Bone spurs, free calcium and Dementia

Free calcium can be of the factors that can cause Alzheimer’s diseases and Dementia. In the presence of free or unbound calcium, the absorbable calcium needed by 90% of our cells cannot work to heal our cells and be absorbed by our cells as they are blocked by free calcium.


Bone Spurs – OAWHealth

Calcium, magnesium, Vitamin D3 and K2 and Omega-3s cut risk of cancer

Eat eggs, fish, pickled veggies and wholefoods from cooked/raw veggies and fruits to promote cell growth. These foods are rich in Vitamin D3 and K2.
Vitamin D3 and K2 ensures calcium in bones and not in other cells.

Cancer risks are prevalent when consuming processed meat and chemicals/drugs/medications rich in un-absorbed free calcium (CA++).

Fish Oil. Calcium, magnesium (Ca:Mg in 60:40 ratio), Vitamin D3 and K2 from whole foods and Omega-3s cut risk of metabolic syndrome and cancer. These nutrients also help improve components of metabolic syndrome and reduce risk for cardiovascular disease.

calcium 2 pluscauses of cell damage

Bioactive Compounds and Cancer – Page 449 – Google Books Result

John A. Milner, ‎Donato F. Romagnolo – 2010 – ‎Medical

Experiments show that unabsorbed calcium in the lumen of the colon can prevent the adverse effects of bile acids and free fatty acids on the epithelial cells. … The bile and fatty acids have been shown to have irritating effects and to stimulate cell proliferation, thereby promoting a variety of cell damagingeffects in the colon.

Overview of Calcium – Dietary Reference Intakes for Calcium and …

by AC Ross – ‎2011 – ‎Cited by 1 – ‎Related articles

Calcium is excreted through the feces as unabsorbed intestinal calcium and is shed in mucosal cellsand secretions including saliva, gastric juices, pancreatic juice, and bile. Endogenous fecal calciumlosses are approximately 2.1 mg/kg per day in adults and about 1.4 mg/kg per day in children (Abrams et al., 1991).

Handbook of Dairy Foods and Nutrition, Second Edition

Parathyroid hormone and 1,25-dihydroxy vitamin D are thought to increase blood pressure through increases in intracellular free calcium and in muscle tone.” These observations serve to … This increases the likelihood that the cells lining the colon will be damaged, proliferate, and progress toward cancer. Epidemiologic …

API Textbook of Medicine (Volume I & II)

YP Munjal – 2015 – ‎Medical

Iron, folic acid and calcium are preferentially absorbed in the duodenum and proximal jejunum, which are also the sites maximally affected in … due to eosinophil infiltration Mucosal damage due to bacteria-laden macrophages Epithelial cell infection with or without mucosal invasion leading to damage to villuscells, often …

Plant Physiological Ecology: Field methods and instrumentation

R. Pearcey, ‎H.A. Mooney, ‎P.W. Rundel – 2012 – ‎Science

This equilibration period also serves to rinse any unabsorbed ions out of the free space between rootcells. Next, roots are transferred for a short time (e.g. 10–20 min) to a radioactively labeled solution (containing calcium) of the nutrient being studied, then rinsed in a … First, does removing roots from soil damage them?

Calcification and Its Treatment with Magnesium and Sodium Thiosulfate…/calcification-and-its-treatment-with-magnesium-and-sodium-thiosulfat…

Dec 8, 2009 – Magnesium acts as an antioxidant against free radical damage of the mitochondria. Magnesium has been called nature’s “calcium channel blocker” because of its ability to prevent coronary artery spasm, arrhythmias, and to reduce blood pressure. “Calcium enters the cells of the heart by way of calcium …

Calcium1 | Basicmedical Key

Jul 27, 2016 – For that reason, cells must keep free calcium ion concentrations in the cytosol at extremely low levels, typically on the order of 100 nmol. This is 10,000-fold lower than the … of proteins to bind calcium. Calcification in tissues other than bones and teeth is generally a sign of tissue damageand cell death.

Chapter 11. Calcium

In the cellular compartment the total calcium concentration is comparable with that in the ECF, but thefree calcium concentration is lower by several orders of …. The unabsorbed component appears in the faeces together with the unabsorbed component of digestive juice calcium known as endogenous faecal calcium. Thus …


Whenever an electron is torn from an atom a little spark is produced that can damage cell membranes. It’s called free radical damage and can be seen under a microscope in live blood cell analysis. … Significant amount of unabsorbed calcium left in the body will interact with other inorganic compounds to form stones.

The Vitamin Combination That May Reduce Your Osteoporosis

May 16, 2012 – When you’re supplementing with calcium and vitamin D3, you must also take vitamin K2 to reduce your osteoporosis risk.

The Delicate Dance Between Vitamins D and K – Dr. Mercola

Mar 26, 2011 – According to recent findings, the benefits of vitamin D, in terms of bone strength and cardiovascular health, are greatly enhanced when combined with vitamin K. Vitamin D improves your bone health by helping you absorb calcium. However, it is vitamin K that directs calcium to your skeleton, to prevent it …

Vitamin D supplements: Are yours helping or hurting you?

Almost every expert recommends it. And everyone’s taking it. But what if we’ve been using it wrong? What if our vitamin D supplements aren’t really helping us at all? If your car’s oil light went on once a week…and every time you checked the oil, it was running low…what would you do? Shrug? Top up the oil tank (again)? …

Vitamins K1 and K2: The Emerging Group of Vitamins Required for …

by GK Schwalfenberg – ‎2017 – ‎Cited by 2 – ‎Related articles

Jun 18, 2017 – Vitamin Dcalcium, and vitamin K2 supplementation reduces undercarboxylated osteocalcin and improves lumbar bone mineral density [18]. … subjects free from myocardial infarction at baseline followed up for 7 years, the odds ratio of the highest tertile intake of menaquinone (vitaminK2) compared to the …

Proper Calcium Use: Vitamin K2 as a Promoter of Bone and …

by K Maresz – ‎2015 – ‎Cited by 18 – ‎Related articles

An increased intake of vitamin K2 could be a means of lowering calcium-associated health risks. … Women’s Health Initiative showed that those women taking 1000 mg/day in the form of calciumsupplements, with or without the addition of 400 IU/day of vitamin D, increased their risk of cardiovascular events by 15% to 22%, …

The use of calcium and vitamin D in the management of osteoporosis

by JA Sunyecz – ‎2008 – ‎Cited by 117 – ‎Related articles

Osteoporosis poses a significant public health issue, causing significant morbidity and mortality.Calcium and vitamin D utilization in the optimization of bone health is often overlooked by patients and health care providers. In addition, the optimal standard of care for osteoporosis should encompass adequate calcium and …

3 Major Benefits of Vitamin K2 For Your Heart and Bones – Dr. Jockers

New studies are looking at another subtype called vitamin K2 and its effect in synergy with Vitamin D3on various health factors. Vitamin K2 appears to be a very important nutrient … Inadequate K2 inhibits osteocalcin production and reduces calcium flow into bone tissue. This leads to reduced bone mass and a weakened …

Prevent Heart Disease with Vitamins A, D3, and K2 : Terry Talks Nutrition

And that lack of knowledge just might be slowly killing them. Vitamins A, D3, and K2 work as partners to: • Keep calcium in your bones and out of your arteries. • Prevent dangerous blood clots, heart attacks, and high blood pressure. • Help keep arteries flexible and strong. • Reduce inflammatory markers in the bloodstream.

Vitamin K2 and Atherosclerosis | LIfe Extension

In addition, subjects taking the combination of vitamins K2 and D3 showed a reduction in carotid artery calcification score in all patients except those with the highest scores at baseline.6 This indicates thatcalcium was staying in the bones, where it belongs, and out of the arteries. These results clearly indicated that vitamin …

Vitamin Code® RAW Calcium™ | Garden of Life

RAW Whole Food Plant Calcium Formula with Magnesium, Vitamins D3 & K2 (MK-7); Free from Crushed Rock, Limestone, Chalk and Animal Bones … ††Regular exercise and a healthy diet with enough calciumand vitamin D helps you maintain good bone health and may reduce the risk of osteoporosis later in life.


Infected water from animal manure, prion disease and Parkinson

Prion diseases and their transmission properties

Diseases caused by prions
Affected animal(s) Disease
sheepgoat Scrapie[43]
cattle Bovine spongiform encephalopathy (BSE), mad cow disease[43]
mink[43] Transmissible mink encephalopathy (TME)
white-tailed deer, elk, mule deer, moose[43] Chronic wasting disease (CWD)
cat[43] Feline spongiform encephalopathy (FSE)
nyalaoryxgreater kudu[43] Exotic ungulate encephalopathy (EUE)
ostrich[44] Spongiform encephalopathy
(Has not been shown to be transmissible.)
human Creutzfeldt–Jakob disease (CJD)[43]
Iatrogenic Creutzfeldt–Jakob disease (iCJD)
Variant Creutzfeldt–Jakob disease (vCJD)
Familial Creutzfeldt–Jakob disease (fCJD)
Sporadic Creutzfeldt–Jakob disease (sCJD)
Gerstmann–Sträussler–Scheinker syndrome (GSS)[43]
Fatal familial insomnia (FFI)[45]
Familial spongiform encephalopathy[46]
Multiple System Atrophy (MSA): Not a TSE and is not by typical prions Prp/PrPSc but by a misfolded α-Synuclein.[47]

Until 2015 all known mammalian prion diseases were considered to be caused by the prion protein, PrP; in 2015 Multiple System Atrophy was found to be likely caused by a new prion, the misfolded form of a protein called alpha-synuclein.[4]The endogenous, properly folded form of the prion protein is denoted PrPC (for Common or Cellular), whereas the disease-linked, misfolded form is denoted PrPSc (for Scrapie), after one of the diseases first linked to prions and neurodegeneration.)[22][48] The precise structure of the prion is not known, though they can be formed by combining PrPC, polyadenylic acid, and lipids in a protein misfolding cyclic amplification (PMCA) reaction.[49] Proteins showing prion-type behavior are also found in some fungi, which has been useful in helping to understand mammalian prions. Fungal prions do not appear to cause disease in their hosts.[50]

Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloid, which disrupt the normal tissue structure. This disruption is characterized by “holes” in the tissue with resultant spongy architecture due to the vacuole formation in the neurons.[51]Other histological changes include astrogliosis and the absence of an inflammatory reaction.[52] While the incubation period for prion diseases is relatively long (5 to 20 years), once symptoms appear the disease progresses rapidly, leading to brain damage and death.[53] Neurodegenerative symptoms can include convulsionsdementiaataxia (balance and coordination dysfunction), and behavioural or personality changes.

All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal.[54] However, a vaccine developed in mice may provide insight into providing a vaccine to resist prion infections in humans.[55] Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production – thus theoretically making them immune to BSE,[56] building on research indicating that mice lacking normally occurring prion protein are resistant to infection by scrapie prion protein.[57] In 2013, a study revealed that 1 in 2,000 people in the United Kingdom might harbour the infectious prion protein that causes vCJD.[58]

Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.[59] Due to small differences in PrP between different species it is unusual for a prion disease to transmit from one species to another. The human prion disease variant Creutzfeldt–Jakob disease, however, is believed to be caused by a prion that typically infects cattle, causing Bovine spongiform encephalopathy and is transmitted through infected meat.[60]


It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.[61] It is often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One idea, the “Protein X” hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrPC to PrPSc by bringing a molecule of each of the two together into a complex.[62]

Current research suggests that the primary method of infection in animals is through ingestion. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.[63]

A University of California research team, led by Nobel Prize winner Stanley Prusiner, has provided evidence for the theory that infection can occur from prions in manure.[64] And, since manure is present in many areas surrounding water reservoirs, as well as used on many crop fields, it raises the possibility of widespread transmission. It was reported in January 2011 that researchers had discovered prions spreading through airborne transmission on aerosol particles, in an animal testingexperiment focusing on scrapie infection in laboratory mice.[65] Preliminary evidence supporting the notion that prions can be transmitted through use of urine-derived human menopausal gonadotropin, administered for the treatment of infertility, was published in 2011.[66]

Prions in plants

In 2015, researchers at The University of Texas Health Science Center at Houston found that plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with chronic wasting disease (CWD) was buried, the hamsters became ill with CWD, suggesting that prions can bind to plants, which then take them up into the leaf and stem structure, where they can be eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment.[67][68]


Infectious particles possessing nucleic acid are dependent upon it to direct their continued replication. Prions, however, are infectious by their effect on normal versions of the protein. Sterilizing prions, therefore, requires the denaturation of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal proteins. In general, prions are quite resistant to proteases, heat, ionizing radiation, and formaldehyde treatments,[69] although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein hydrolysis or reduction or destruction of protein tertiary structure. Examples include sodium hypochloritesodium hydroxide, and strongly acidic detergents such as LpH.[70] 134 °C (274 °F) for 18 minutes in a pressurized steam autoclave has been found to be somewhat effective in deactivating the agent of disease.[71][72] Ozone sterilization is currently being studied as a potential method for prion denaturation and deactivation.[73] Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.[74]

The World Health Organization recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:

  1. Immerse in 1N sodium hydroxide and place in a gravity-displacement autoclave at 121 °C for 30 minutes; clean; rinse in water; and then perform routine sterilization processes.
  2. Immerse in 1N sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; transfer instruments to water; heat in a gravity-displacement autoclave at 121 °C for 1 hour; clean; and then perform routine sterilization processes.
  3. Immerse in 1N sodium hydroxide or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121 °C) or in a porous-load (134 °C) autoclave for 1 hour; clean; and then perform routine sterilization processes.[75]

Prion-like domains

While PrP is considered the only mammalian prion, prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS, known as Motor Neurone Disease outside the US), frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), Alzheimer’s disease, and Huntington’s disease,[76] as well as some forms of Systemic Amyloidosis including AA (Secondary) Amyloidosis that develops in humans and animals with inflammatory and infectious diseases such as TuberculosisCrohn’s diseaseRheumatoid arthritis, and HIV AIDSAA amyloidosis, like prion disease, may be transmissible.[77] This has given rise to the ‘prion paradigm’, where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins.[78]

The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP.[76] These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.[5]

Bioinformatic screens have predicted that over 250 human proteins contain prion-like domains (PrLD). These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins. As in yeast, proteins involved in gene expression and RNA binding seem to be particularly enriched in PrLD’s, compared to other classes of protein. In particular, 29 of the known 210 proteins with an RNA recognition motif also have a putative prion domain. Meanwhile, several of these RNA-binding proteins have been independently identified as pathogenic in cases of ALS, FTLD-U, Alzheimer’s disease, and Huntington’s disease.[79]

Role in neurodegenerative disease

The pathogenicity of prions and proteins with prion-like domains arises from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of amyloid fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates.[79] While this does not necessarily imply a causal relationship between amyloid and degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.

Specifically, aggregation of TDP-43, an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes coding for these proteins have been identified in familial cases of ALS/MND. These mutations promote the misfolding of the proteins into a prion-like conformation. The misfolded form of TDP-43 forms cytoplasmic inclusions in afflicted neurons, and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while pathological mutations in TDP-43 have been found to increase this propensity to misfold, explaining the presence of these mutations in familial cases of ALS/MND. As in yeast, the prion-like domain of TDP-43 has been shown to be both necessary and sufficient for protein misfolding and aggregation.[76]

Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.[80]


Fungal proteins exhibiting templated conformational change were discovered in the yeast Saccharomyces cerevisiae by Reed Wickner in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed yeast prions. Subsequent to this, a prion has also been found in the fungus Podospora anserina. These prions behave similarly to PrP, but, in general, are nontoxic to their hosts. Susan Lindquist‘s group at the Whitehead Institute has argued some of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state.[81] There is mounting evidence that fungal proteins have evolved specific functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments.[82]

As of 2012, there are eight known prion proteins in fungi, seven in Saccharomyces cerevisiae (Sup35, Rnq1, Ure2, Swi1, Mot3, Cyc8, and Mod5) and one in Podospora anserina (HET-s).[contradictory] The article that reported the discovery of a prion form, the Mca1 protein, was retracted due to the fact that the data could not be reproduced.[83] Notably, most of the fungal prions are based on glutamine/asparagine-rich sequences, with the exception of HET-s and Mod5.

Research into fungal prions has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form in vitro, and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions, though fungal prions appear distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion domains may vary between species—e.g., characteristic fungal prion domains are not found in mammalian prions.

Connie’s comments: I have a client with Parkinson, Dementia and Lew Body diseases who likes to drink raw milk. Do drink pasteurized milk and milk products. I do not drink milk.

Match Dementia and Alzheimer studies

Alzheimer's & Related Dementia updates from the National Institute on Aging, the lead US government agency for Alzheimer's research

Interested in volunteering for research on Alzheimer’s, related dementias, and cognitive health? Search for clinical trials and studies near you with NIA’s clinical trials finder.

Below are the newest listings. Click on the trial name for details, including contact information.


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Melatonin counteract estrogen’s tendency to stimulate cell growth

Oct 10, 2013  Melatonin is a powerful antioxidant that helps protect you against heart disease, diabetes, migraine headaches, Alzheimer’s disease, and cancer. … When this hormone latches onto a breast cancer cell, it has been found to counteract estrogen’s tendency to stimulate cell growth. In fact, melatonin has a ……/alzheimers-dementia-treatment.aspx
Jun 13, 2013  A study reveals that vitamins B6, B12, and folic acid, as well as cinnamon, may help slow the progression of Alzheimer’s disease.
Sep 12, 2013  When used at extreme levels, copper can be very toxic and can increase your risk of Alzheimer’s disease.
Nov 8, 2008  Eating the wrong diet could increase your risk of developing Alzheimer’s disease. Scientists have found a link between the degenerative brain disease and raised levels of an omega-6 fatty acid. Researchers compared the brains of mice bred with a condition that mimics Alzheimer’s to those of normal mice.…/estrogen-levels-and-cognitive-decline.aspx
Jan 2, 2008  Another nail in the coffin for postmenopausal estrogen therapy. Last year, NEJM published a study that suggested that estrogen helps prevent Alzheimers disease in women. This information provided another false justification for traditional medicine to prescribe it. If you have not purchased Dr. Lee’s book, …
Apr 27, 2017  Mounting research also suggests Alzheimer’s disease is intricately connected to insulin resistance; even mild elevation of blood sugar is associated with an elevated risk for dementia. Diabetes and heart disease are also known to elevate your risk, and both are rooted in insulin resistance.
Feb 11, 2010  Copper pipes have no place in your home. Learn why installing special filters can help you avoid heart disease, Alzheimer’s disease and diabetes.
Aug 4, 2013  Not only heart disease and stroke, but I’m thinking cancer, Alzheimer’s, multiple sclerosis, or any illness that requires good oxygenation to the tissues. … One of the mechanisms that causes this increased risk is that synthetic estrogens and progesterones increase blood viscosity, i.e., they decrease the zeta …
Feb 16, 2010  Alzheimer’s disease is not the only reason to ditch your aluminum-containing antiperspirant and deodorant, as this metal has also been linked to cancer. A 2006 study found that aluminum salts can mimic the hormone estrogen, and chemicals that imitate that hormone are known to increase breast cancer …
Nov 6, 2014  A six-year study reveals that those with vitamin D deficiency are more than twice as likely to develop dementia and Alzheimer’s disease.

Low Frequency Brain Stimulation Improves Cognition in Parkinson’s Patients

Low Frequency Brain Stimulation Improves Cognition in Parkinson’s Patients

Summary: Researchers report low frequency deep brain stimulation can help to improve cognitive function in people with Parkinson’s disease.

Source: University of Iowa Health Care.

A multidisciplinary neuroscience study using rare, intraoperative brain recordings suggests that low frequency stimulation of a deep brain region may be able to improve cognitive function in patients with Parkinson’s disease (PD). The study findings, published Nov. 28 online in the journal Brain, also hint at the broader potential of brain stimulation for treating other cognitive diseases.

The new work by neurologists and neurosurgeons with the Iowa Neuroscience Institute at the University of Iowa provides the first direct evidence of a connection in the human brain between the thinking region of the brain (the frontal cortex) and a deeper structure called the subthalamic nucleus (STN) that is involved in controlling movement. The study also shows that stimulation of the STN at low frequencies improves the performance of PD patients on a simple cognitive task that is usually disrupted by PD.

“It’s not very often that you identify a new connection in the human brain,” says Nandakumar Narayanan, MD, PhD, UI assistant professor of neurology in the UI Carver College of Medicine and senior study author. “The existence of this hyperdirect pathway from the prefrontal cortex to the STN has been bandied about for around a decade, but this is the first time we’ve experimentally shown that it exists and functions in people.

“We were also able to show that if we stimulate the STN, we change the frontal cortical activity and we think it’s by this pathway,” he adds. “And if we stimulate the STN and change cortical activity, we can actually change behavior in a beneficial way, improving the patients’ cognitive performance.”

Parkinson’s disease is a progressive neurodegenerative condition that affects about one million people in the United States. Deep brain stimulation of the STN at high frequencies is already approved to treat movement problems in some patients with PD. In addition to causing movement problems, however, PD also affects thinking. The new findings raise the possibility that STN deep brain stimulation at a different (low) frequency might also improve cognitive symptoms in PD, and possibly even in other neurologic and psychiatric diseases.

Listening in on the brain

The team was able to map the STN-cortex connection by “listening in” on brain activity during surgeries to implant deep brain stimulation (DBS) electrodes in patients with PD.

UI neurosurgeon Jeremy Greenlee, MD, conducts more than 30 such surgeries every year and his expertise was vital to the mapping experiment. Using specialized recording electrodes placed inside the patients’ brains, Greenlee listens in on brain activity in order to accurately place the DBS device. Those electrodes also allow direct recording of brain activity for experimental purposes in patients who are awake during the procedure without adding any risk. This kind of intraoperative recordings is not very common, but Greenlee and his UI colleagues have a long history of expertise in the technique.

During the surgery, the patients did a simple cognitive task as a way of stimulating one part of the brain while recording electrical activity from other parts that are connected. Listening to the neural activity during the task allowed the team to map the connection.

“We were able to evoke a response to show the functional connection,” Greenlee explains. “The very fast response suggests a single, direct synaptic connection – that is what hyperdirect means.”

Stimulation improves cognitive performance

Having established the existence of the hyperdirect connection, the researchers next investigated the effect of low frequency STN stimulation on cognitive abilities. Narayanan’s team uses a very simple thinking task–accurately estimating the passage of a short interval of time–to study cognitive impairment in PD patients and animal models of PD.

During post-surgery follow up visits, the researchers had the patients do the interval timing task with the DBS stimulator set to one of three settings: high frequency (normal for controlling movement), no stimulation, or a low frequency setting of 4 Hz. Only the 4 Hz stimulation improved the patients’ performance on the timing test.

Previous research from Narayanan’s labs has shown that people with PD and rodent models of the disease are missing a specific brain wave known as the delta wave in their frontal cortex while they are doing the timing task. The delta wave cycles at a frequency of about 4 Hz.

“When we stimulate the STN at 4 Hz, the delta wave is restored in the mid frontal cortex,” Narayanan says. “By stimulating the STN we can rescue cortical activity (which is disrupted in PD) and we can improve cognitive behavior.”

The researchers think that the frequencies are like communication channels between networks. If two networks are working together at the same frequency, that might be a unique way that the networks interact and information is transmitted.

“The fact that we are able to test a lot of our ideas (that come from the rodent studies) about how the neural networks work in awake behaving humans, is something I never dreamed I’d be able to do, but it enables us to ask questions that might actually help a lot of people,” Narayanan says.

“It is exciting to potentially have a way to improve cognition that could be life changing for patients,” Greenlee adds.


In addition to Narayanan and Greenlee, the UI study team included Ryan Kelley, Oliver Flouty, Eric Emmons, Youngcho Kim, Johnathan Kingyon, Jan Wessel, and Hiroyuki Oya.

Funding: The study was funded in part by a grant from the National Institute of Neurological Disorders and Stroke (NINDS) to Narayanan (R01 NS100849).

Source: Jennifer Brown – University of Iowa Health Care
Publisher: Organized by
Image Source: image is credited to Narayanan Lab, University of Iowa.
Original Research: Abstract for “A human prefrontal-subthalamic circuit for cognitive control” by Ryan Kelley, Oliver Flouty, Eric B Emmons, Youngcho Kim, Johnathan Kingyon, Jan R Wessel, Hiroyuki Oya, Jeremy D Greenlee, and Nandakumar S Narayanan in Brain. Published online November 28 2017 doi:10.1093/brain/awx300

University of Iowa Health Care “Low Frequency Brain Stimulation Improves Cognition in Parkinson’s Patients.” NeuroscienceNews. NeuroscienceNews, 28 November 2017.


A human prefrontal-subthalamic circuit for cognitive control

The subthalamic nucleus is a key site controlling motor function in humans. Deep brain stimulation of the subthalamic nucleus can improve movements in patients with Parkinson’s disease; however, for unclear reasons, it can also have cognitive effects. Here, we show that the human subthalamic nucleus is monosynaptically connected with cognitive brain areas such as the prefrontal cortex. Single neurons and field potentials in the subthalamic nucleus are modulated during cognitive processing and are coherent with 4-Hz oscillations in medial prefrontal cortex. These data predict that low-frequency deep brain stimulation may alleviate cognitive deficits in Parkinson’s disease patients. In line with this idea, we found that novel 4-Hz deep brain stimulation of the subthalamic nucleus improved cognitive performance. These data support a role for the human hyperdirect pathway in cognitive control, which could have relevance for brain-stimulation therapies aimed at cognitive symptoms of human brain disease.

“A human prefrontal-subthalamic circuit for cognitive control” by Ryan Kelley, Oliver Flouty, Eric B Emmons, Youngcho Kim, Johnathan Kingyon, Jan R Wessel, Hiroyuki Oya, Jeremy D Greenlee, and Nandakumar S Narayanan in Brain. Published online November 28 2017 doi:10.1093/brain/awx300

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