engagement of the bilateral DMN. Both interpersonal and risk judgement were shown to involve a right-sided frontoparietal network with accompanying engagement of the left insular cortex, converging at the right-sided CEN. Cortical activation in normophysiological judgement function followed two separable patterns involving the large-scale neurocognitive networks. Specifically, the DMN was found to subserve judgement centered around social inferences and moral cognition, while the CEN subserved tasks involving probabilistic reasoning, risk estimation, and strategic contemplation.

Graph Theory Measures and Their Application to Neurosurgical Eloquence.

Improving patient safety and preserving eloquent brain are crucial in neurosurgery. Since there is significant clinical variability in post-operative lesions suffered by patients who undergo surgery in the same areas deemed compensable, there is an unknown degree of inter-individual variability in brain 'eloquence'. Advances in connectomic mapping efforts through diffusion tractography allow for utilization of non-invasive imaging and statistical modeling to graphically represent the brain. Extending the definition of brain eloquence to graph theory measures of hubness and centrality may help to improve our understanding of individual variability in brain eloquence and lesion responses. While functional deficits cannot be immediately determined intra-operatively, there has been potential shown by emerging technologies in mapping of hub nodes as an add-on to existing surgical navigation modalities to improve individual surgical outcomes. This review aims to outline and review current research surrounding novel graph theoretical concepts of hubness, centrality, and eloquence and specifically its relevance to brain mapping for pre-operative planning and intra-operative navigation in neurosurgery.

Fragile X-Associated Neuropsychiatric Disorders (FXAND) in Young Fragile X Premutation Carriers.

Background: The fragile X premutation carrier state (PM) (55-200 CGG repeats in the fragile X messenger ribonucleoprotein 1, FMR1 gene) is associated with several conditions, including fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor ataxia (FXTAS), with current literature largely primarily investigating older PM individuals. The aim of this study was to identify the prevalence of fragile X-associated neurodevelopmental disorders (FXAND) in a sample of young PM individuals. Methods: This was a retrospective study conducted through a medical record review of PM individuals who were seen either for clinical concerns (probands, 45.9%) or identified through the cascade testing (non-probands, 54.1%) of an affected sibling with fragile X syndrome. Information on the presence of autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, depression, long-term psychiatric medication intake, and cognitive function, based on standardized assessments, was obtained. Molecular data, including CGG repeat number and FMR1 mRNA levels, were also available for a subset of participants. Analysis included descriptive statistics and a test of comparison to describe the clinical profile of PM individuals pertinent to FXAND. Results: Participants included 61 individuals (52 males and 9 females) aged 7.8 to 20.0 years (mean 12.6 ± 3.4) with a mean full-scale IQ of 90.9 ± 22.7. The majority (N = 52; 85.2%) had at least one mental health disorder, with anxiety being the most common (82.0% of subjects), followed by ADHD (66.5%), and ASD (32.8%). Twenty-seven (87.1%) of non-probands also had at least one mental health condition, with probands having lower cognitive and adaptive skills than non-probands. ASD was present in 20 participants (17/52 males and 3/9 females; 15 probands) with significantly lower FSIQ in those with ASD (mean 73.5 vs. 98.0, p < 0.001). Participants with ASD had a higher number of long-term medications compared to those without (2.32 vs. 1.3, p = 0.002). Conclusions: Our findings indicate a high rate of FXAND diagnoses within a cohort of young PM individuals, including those identified via cascade testing, although this was not a population sample. An awareness of the entity of FXAND and the early recognition of the symptoms of associated conditions may facilitate timely and appropriate care for PM individuals.

Tophaceous gout of the nose in a male FMR1 premutation carrier.

Premutation alleles with 55-200 CGG repeats in FMR1 can lead to fragile X-associated tremor/ataxia syndrome (FXTAS). In this case study, we report uncontrolled gout in a 68-year-old male with FXTAS with multiple sites of involvement including a rare gouty tophus in the nasal region.

Improving quality of life post-tumor craniotomy using personalized, parcel-guided TMS: safety and proof of concept.

PURPOSE: Deficits in neuro-cognitive function are not uncommon for patients who have undergone surgical removal of brain tumors. Our goal is to evaluate the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) as a non-invasive tool for the treatment of neuro-cognitive dysfunctions following craniotomy. METHODS: We present a retrospective review of individualized rTMS in twelve patients from Cingulum Health from December 2019 to July 2021 who presented with neuro-cognitive deficits following craniotomy. Multiple cortical targets were selected based on the patient's neurological disorder, associated networks, and anomalies in the functional connectivity of the brain as determined by machine-learning. TMS treatment was performed for five consecutive days. EuroQol quality of life (EQ-5D), functional extremity scales, and neuropsychiatric questionnaires related to the patient's deficit were assessed prior to, after, and during two-month follow-up of rTMS treatment. RESULTS: Nine patients had unilateral functional deficits in either upper, lower, or both limbs. One patient reported post-operative depression, another experienced short term memory difficulties, and a third reported hypobulia. All twelve patients reported significantly improved EQ5D after rTMS treatment and during follow-up. More than half of the patients with lower and upper functional deficits had a 9-point improvement during follow-up. In the patient who developed depression, an 88% reduction in depressive symptoms based on the Beck's Depression Inventory (BDI) was observed during follow-up. No adverse events, such as seizures, occurred. CONCLUSION: The personalized functional connectivity approach to rTMS treatment may be effective and safe for patients with post-craniotomy neuro-cognitive dysfunction.

Fragile X Syndrome: From Molecular Aspect to Clinical Treatment.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990-2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.

Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy.

Accumulation of misfolded phosphorylated Tau (Tauopathy) can be triggered by mutations or by trauma, and is associated with synapse loss, gliosis, neurodegeneration and memory deficits. Fyn kinase physically associates with Tau and regulates subcellular distribution. Here, we assessed whether pharmacological Fyn inhibition alters Tauopathy. In P301S transgenic mice, chronic Fyn inhibition prevented deficits in spatial memory and passive avoidance learning. The behavioral improvement was coupled with reduced accumulation of phospho-Tau in the hippocampus, with reductions in glial activation and with recovery of presynaptic markers. We extended this analysis to a trauma model in which very mild repetitive closed head injury was paired with chronic variable stress over 2 weeks to produce persistent memory deficits and Tau accumulation. In this model, Fyn inhibition beginning 24 h after the trauma ended rescued memory performance and reduced phospho-Tau accumulation. Thus, inhibition of Fyn kinase may have therapeutic benefit in clinical Tauopathies.

Non-canonical Notch Signaling Regulates Actin Remodeling in Cell Migration by Activating PI3K/AKT/Cdc42 Pathway.

Tumor cell migration is a critical step in cancer metastasis. Over-activated Notch pathway can promote the migration of cancer cells, especially in the breast cancer. However, the underlying mechanism of non-canonical Notch signaling in modulating the migration has not yet been clearly characterized. Here we demonstrated that DAPT, a gamma secretase inhibitor, inhibited protrusion formation and cell motility, and then reduced the migration of triple-negative breast cancer cells, through increasing the activity of Cdc42 by non-canonical Notch pathway. Phosphorylation of AKT on S473 was surprisingly increased when Notch signaling was inhibited by DAPT. Inhibition of PI3K and AKT by LY294002 and MK2206, respectively, or knockdown of AKT expression by siRNA blocked DAPT-induced activation of Cdc42. Moreover, immunofluorescence staining further showed that DAPT treatment reduced the formation of lamellipodia and induced actin cytoskeleton remodeling. Taken together, these results indicated that DAPT inhibited Notch signaling and consequently activated PI3K/AKT/Cdc42 signaling by non-canonical pathway, facilitated the formation of filopodia and inhibited the assembly of lamellipodia, and finally resulted in the decrease of migration activity of breast cancer cells.