United States

Background: Opioid dependence is a major public health concern. Genetic factors likely contribute to opioid addiction vulnerability. A number of studies have examined associations between specific gene variants and opioid dependence, but results have been mixed.
Methods: A systematic literature search was conducted through January 2024 to identify studies evaluating relationships between single nucleotide polymorphisms (SNPs) and opioid dependence. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using random-effects meta-analysis models. Between-study heterogeneity was assessed with I2 statistics.
Results: 66 studies involving 21,485 participants were included in the meta-analysis. Significant associations were found between opioid dependence and variants in the mu-opioid receptor (OPRM1) gene (OR=0.466, 95% CI 0.346-0.628, p=5.456x10-7), prodynorphin (PDYN) gene (OR=0.296, 95% CI 0.221-0.398, p&lt;0.001), catechol-O-methyltransferase (COMT) gene (OR=0.438, 95% CI 0.383-0.501, p&lt;0.001), and other genes. Effects were detected across multiple genetic models and ancestral groups.
Conclusion: This meta-analysis identified multiple single nucleotide polymorphisms associated with heightened opioid dependence susceptibility. The findings advance knowledge of genetic contributions to opioid addiction vulnerability across diverse populations.

AMA Research Challenge 2024 

Single Nucleotide Polymorphisms Associated with Risk of Opioid Dependence

Background: Opioid dependence is a major public health concern. Genetic factors likely contribute to opioid addiction vulnerability. A number of studies have examined associations between specific gene variants and opioid dependence, but results have been mixed.
Methods: A systematic literature search was conducted through January 2024 to identify studies evaluating relationships between single nucleotide polymorphisms (SNPs) and opioid dependence. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using random-effects meta-analysis models. Between-study heterogeneity was assessed with I2 statistics.
Results: 66 studies involving 21,485 participants were included in the meta-analysis. Significant associations were found between opioid dependence and variants in the mu-opioid receptor (OPRM1) gene (OR=0.466, 95% CI 0.346-0.628, p=5.456x10-7), prodynorphin (PDYN) gene (OR=0.296, 95% CI 0.221-0.398, p<0.001), catechol-O-methyltransferase (COMT) gene (OR=0.438, 95% CI 0.383-0.501, p<0.001), and other genes. Effects were detected across multiple genetic models and ancestral groups.
Conclusion: This meta-analysis identified multiple single nucleotide polymorphisms associated with heightened opioid dependence susceptibility. The findings advance knowledge of genetic contributions to opioid addiction vulnerability across diverse populations.

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Introduction: Stroke patients often experience motor deficits in the limbs and do not reach satisfactory recovery. Deep brain stimulation (DBS) can target intrinsic pathways that project to vital cortical areas. One structure of interest is the ventro-oralis posterior (VOP)/ventro-intermedium (VIM) of the motor thalamus. The VOP/VIM is a thalamic relay with outgoing excitatory connectivity to the primary motor cortex (M1) and could be a potential target for DBS to facilitate motor function after stroke. We hypothesized that VOP/VIM stimulation may increase the excitability of M1 and strengthen corticospinal motor output and control.
Methods: Five non-human primates (NHP) were implanted with DBS electrodes into the ventral lateral motor thalamus, the internal capsule (IC), and intracortical microelectrode arrays over M1. This setup was replicated in six patients undergoing implantation of DBS electrodes targeting the VOP/VIM for essential tremor with the addition of a macroarray placed over M1. Intraoperatively, direct cortical stimulation (DCS) was paired with VOP/VIM stimulation. Additionally, a single patient with a traumatic brain injury (TBI) with motor deficits was implanted. When the TBI patient returned for DBS programming, he was asked to modulate their force along a trace and the error of deviation was measured with and without DBS while performing weighted and unweighted arm exercises.
Results: In the NHPs, a significantly increased amplitude of evoked potentials (EP) and single unit spike counts recorded in M1 with VOP/VIM stimulation was observed. IC stimulation with VOP/VIM stimulation increased the amplitude of motor evoked potentials (MEP) and kinematics of hand muscles. In the intraoperative human studies, when VOP/VIM was stimulated, similar amplification in M1 EPs and MEPs recorded in upper extremity muscles were observed. Stimulation also increased the height the TBI patient was able to reach in the arm exercises as well as reduced the error during force modulation tasks.
Conclusion: This study documented that direct electrical stimulation of the motor thalamus strengthens motor output, both in NHPs and humans. These outcomes support DBS of the motor thalamus as a potential therapeutic approach to treat post-stroke motor deficits.


Strengthening Motor Output with Direct Motor Thalamus Stimulation. Evidence For A Novel Deep Brain Neuromodulation Modality For Stroke.

Background: This systematic review and meta-analysis comprehensively compares
and analyzes the strengths and weaknesses of three neuromodulating treatment
options—electroconvulsive therapy (ECT), transcranial magnetic stimulation (rTMS),
and psychedelics—for pain management in individuals with Fibromyalgia.

Methods: A systematic literature search began May 31, 2023 and ended July 31,
2023 and was conducted across multiple databases, including PubMed, Google
Scholar, ScienceDirect, EMBASE, Wiley Online Library, Cochrane Library, and
EBSCO, using relevant keywords and controlled vocabulary terms. Key terms for
search included: “Fibromyalgia,” “Neuromodulation therapy,” “Electroconvulsive
Therapy,” “ECT,” “Transcranial Magnetic Stimulation.” Studies published between
2004-2023 were included in the review. The inclusion criteria encompassed
randomized controlled trials, qualitative studies, surveys, prospective cohort studies,
and case-control studies evaluating the effectiveness of ECT, TMS, and psychedelics
as neurocognitive treatments for Fibromyalgia pain management. The exclusion
criteria included animal trials, articles written in a language other than English, case
reports, and case studies.

Results: The search yielded ten studies with a total of 541 subjects, meeting the
inclusion criteria. There was an overall 2.7 mean pain decrease in pain rating scale
after therapy.

Conclusion: This review on neuromodulating Fibromyalgia pain treatments
recognizes marked improvement in pain perception in Fibromyalgia patients
receiving neuromodulating treatment.

A Systematic Review Comparing the Strengths and Weaknesses of Neuromodulating
Treatments for Pain Management in Fibromyalgia: ECT, TMS, and Psychedelics


Neuropathology holds the potential to advance our understanding of Alzheimer's disease and related dementias. Artificial intelligence (AI) models through well-labeled datasets can effectively perform complex tasks at or above human performance. Recent studies have analyzed neuropathological biomarkers like amyloid beta plaques and neurofibrillary tangles in whole slide images through AI models. However, appropriately labeled images are needed to detect which brain region the neuropathological biomarkers originate from for analytical purposes. The study aims to develop automated detection of gray matter regions in WSIs for downstream testing of established AI pipelines in neuropathology.The study involves manual annotations of gray matter regions on Bielschowsky silver stained WSIs from the Emory ADRC digital cohort. These annotations are used to train UNET semantic segmentation models for automated detection of gray matter regions on a larger cohort of non-annotated WSIs. Co-registration to immunohistochemically stained WSIs (amyloid beta, tau, TDP-43) is used to define gray matter annotations across stains. Established AI pipelines are then deployed in these regions to assess improvement on original results. 300 gray matter masks have been generated and an initial classifier has been trained using the YOLOv8 (You Only Look Once) model developed by Ultralytics. While the project is ongoing, our initial results have demonstrated the feasibility of developing an automated gray matter segmentation model to further understanding of biomarkers associated with clinical care.


Artificial Intelligence Powered Neuropathology: Automated Gray Matter Segmentation For Biomarker Analysis

Migraine is a common, disabling medical condition affecting over 40 million people in the United States. Cervical pain has been reported to be more prevalent among migraine sufferers than nausea (Calhoun et al., 2010), yet there is limited research describing the characteristics of the neck pain experienced by persons with migraine. We designed a 10-question survey to analyze the types and characteristics of neck pain experienced by patients with episodic migraine (EM, defined as 14 or fewer headache days per month.)
Subjects were recruited via patient portal message at the New England Institute of Neurology and Headache (NEINH, Stamford, CT) or through school newsletter at the Frank H Netter MD School of Medicine at Quinnipiac University (North Haven, CT). Subjects who met the inclusion criteria (diagnosed with EM, age 18-55, self-report of cervical pain with migraines) and had no history of cervicogenic headache or cervical trauma were interviewed. 
The majority of patients (58%) described their neck pain using the terms “tight or stiff”. The VAS score rating for those whose neck pain began before the migraine (M = 6.7, SD = 2.1) was significantly higher than those whose pain began during the headache (M = 4.2, SD = 1.3, p < 0.05). Patients with aura rated the neck pain (M = 6.7, SD = 1.9) significantly higher than those who do not have aura (M = 5.2, SD = 2.0, p <0.05). There was a strong, positive correlation between age and how much the neck pain contributed to overall disability (Pearson = 0.648, p<0.001). 
Our study demonstrates a small portion of the complex interplay between neck pain and migraine. The significantly higher VAS rating by those whose neck pain begins before their migraine may suggest the pain as a trigger. The difference in VAS scores based on aura may also suggest some relationship between neck pain and aura. Though we attempted to eliminate confounding neck pain that may arise due to age, the significant positive correlation may suggest that we set the age cut off too high. We recognize that our study had a small sample size and our survey only captured a small snapshot of the interplay that exists between neck pain and migraine. The study should be expanded to investigate if similar relationships between neck pain and migraine exist with a larger, more diverse sample size.

Incidence and Characteristics of Neck Pain in Episodic Migraine

Background
The International Mouse Phenotyping Consortium (IMPC) is a database that characterizes the function of over 20,000 protein-encoding genes in mice through knockout. Each knockout gene and its associated phenotype can be accessed through their website. For this project, we used the IMPC to explore the Atlastin GTPase 3 gene (Atl3), a gene related to Hereditary Sensory Neuropathy Type 1F (HSN1F). HSN1F is a rare neurological genetic disorder, characterized by the loss of sensation to the hands and feet due to a mutation in Atl3. When Atl3 is knocked out in mice, the IMPC revealed seven phenotypes: enlarged prostate gland, abnormal liver morphology, small adrenal glands, small kidney, enlarged lymph nodes, cataract, and enlarged urinary bladder.

Methods
The National Organization for Rare Disorders (NORD) was used to identify the disease of interest and its associated gene, Atl3. Using the IMPC database, seven phenotypes associated with the Atl3 knockout mice were identified and compiled into a well-known analytical tool, Microsoft Excel. The genes that showed that phenotype when knocked out in mice were compiled for each phenotype. Using variations of a common algorithm and conditional formatting in Microsoft Excel, the specific number of times a gene showed up and the number of phenotypes each gene was associated with were sorted visually with a specific color. Further analysis, totaling the number of times each specific gene appeared in multiple times was formatted graphically.

Results
The seven phenotypes associated with the Atl3 knockout mice were enlarged prostate gland, abnormal liver morphology, small adrenal glands, small kidney, enlarged lymph nodes, cataract, and enlarged urinary bladder. Our analysis revealed four genes, dynein cytoplasmic 1 light intermediate chain 1 (dync1li1), piggyBac transposable element derived 1 (Pgbd1), MAS-related GPR, member B2 (Mrgprb2), and ADNP homeobox 2 (Adnp2), that when knocked out in mice shared five of the seven phenotypes associated with the Atl3 knockout mouse.

Conclusion
Through the IMPC database, we identified dync1li1, Pgbd1, Mrgprb2, and Adnp2 as genes that potentially have an interaction or could be involved in pathways with Atl3 because they share five of the seven phenotypes. Based on our data, further research is recommended into these genes and how they relate to Atl3 as it shares these phenotypes. Utilizing currently existing tools such as the IMPC, genes and their interactions can be identified to further find genes that may have not been extensively studied yet that mimic the loss of Atl3.

Investigating Atl3-Related Genes Utilizing Data from the International Mouse Phenotyping Consortium

Background: Brain metastases, secondary brain tumors originating from cancers elsewhere in the body, can present with focal neurologic deficits without systemic symptoms and are usually evaluated using magnetic resonance imaging (MRI). Multimodal imaging methods are usually used to determine the primary cancer source. Radiomic analysis involves extracting quantitative features from medical images using data-characterization algorithms. Recent advances in deep learning and radiomics, which quantitatively analyze imaging data, offer the potential for improved prediction of primary tumor origin through MR imaging analysis. Using longitudinal MRI data, we developed and validated a mixed-effects neural network model for predicting the primary origin of brain metastases.

Methods: We used the open-source dataset from 5 different institutions made available by Ocaña-Tienda et al. (2023) to build the model. We extracted 2446 radiomic features, out of which 60 features were retained after feature selection using wrapper- and filter-based techniques. For the nested mixed-effects neural network model, we incorporated a dual-layer structure with ReLU activation for the fixed effects and unique embeddings for each cluster, leading to a nested structure. The model was compiled using an Adam optimizer and trained across several epochs with a steadily declining learning rate facilitated by exponential decay. Regularization was implicitly managed through embedding and learning rate adjustments. Model performance was evaluated using receiver operating characteristic curve (ROC) analysis.

Results: Our mixed-effects model demonstrated high accuracy (90.5%), precision (92.7%), recall (87.8%), and F1 score (90.2%), with an area under the ROC (AUC-ROC) curve of 0.944 in identifying the primary tumor site. The nested mixed-effects model was superior to the fixed-effects model with an AUC-ROC of 0.719.

Conclusion: Our mixed-effects neural network model accurately predicts the primary origin of brain metastases with high internal and external validity. Using advanced radiomic feature selection and deep learning techniques. Our model achieved high-performance metrics, thus providing a promising tool for enhancing diagnostic capability and tailoring patient-specific management strategies. We are exploring it's clinical utility further by adding more data from a tertiary cancer hospital. We have also deployed a patented prototype software for research use to study the effect of integrating this model in clinical workflows to optimize patient care.

Mixed-effects deep-learning based quantitative radiomic analysis of longitudinal magnetic resonance imaging of brain metastases predict primary tumor origin

Introduction:
Traumatic brain injury (TBI) from closed-head trauma is a leading cause of disability, with limited effective interventions. Many murine models for researching TBI impact the brain parenchyma directly and are limited by the fact that these forces do not recapitulate clinically relevant closed head injury. An alternative model applying clinically relevant injury mechanics to the intact skull may lead to variable results and as a result, preclinical modeling of TBI remains a challenge. Current models often do not explore sex differences in TBI, which is critically important for translation to clinical practice. 

Objective:
The current study aims to characterize a clinically relevant murine model of closed-head TBI and analyze the impact of system parameters on motor coordination, spatial learning, and neuronal damage, with comparisons made between sexes.

Methods:
We systematically investigated sources of variability in a murine model of closed-head TBI and developed a framework to reduce variability across severity and sex. We manipulated pressure, dwell time, and displacement to determine effects on motor coordination, spatial learning, and neuronal damage in 10-week-old male and female mice. 

Results:
Increasing pressure beyond 70 psi had a ceiling effect on cellular and behavioral outcomes, while manipulating dwell time only affected behavioral performance. Increasing displacement precisely graded injury severity in both sexes across all outcomes. Physical signs of trauma occurred more frequently at higher displacements. Stratifying severity based on day-1 rotarod performance retained histological relationships and separated both sexes into injury severity cohorts with distinct patterns of behavioral recovery. Utilizing this stratification strategy, within-group rotarod variability over 6 days post-injury was reduced by 50%. 

Conclusions:
These results have important implications for translational research in TBI and provide a framework for using this clinically relevant model in both male and female mice.

Optimization of a translational murine model of closed-head traumatic brain injury

Abstract Title
Psychiatric outcomes in patients with mild concussion following differential treatment timing by age
Background
The temporary pathophysiological changes after a mild concussion may offer a therapeutic window in which timely intervention can influence long-term post-concussion sequelae. We sought to understand if the risk of depression or anxiety, two well-established sequelae following mild concussion, could be affected by the choice of immediate treatment versus delayed treatment. Our study provides quantifiable risks to different treatment windows across multiple ages and treatment time periods.

Our goal was to examine if patients who received an immediate treatment within one week of mild concussion had different risks for subsequent depression or anxiety compared with those who received delayed treatment after one week of the event, stratified by age groups.

Methods
This was a nationwide multicenter retrospective cohort study that used the TriNetX Analytics platform to access de-identified electronic health records of over 100 million patients. The study population was comprised of a total of 9,652 patients with a diagnosis of mild concussion, who received either immediate treatment defined as within 1 week (n = 5,266), or delayed treatment which was defined as 1 week to 6 months (n = 4,386) following the diagnosis of mild concussion. Each treatment group was separated into 3 age groups: <=25, 26-64, and 65+ years. Treatment was defined by CPT code and included one or more of the following neuro-rehabilitative services: CPT96132, CPT92507, CPT1013510, and CPT97165.

Results
Among patients aged <=25, those who received immediate treatment had a significantly higher lower risk for depression (HR: 0.782, 95% CI 0.613 –0.998) and anxiety (HR: 0.68, 95% CI: 0.564–0.819) compared with those who received delayed treatment. For those aged 26–64 years, there was a significantly reduced risk of depression (HR: 0.726, 95% CI: 0.593–0.89) and anxiety (HR: 0.635, 95% CI: 0.54–0.747) in the immediate treatment group. However, among patients in the oldest cohort of 65+, there was no significant decrease in risk of depression (HR: 0.735, 95% CI: 0.538–1.004), but there was a significant decrease in anxiety (HR: 0.608, 95% CI: 0.444–0.831) in the immediate treatment group compared to delayed treatment.

Conclusion

This study indicates that patients with a mild concussion who received treatment within one week had significantly reduced risk of depression and anxiety disorders than those who received treatment after one week. Prompt treatment of even mild concussions may mitigate adverse psychiatric outcomes following mild concussion.

Psychiatric Outcomes in Patients with Mild Concussion Following Differential Treatment Timing by Age

Introduction: Cannabis use among adults in the United States is growing, and while case reports and animal studies suggest a relationship between its use and delirium, no clinical studies have assessed the potential association. Therefore, this study aims to determine whether there is an association between a history of cannabis use disorder and delirium. 
Methods: The TriNetX Analytics Network, a research platform containing de-identified electronic health records from over 116 million patients and 63 healthcare organizations across the United States was utilized. History of cannabis use disorder was defined as at least 1 diagnosis of Cannabis related disorders (ICD-10-CM F12) within 1 year prior to hospitalization or surgery. Propensity score matching based on demographic characteristics (age, sex, race, and ethnicity) and comorbidities (diabetes, cardiovascular disease, neurological disease, dementia, depression, substance use, physical disabilities) was performed. The primary outcome is a diagnosis of delirium due to a known physiological condition (ICD-10-CM F05) within either 2 weeks (in-patient hospitalization analyses) or 1 week (post-operative analyses) of the respective hospital event.
Results: Following a propensity score match, 178,275 individuals were included in the 18-64 years in-patient cohort, 16,307 individuals in the 65+ in-patient cohort, 85,314 individuals in the 18-64 post-operative cohort, and 11,136 individuals in the 65+ post-operative cohort. In the in-patient hospitalization analysis, there was a significant association between cannabis use and delirium in the 18-64 cohort (HR: 1.43, 95% CI: 1.11 – 1.85) but not in the 65+ cohort (HR: 1.19, 95% CI: 0.66 – 2.12). In the postoperative setting, there was a significantly increased risk of delirium in the cannabis cohort in both the 18-64 (HR: 3.37, 95% CI: 2.59 – 4.39) group and 65+ years old group (HR: 2.37, 95% CI: 1.51 – 3.72).
Conclusions and Relevance: The findings of this investigation suggest that documented cannabis-use disorder within one year of hospitalization or surgery is associated with a significantly increased risk of delirium. Delirium is associated with considerable patient morbidity, which can be mitigated through early diagnosis. Documented cannabis use may, therefore, warrant additional delirium screening measures and clinical discretion.



The Association between Cannabis Use and Delirium in the Postoperative and Inpatient Settings

Background
Stroke ranks as the fifth leading cause of death in the United States and is the primary contributor to neurological impairments and cognitive deficits, responsible for 5.2% of global deaths. Approximately half of stroke survivors suffer from long-term disabilities, making it a leading cause of disability worldwide. Currently approved treatments for ischemic stroke focus on restoring cerebral blood flow through intravenous thrombolysis and mechanical thrombectomy. Minocycline, a lipophilic protease inhibitor capable of crossing the blood-brain barrier, exhibits anti-inflammatory, antioxidant, and antiapoptotic properties both centrally and peripherally. This literature review aims to assess the efficacy and safety of Minocycline as an adjunctive therapy in treating ischemic stroke and improving post-stroke functional outcomes.
Methods
We searched PubMed, Google Scholar, and clinicaltrials.gov databases. We used a combination of keywords: acute ischemic stroke, Minocycline, neuroprotection, and neuroinflammation. We included full-text peer-reviewed scholarly articles published within the last decade, randomized controlled trials, and systematic reviews with meta-analyses. We excluded articles in languages other than English, experimental studies and animal studies.
Results
We systematically reviewed nine articles that met our predefined eligibility criteria and involved 1,010 participants. These studies assessed the effectiveness and safety of Minocycline by comparing groups treated with Minocycline to control groups using the National Institute of Health Stroke Scale. Across the nine studies, there was consistent evidence of substantial clinical improvement among patients treated with Minocycline. However, two of the studies indicated that although Minocycline was deemed safe, it did not result in improved outcomes for patients with acute stroke.
Conclusion
Minocycline shows promise in mitigating both immediate and prolonged effects of ischemic stroke, demonstrating efficacy with minimal adverse effects even at high dosages. Nonetheless, conflicting results in two studies suggest that small sample sizes might contribute to varying conclusions. Despite the scarcity of data from clinical trials, Minocycline could serve as a valuable adjunctive therapy, particularly for patients in remote areas lacking access to specialized stroke care or those unsuitable for intravenous thrombolysis. Additional randomized clinical studies on a large scale are needed to verify the Minocycline's neuroprotective effects and its potential to improve outcomes and reduce long-term disabilities in ischemic stroke patients.


Next from AMA Research Challenge 2024

Strengthening Motor Output with Direct Motor Thalamus Stimulation. Evidence For A Novel Deep Brain Neuromodulation Modality For Stroke.

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