Addressing cortex dysregulation in youth through brain health check coaching and prophylactic brain development.

The Carter Center has estimated that the addiction crisis in the United States (US), if continues to worsen at the same rate, may cost the country approximately 16 trillion dollars by 2030. In recent years, the well-being of youth has been compromised by not only the coronavirus disease 2019 pandemic but also the alarming global opioid crisis, particularly in the US. Each year, deadly opioid drugs claim hundreds of thousands of lives, contributing to an ever-rising death toll. In addition, maternal usage of opioids and other drugs during pregnancy could compromise the neurodevelopment of children. A high rate of DNA polymorphic antecedents compounds the occurrence of epigenetic insults involving methylation of specific essential genes related to normal brain function. These genetic antecedent insults affect healthy DNA and mRNA transcription, leading to a loss of proteins required for normal brain development and function in youth. Myelination in the frontal cortex, a process known to extend until the late 20s, delays the development of proficient executive function and decision-making abilities. Understanding this delay in brain development, along with the presence of potential high-risk antecedent polymorphic variants or alleles and generational epigenetics, provides a clear rationale for embracing the Brain Research Commission's suggestion to mimic fitness programs with an adaptable brain health check (BHC). Implementing the BHC within the educational systems in the US and other countries could serve as an effective initiative for proactive therapies aimed at reducing juvenile mental health problems and eventually criminal activities, addiction, and other behaviors associated with reward deficiency syndrome.

Identification of stress-induced epigenetic methylation onto dopamine D2 gene and neurological and behavioral consequences.

The D2 dopamine receptor (DRD2) gene has garnered substantial attention as one of the most extensively studied genes across various neuropsychiatric disorders. Since its initial association with severe alcoholism in 1990, particularly through the identification of the DRD2 Taq A1 allele, numerous international investigations have been conducted to elucidate its role in different conditions. As of February 22, 2024, there are 5485 articles focusing on the DRD2 gene listed in PUBMED. There have been 120 meta-analyses with mixed results. In our opinion, the primary cause of negative reports regarding the association of various DRD2 gene polymorphisms is the inadequate screening of controls, not adequately eliminating many hidden reward deficiency syndrome behaviors. Moreover, pleiotropic effects of DRD2 variants have been identified in neuropsychologic, neurophysiologic, stress response, social stress defeat, maternal deprivation, and gambling disorder, with epigenetic DNA methylation and histone post-translational negative methylation identified as discussed in this article. There are 70 articles listed in PUBMED for DNA methylation and 20 articles listed for histone methylation as of October 19, 2022. For this commentary, we did not denote DNA and/or histone methylation; instead, we provided a brief summary based on behavioral effects. Based on the fact that Blum and Noble characterized the DRD2 Taq A1 allele as a generalized reward gene and not necessarily specific alcoholism, it now behooves the field to find ways to either use effector moieties to edit the neuroepigenetic insults or possibly harness the idea of potentially removing negative mRNA-reduced expression by inducing "dopamine homeostasis."

Blood pressure response to extended-release naltrexone in heroin and prescription opioid users and its implications for cardiovascular morbidity.

BACKGROUND: Consuming opioid agonists is a risk factor for cardiovascular disease particularly in intravenous heroin users. The monthly injectable extended-release opioid antagonist, naltrexone (XR-NTX) is an effective treatment for opioid use disorder. The impact of opioid receptor blockade through XR-NTX on blood pressure, a critical risk factor for cardiovascular morbidity, has not yet been characterized. METHODS: The study evaluated the change in blood pressure during XR-NTX treatment among 14 patients who predominately used intravenous heroin and 24 patients who used prescription oral opioids, all with opioid use disorder. Blood pressure was measured in each patient immediately before the first XR-NTX injection and ∼two weeks after the first injection. The change in diastolic and systolic pressure was compared between the heroin users and the prescription opioids users using analysis of variance. RESULTS: XR-NTX treatment was associated with significant decreases in diastolic blood pressure in the heroin group, but not in the prescription opioids group. Systolic blood pressure values in the heroin users showed a decline at trend level only. CONCLUSIONS: Further research is warranted to replicate our findings and to determine whether XR-NTX effect is relatively specific to blood pressure or generalizes to other components of metabolic syndrome. Distinguishing between heroin and prescription opioid users could shed light on the unique clinical and pharmacological profiles of opioid drugs, particularly regarding their cardiovascular safety. This information can be useful in developing personalized therapeutic strategies based on the route of opioid administration.

Validity of mental and physical stress models.

Different stress models are employed to enhance our understanding of the underlying mechanisms and explore potential interventions. However, the utility of these models remains a critical concern, as their validities may be limited by the complexity of stress processes. Literature review revealed that both mental and physical stress models possess reasonable construct and criterion validities, respectively reflected in psychometrically assessed stress ratings and in activation of the sympathoadrenal system and the hypothalamic-pituitary-adrenal axis. The findings are less robust, though, in the pharmacological perturbations' domain, including such agents as adenosine or dobutamine. Likewise, stress models' convergent- and discriminant validity vary depending on the stressors' nature. Stress models share similarities, but also have important differences regarding their validities. Specific traits defined by the nature of the stressor stimulus should be taken into consideration when selecting stress models. Doing so can personalize prevention and treatment of stress-related antecedents, its acute processing, and chronic sequelae. Further work is warranted to refine stress models' validity and customize them so they commensurate diverse populations and circumstances.

Neurogenetics and Epigenetics of Loneliness.

Loneliness, an established risk factor for both, mental and physical morbidity, is a mounting public health concern. However, the neurobiological mechanisms underlying loneliness-related morbidity are not yet well defined. Here we examined the role of genes and associated DNA risk polymorphic variants that are implicated in loneliness via genetic and epigenetic mechanisms and may thus point to specific therapeutic targets. Searches were conducted on PubMed, Medline, and EMBASE databases using specific Medical Subject Headings terms such as loneliness and genes, neuro- and epigenetics, addiction, affective disorders, alcohol, anti-reward, anxiety, depression, dopamine, cancer, cardiovascular, cognitive, hypodopaminergia, medical, motivation, (neuro)psychopathology, social isolation, and reward deficiency. The narrative literature review yielded recursive collections of scientific and clinical evidence, which were subsequently condensed and summarized in the following key areas: (1) Genetic Antecedents: Exploration of multiple genes mediating reward, stress, immunity and other important vital functions; (2) Genes and Mental Health: Examination of genes linked to personality traits and mental illnesses providing insights into the intricate network of interaction converging on the experience of loneliness; (3) Epigenetic Effects: Inquiry into instances of loneliness and social isolation that are driven by epigenetic methylations associated with negative childhood experiences; and (4) Neural Correlates: Analysis of loneliness-related affective states and cognitions with a focus on hypodopaminergic reward deficiency arising in the context of early life stress, eg, maternal separation, underscoring the importance of parental support early in life. Identification of the individual contributions by various (epi)genetic factors presents opportunities for the creation of innovative preventive, diagnostic, and therapeutic approaches for individuals who cope with persistent feelings of loneliness. The clinical facets and therapeutic prospects associated with the current understanding of loneliness, are discussed emphasizing the relevance of genes and DNA risk polymorphic variants in the context of loneliness-related morbidity.

EPIC Spinal Procedure with Sound Wave Technology Induces Biomechanical Alignment Putatively Influencing Pain Response.

Spinal biomechanical alignment is now able to be altered through the use of unique sound wave technology. This methodological commentary will correlate recent studies demonstrating the ability of sound waves to carry mass, how the EPIC technique spinal procedure uses a sound wave impulse to create measurable changes in spinal alignment, and the clinical safety and efficacy of this approach. The EPIC technique is a direct genealogical descendant of the technique originally developed by the founding family of chiropractic. With sound wave therapies currently being used to break up kidney stones, called lithotripsy, in physical therapy for the treatment of soft tissue injuries, in the treatment of prostate cancer, and in the treatment of Alzheimer's disease, it is possible that the use of sound wave therapies may enter into the realm of altering joint biomechanics. Through a neurovascular examination, the EPIC technique spinal procedure can ascertain the presence of craniocervical subluxation, followed by acquiring multi-dimensional radiographic images for structural analysis. Currently using digital radiographic analysis, the EPIC technique acquires an epigenetic profile of structural asymmetries as well as a multi-directional biomechanical malposition profile of the spine, combining both profiles to ascertain the exact degrees for realignment. EPIC clinics have successfully utilized EPIC on over 20,000 cases. Comparison of pre-treatment biomechanical lateral displacement of the C1 vertebra around the Z-axis measured on digital radiographs, and post-treatment biomechanical lateral displacement of the C1 vertebra measured on digital radiographs immediately following the procedure, demonstrated an average 52% reduction in lateral biomechanical displacement around the Z-axis in a select group of over 2,000 cases. While more research is required, we are encouraged by these preliminary results. WC 265.

"TO BE OR NOT TO BE" GWAS Ends the Controversy about the DRD2 Gene as a Determinant of Reward Deficiency Syndrome (RDS).

Since 1990, there have been thousands of published studies on addiction psychiatry. Several from Blum et al showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance abuse and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, reactions have been mixed. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al 1990; a significant association between the minor DRD2 allele, Taq A1 and severe alcoholism. Additionally, the DRD2 rs1800497 is robustly associated with suicidal behaviors. Furthermore, DNA polymorphic alleles underlying substance use disorder (SUD) with multiple substances were mapped via chromatin refolding, revealing that the DRD2 gene and associated polymorphism(s) as the top gene signal. Based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being one determinant of Reward Deficiency Syndrome (RDS) first reported in 1996.

Dopaminergic dysfunction: Role for genetic & epigenetic testing in the new psychiatry.

Reward Deficiency Syndrome (RDS), particularly linked to addictive disorders, costs billions of dollars globally and has resulted in over one million deaths in the United States (US). Illicit substance use has been steadily rising and in 2021 approximately 21.9% (61.2 million) of individuals living in the US aged 12 or older had used illicit drugs in the past year. However, only 1.5% (4.1 million) of these individuals had received any substance use treatment. This increase in use and failure to adequately treat or provide treatment to these individuals resulted in 106,699 overdose deaths in 2021 and increased in 2022. This article presents an alternative non-pharmaceutical treatment approach tied to gene-guided therapy, the subject of many decades of research. The cornerstone of this paradigm shift is the brain reward circuitry, brain stem physiology, and neurotransmitter deficits due to the effects of genetic and epigenetic insults on the interrelated cascade of neurotransmission and the net release of dopamine at the Ventral Tegmental Area -Nucleus Accumbens (VTA-NAc) reward site. The Genetic Addiction Risk Severity (GARS) test and pro-dopamine regulator nutraceutical KB220 were combined to induce "dopamine homeostasis" across the brain reward circuitry. This article aims to encourage four future actionable items: 1) the neurophysiologically accurate designation of, for example, "Hyperdopameism /Hyperdopameism" to replace the blaming nomenclature like alcoholism; 2) encouraging continued research into the nature of dysfunctional brainstem neurotransmitters across the brain reward circuitry; 3) early identification of people at risk for all RDS behaviors as a brain check (cognitive testing); 4) induction of dopamine homeostasis using "precision behavioral management" along with the coupling of GARS and precision Kb220 variants; 5) utilization of promising potential treatments include neuromodulating modalities such as Transmagnetic stimulation (TMS) and Deep Brain Stimulation(DBS), which target different areas of the neural circuitry involved in addiction and even neuroimmune agents like N-acetyl-cysteine.

Personalized repetitive transcranial magnetic stimulation (prtms®) for post-traumatic stress disorder (ptsd) in military combat veterans.

Emerging data suggest that post-traumatic stress disorder (PTSD) arises from disrupted brain default mode network (DMN) activity manifested by dysregulated encephalogram (EEG) alpha oscillations. Hence, we pursued the treatment of combat veterans with PTSD (n = 185) using an expanded form of repetitive transcranial magnetic stimulation (rTMS) termed personalized-rTMS (PrTMS). In this treatment methodology spectral EEG based guidance is used to iteratively optimize symptom resolution via (1) stimulation of multiple motor sensory and frontal cortical sites at reduced power, and (2) adjustments of cortical treatment loci and stimulus frequency during treatment progression based on a proprietary frequency algorithm (PeakLogic, Inc. San Diego) identifying stimulation frequency in the DMN elements of the alpha oscillatory band. Following 4 - 6 weeks of PrTMS® therapy in addition to routine PTSD therapy, veterans exhibited significant clinical improvement accompanied by increased cortical alpha center frequency and alpha oscillatory synchronization. Full resolution of PTSD symptoms was attained in over 50% of patients. These data support DMN involvement in PTSD pathophysiology and suggest a role in therapeutic outcomes. Prospective, sham controlled PrTMS® trials may be warranted to validate our clinical findings and to examine the contribution of DMN targeting for novel preventive, diagnostic, and therapeutic strategies tailored to the unique needs of individual patients with both combat and non-combat PTSD.

Preliminary Observations of Personalized Repetitive Magnetic Stimulation (PrTMS) Guided by EEG Spectra for Concussion.

There are no FDA-approved treatments for the chronic sequelae of concussion. Repetitive magnetic transcranial stimulation (rTMS) has been explored as a therapy but outcomes have been inconsistent. To address this we developed a personalized rTMS (PrTMS) protocol involving continual rTMS stimulus frequency adjustment and progressive activation of multiple cortical sites, guided by spectral electroencephalogram (EEG)-based analyses and psychological questionnaires. We acquired pilot clinical data for 185 symptomatic brain concussion patients who underwent the PrTMS protocol over an approximate 6 week period. The PrTMS protocol used a proprietary EEG spectral frequency algorithm to define an initial stimulation frequency based on an anteriorly graded projection of the measured occipital alpha center peak, which was then used to interpolate and adjust regional stimulation frequency according to weekly EEG spectral acquisitions. PrTMS improved concussion indices and normalized the cortical alpha band center frequency and peak EEG amplitude. This potentially reflected changed neurotransmitter, cognitive, and perceptual status. PrTMS may be a promising treatment choice for patients with persistent concussion symptoms. This clinical observational study was limited in that there was no control group and a number of variables were not recorded, such as time since injury and levels of depression. While the present observations are indeed preliminary and cursory, they may suggest further prospective research on PrTMS in concussion, and exploration of the spectral EEG as a concussion biomarker, with the ultimate goals of confirmation and determining optimal PrTMS treatment parameters.

Association between body mass index and treatment completion in extended-release naltrexone-treated patients with opioid dependence.

Background: Excessive consumption of opioids is associated with impaired metabolic function including increased body mass index (BMI). Opioid antagonist naltrexone (NTX) is an effective treatment for opioid use disorder (OUD) that has the potential to mitigate such metabolic disturbances. Understanding the relationship between treatment adherence and BMI in NTX-treated OUD patients may provide valuable insights into optimizing clinical outcomes. Methods: Patients with opioid dependence were offered up to three monthly injections of extended-release (XR) NTX. Treatment completers (n = 41) were defined as those who had received all three XR-NTX injections, and non-completers (n = 20) as those missing at least one injection. Logistic regression was performed to examine the association between pre-treatment BMI and treatment completion. Results: BMI was positively associated with treatment completion. This association remained significant after adjusting for potentially confounding variables. Conclusion: Our findings suggest that baseline BMI may serve as a potential predictor of XR-NTX treatment adherence in patients with OUD and could help healthcare providers and policy makers alike in developing strategies to improve retention and tailor interventions for specific patient subgroups.

Evidence for the DRD2 Gene as a Determinant of Reward Deficiency Syndrome (RDS).

Since 1990, published addiction psychiatry articles have exceeded 11,495. Several from Blum et al. showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, confirmation has been mixed and controversial. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs 1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al. 1990; a significant association between the minor DRD2 allele, Taq A1 (rs 1800497 C>T) and severe alcoholism. Additionally, the DRD2 rs1800497 is associated with suicide behaviors robustly at P=1.77 × 10-7. Furthermore, DNA polymorphic alleles underlying SUD with multiple substances were mapped via chromatin refolding, revealed that the DRD2 gene and associated polymorphism(s) was the top gene signal (DRD2, P=7.9 × 10-12). Additionally, based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being at least one determinant of Reward Deficiency Syndrome (RDS) first reported in the Royal Society of Medicine journaling 1996.

Psychostimulants for Children: Are We Over or Under Dosing?

An estimated 3% to 10% of school children meet the DSM-V criteria for ADHD (Attention-Deficit/Hyperactivity Disorder), however, to be over-diagnosed, the rate of children inappropriately diagnosed with ADHD (false positives) would have to be larger than the number of children with ADHD who are under-identified and not diagnosed (false negatives). Accordingly, a number of investigators take the position that under-treatment with psychostimulants, especially in children and adolescence, will result in continued ADHD symptomatology including future Substance Use Disorder (SUD). However, other researchers and clinicians believe otherwise and espouse laudable arguments for caution and prolonged methamphetamine treatment. While there is ongoing controversy of the role of genetics and epigenetics linked to ADHD, it seems clear that a number of dopaminergic genes and their risk polymorphisms act as DNA antecedents impacted by epigenetic induced methylation. Our hypothesis and literature review suggest that one possible solution is to embrace non addictive interventions to induce global dopamine homeostasis.

How to Combat the Global Opioid Crisis.

Since 2000 there have been 915,515 people who have died from a drug overdose in the United States (US). This number continues to increase and in 2021 drug overdose deaths reached a record high of 107,622, and opioids specifically were responsible for 80,816 of those deaths. This unprecedented rate of drug overdose deaths is the direct result of increasing rates of illicit drug use in the US. It was estimated that in the US in 2020, approximately 59.3 million individuals had used illicit drugs, 40.3 million had a substance use disorder (SUD), and 2.7 million had opioid use disorder (OUD). Typical treatment for OUD involves an opioid agonist (i.e., buprenorphine or methadone) along with a variety of psychotherapeutic interventions (i.e., motivational interviewing, cognitive-behavioral therapy (CBT), behavioral family counseling, mutual help groups, etc.). In addition to the aforementioned treatment options, there is an urgent need for new therapies and screening methods that are reliable, safe, and effective. Similar to the concept of prediabetes is the novel concept of "preaddiction." Preaddiction is defined as individuals with mild to moderate SUD or those at risk for developing a severe SUD/addiction. Screening for preaddiction could be achieved through genetic testing (i.e., the genetic addiction risk severity (GARS) test) and/or through other neuropsychiatric testing (i.e., Memory (CNSVS), Attention (TOVA), Neuropsychiatric (MCMI-III), Neurological Imaging (qEEG/P300/EP)). The concept of preaddiction, when used in conjunction with standardized and objective diagnostic screening/testing, would halt the rise of SUD and overdoses with early detection and treatment.

Positive Clinical Outcomes for Severe Reported Pain Using Robust Non-Addictive Home Electrotherapy-A Case-Series.

The North American opioid epidemic has resulted in over 800,000 related premature overdose fatalities since 2000, with the United States leading the world in highest opioid deaths per capita. Despite increased federal funding in recent years, intended to address this crisis, opioid overdose mortality has continued to increase. Legally prescribed opioids also chronically induce a problematic reduction in affect. While an ideal analgesic has yet to be developed, some effective multimodal non-opioid pharmacological regimens for acute pain management are being more widely utilized. Some investigators have suggested that a safer and more scientifically sound approach might be to induce "dopamine homeostasis" through non-pharmacological approaches, since opioid use even for acute pain of short duration is now being strongly questioned. There is also increasing evidence suggesting that some more robust forms of electrotherapy could be applied as an effective adjunct to avoid the problems associated with opioids. This 4-patient case-series presents such an approach to treatment of severe pain. All 4 of these chiropractic treatment cases involved a component of knee osteoarthritis, in addition to other reported areas of pain. Each patient engaged in a home recovery strategy using H-Wave® device stimulation (HWDS) to address residual extremity issues following treatment of spinal subluxation and other standard treatments. A simple statistical analysis was conducted to determine the change in pain scores (Visual Analogue Scale) of pre and post electrotherapy treatments, resulting in significant reductions in self-reported pain (p-value = 0.0002). Three of the four patients continued using the home therapy device long-term as determined by a post-analysis questionnaire. This small case-series demonstrated notably positive outcomes, suggesting consideration of home use of HWDS for safe, non-pharmacological and non-addictive treatment of severe pain.

Are We Getting High Cause the Thrill is Gone?

In the USA alone, opioid use disorder (OUD) affects approximately 27 million people. While the number of prescriptions may be declining due to increased CDC guidance and prescriber education, fatalities due to fentanyl-laced street heroin are still rising. Our laboratory has extended the overall concept of both substance and non-substance addictive behaviors, calling it "Reward Deficiency Syndrome (RDS)." Who are its victims, and how do we get this unwanted disorder? Is RDS caused by genes (Nature), environment (Neuro-epigenetics, Nurture), or both? Recent research identifies resting-state functional connectivity in the brain reward circuitry as a crucial factor. Analogously, it is of importance to acknowledge that the cumulative discharge of dopamine, governed by the nucleus accumbens (NAc) and modulated by an array of additional neurotransmitters, constitutes a cornerstone of an individual's overall well-being. Neuroimaging reveals that high-risk individuals exhibit a blunted response to stimuli, potentially due to DNA polymorphisms or epigenetic alterations. This discovery has given rise to the idea of a diminished 'thrill,' though we must consider whether this 'thrill' may have been absent from birth due to high-risk genetic predispositions for addiction. This article reviews this issue and suggests the general concept of the importance of "induction of dopamine homeostasis." We suggest coupling a validated genetic assessment (e.g., GARS) with pro-dopamine regulation (KB220) as one possible frontline modality in place of prescribing potent addictive opioids for OUD except for short time harm reduction. Could gene editing offer a 'cure' for this undesirable genetic modification at birth, influenced by the environment and carried over generations, leading to impaired dopamine and other neurotransmitter imbalances, as seen in RDS? Through dedicated global scientific exploration, we hope for a future where individuals are liberated from pain and disease, achieving an optimal state of well-being akin to the proverbial 'Garden of Eden'.