Background Elevated resting heart rate (RHR) is known to be associated with reduced survival but inconsistencies remain, including lack of significance in most studies of healthy women, lack of independence from systolic blood pressure (SBP) in some, and the suggestion that RHR is merely functioning as a marker of physical inactivity or other comorbidities. We aimed to clarify these inconsistencies. Methods We analyzed the effect of RHR on end points in the National FINRISK Study; a representative, prospective study using Cox proportional hazards model. Ten-thousand five-hundred nineteen men and 11,334 women were included, excluding those with preexisting coronary heart disease, angina, heart failure, or on antihypertensive therapy. Results The hazard ratios for cardiovascular disease (CVD) mortality for each 15 beats/min increase in RHR were 1.24 (1.11-1.40) in men and 1.32 (1.08-1.60) in women, adjusted for age, gender, total cholesterol, physical activity (categorical), SBP, body mass index, and high-density lipoprotein cholesterol. This relationship remained significant after exclusion of those with comorbidities and events occurring within first 2 years of observation. Relationship with coronary mortality was stronger and with total mortality was slightly weaker. Inclusion of nonfatal end points weakened the relationship. Conclusions A strong, graded, independent relationship between RHR and incident CVD was demonstrated. This was consistent in healthy men and women. We have clarified that the relationship is independent of SBP and that the temporal sequence would be compatible with a causal relationship. New findings include independence from both a validated measure of physical activity and comorbidities and the demonstration of a stronger effect for fatal than nonfatal events, supporting increased arrhythmogenicity of one of the mechanisms.

Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women

A partially purified extract from American ginseng has been shown to have anticonvulsant activity. To identify the active components in this extract, the activities of the individual ginsenosides (Rb(1), Rb(3) and Rd), mixtures of the purified ginsenosides and a newly prepared Rb fraction were determined. One hour after treatment with vehicle or one of the ginseng products, seizures were induced in adult, Sprague-Dawley rats with kainic acid (KA, 10 mg/kg), pilocarpine (300 mg/kg) or pentylenetetrazole (PTZ, 50mg/kg i.p. or 90 mg/kg s.c.). Time to seizure onset, duration of seizure activity and seizure severity were determined. Weight change and neuronal damage were assessed 24h after administration of KA or pilocarpine. Mixtures of purified Rb(1), Rb(3) with or without Rd had significant anticonvulsant effects in all three models of acutely induced seizures demonstrating that the ginsenosides are the active components in the Rb extract. The individual ginsenosides significantly increased the latency to onset of seizures after administration of kainic acid. Since no one individual ginsenoside accounted for the majority of the activity of the Rb extract, the results suggest that the most effective anticonvulsant product is a combination of ginsenosides. In addition, all of the ginseng products had significant neuroprotective activity beyond the reduction in seizure severity and duration.

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Anticonvulsant and Neuroprotective Effects of Ginsenosides in Rats (Abstract)

After nearly a century of intensive research and clinical investigation, the pathophysiology of psychiatric disorders remains an enigma. Short of a clear understanding of how psychiatric symptoms are produced, the various cognitive, emotional, and behavior patterns that characterize psychiatric disorders continue to be grouped into syndromes and treated accordingly. The weakness of this approach is that the treatment is administered without a clear understanding of what pathological process is being treated. Moreover, the symptoms of most psychiatric disorders are frequently changing and melding into one another. This leads to diagnostic confusion, medication stacking, and poor treatment outcomes, all of which erode patient trust and perpetuate the stigma of mental illness. In this seminal report, a new hypothesis on the pathophysiology of psychiatric disorders will be presented based on multidisciplinary evidence that nearly all psychiatric disorders and their functional comorbidities are rooted in a single, shared, neurophysiological abnormality. The report will then trace that abnormality to its molecular roots and introduce a new paradigm through which the many faces of mental illness can be understood and uniformly treated. The Multi-Circuit Neuronal Hyperexcitability hypothesis of psychiatric disorders posits that an inherent hyperexcitability of the neurological system is at the root of mental illness and provides a precise, functionally-specific framework that eliminates diagnostic confusion, informs a unified treatment approach, and helps remove the long-held stigma of mental illness.

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The Multi-Circuit Neuronal Hyperexcitability Hypothesis of Psychiatric Disorders

Capric acid (also known as decanoic acid or C10) is one of the fatty acids in the medium‐chain triglycerides (MCTs) commonly found in dietary fats. Although dietary treatment with MCTs is recently of great interest for the potential therapeutic effects on neuropsychiatric disorders, the effects of oral administration of C10 on behavior remain to be examined. This study investigated acute and chronic effects of oral administration of C10 on locomotor activity and anxiety‐like and depression‐related behaviors in adult male C57BL/6J mice.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/npr2.12226

Acute and chronic effects of oral administration of a medium‐chain fatty acid, capric acid, on locomotor activity and anxiety‐like and depression‐related behaviors in adult male C57BL/6J mice

It has now been established that persons with higher resting heart rates are at increased risk of morbidity and mortality from a plethora of mental and physical illnesses. However, the mechanism underlying the predictive value of this core vital sign remains obscure. This seminal report will integrate clinical, neuropsychological, physiological, and genetic evidence to assert that an inherent hyperexcitability of the neurological system is at the heart of the connection between resting heart rate and disease. Hypothetically, neuronal hyperexcitability can cause multiple circuits in the brain to overfire, including cognitive circuits, limbic circuits, and autonomic circuits, thereby dysregulating the associated systems of the body and allowing the aberration to be detected through standard vital signs and related measures of autonomic activity. Because the cognitive-emotional system is exquisitely sensitive to neuronal excitation, the aberration could also manifest as psychiatric symptomatology, thus suggesting that psychiatric symptoms may be the first subjective markers of the abnormality. Based on the well-recognized link between mental illness, autonomic dysregulation, and systemic disease together with mounting evidence that the related illnesses are associated with gene variants whose protein products fail to adequately regulate the firing of neurons, the vulnerability trait could aptly be called Familial Limbic Autonomic System Hyperexcitability or “FLASH.” Because the trait appears to be so common, its effects so pervasive, and its expression so modifiable, its identification is of critical importance to every medical specialty. FLASH could give clinicians the first comprehensive biological target through which to treat and prevent a plethora of mental, emotional, and physical illnesses.

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FLASH Syndrome: Tapping into the Root of Chronic Illness

Despite the increasing burden of mental illness, social stigma and fears that psychological and emotional problems are a sign of character weakness prevent most sufferers from seeking treatment. These barriers are reinforced by diagnostic ambiguity, frequent drug side effects, variable treatment success, and a lack of clarity about the cause of mental illness. Much more progress has been made with epilepsy, a closely related group of disorders for which the pathophysiology is better understood. Although psychiatric disorders and seizure disorders are known to be distinctly different conditions, they have many shared features including their disruptive effects on mentation, their migratory nature, and their responsiveness to anticonvulsant drugs. In addition, a comparative analysis of the two disorder-types strongly suggests that they have shared mechanisms of symptom production, symptom progression, and symptom prevention. In this side-by-side comparison of the two disorder-types, I will discuss how the electrophysiological patterns that underlie seizure initiation and migration help explain how psychiatric symptoms develop and morph into one another, thus providing important insights into the pathophysiology of mental illness and potentially serving as a guide to the development of more effective treatments.

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Electrophysiology of Seizure Disorders May Hold Key to the Pathophysiology of Psychiatric Disorders

Despite the increasing burden of mental illness, social stigma and fears about the potential mind-altering effects of psychotropic drugs prevent most persons from seeking treatment. The problem is compounded by the high rate of diagnostic uncertainty in psychiatry and psychotropic drug labels that can be as confusing as the diagnosis. The terms “anticonvulsant” and “antipsychotic” often have little to do with what is being treated, and the replacement term “mood stabilizer” is inadequate because many patients for whom mood stabilizers are prescribed do not experience any significant mood instability. This calls for a more appropriate label for these psychotropic drugs. Anticonvulsants and antipsychotics have neuroregulatory effects, and converging lines of evidence suggest that most psychiatric disorders are rooted in an inherent hyperexcitability of the neurological system—the neurons won’t shut off. Based on these observations, I propose that the terms anticonvulsant, antipsychotic, and mood stabilizer be replaced with the more pharmacologically and pathophysiologically-related term “NEUROREGULATOR.” The adoption of this descriptive, user-friendly term by prescribing clinicians and dispensing pharmacists would help avoid patient confusion and improve medication compliance by helping patients conceptualize what these drugs do in the brain and how they might be working to relieve symptoms.

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Michael Raymond Binder

Papers

The Multi-Circuit Neuronal Hyperexcitability Hypothesis of Psychiatric Disorders

FLASH Syndrome: Tapping into the Root of Chronic Illness

Electrophysiology of Seizure Disorders May Hold Key to the Pathophysiology of Psychiatric Disorders

Introducing the Term “Neuroregulator” in Psychiatry