TED Talk Tuesday - Apollo Robbins

I love magic.  The acting, the misdirection.  All of it playing on the frailty of our senses and perceptions.  Magic and neuroscience go together.  Apollo Robbins is a magician on the show Brain Games.  He came to TED to talk about the art of misdirection.  People are not as perceptive as they believe themselves to be.  A little feint in one direction distracts us from the real action the other way.  Magicians master this skill and teach us a lot about our ability to perceive the world around us.

Intranasal-to-Brain Drug Delivery - A Review

Neurodegenerative diseases impact the lives of patients and their families.  As the brain slowly deteriorates, patients lose control of their bodies, thoughts, and ultimately succumb to the disease.  An aging population generates a higher incidence of Alzheimer’s disease, Parkinson’s disease, and other neurological disorders.  Concurrently, the rise of Autism Spectrum disorders has become an interesting area of potential research.  As of now, neurological medicines only treat the symptoms and rarely address the root cause – dying or misfiring neurons.  Getting drugs into the brain has proven a difficult task because of the impermeable blood-brain barrier (BBB).  Newly developed tools circumvent the BBB by going through the nose.  Intranasal-to-brain (INB) delivery provides a hopeful avenue to slow, treat, and prevent the progression of the diseases of the central nervous system (CNS) with greater efficacy, less invasion and reduced toxicity.  Medical professionals should recognize the difficulty of delivering drug to the brain and the need for easier, direct route such as nasal administration.

The Blood Brain Barrier

As the controlling organ of the body, the brain is locked behind two major defense mechanisms.  The cranium provides a hard case that limits access to only highly invasive techniques that inject drugs through the skull directly into the parenchyma or cerebrospinal fluid.  The BBB internally protects the CNS from potentially damaging foreign chemicals travelling through the bloodstream.  Toxins and potential medications are blocked from neurons by several mechanisms.  Despite the rich network of blood vessels reaching all areas of the brain, the endothelial lining of the capillaries are fused together with extremely tight junctions preventing the passage of many molecules.¹  Only the smallest hydrophilic molecules can enter the brain through the paracellular route around the tight junctions.  Some small, lipophilic molecules can cross through the epithelial cells via the transcellular route.²  Prodrugs can increase lipophilicity and nanoparticles can hide polar regions inside a PLGA liposome.  Larger endogenous molecules are selectively allowed across the barrier through transport proteins, like insulin and transferrin, which we can use to transport drugs across.¹  While we can make drugs lipophilic or hijack transporter proteins to cross the membrane, P-gp efflux pumps work to actively remove foreign compounds.  Some drugs can be given with P-gp inhibitors to increase the chances of remaining inside the brain.³  All of these defense mechanisms make getting drugs into the brain incredibly difficult.  Indeed, as little as 1% of an intravenous dose may reach and remain within the CNS.  The larger doses required leads to toxic side effects elsewhere in the body.⁴  To treat the growing problem of neurodegenerative disorder, we need a less invasive, patient directed route of administration that provides rapid onset of action, higher brain concentrations, and lower systemic distribution and side effects.  Going through the nose to the olfactory bulb provides each of our requirements.

The Nasal Anatomy

The nasal cavity performs three functions for the human body: warms air, filters large particles, samples odors.  In direct contact with the external environment, the cavity is lined with mucosal epithelium.  Mucus, secreted from surrounding glands, traps foreign bodies, while the cilia continuously push the mucus to the esophagus for elimination.  Any nasal medication must be absorbed quickly or be washed into the stomach.  When we breathe, air enters through the nares, past the vestibule and into a large nasal cavity.  The empty space contains specialized folds, called conchae, which increase the surface area and create turbulence to help warm the air on the way to the lungs.  Most nasal sprays for the treatment of rhinitis target the inferior and middle conchae. The rich vasculature in the area provides access to systemic circulation, but effects are limited due to nasal mucus.  To target the CNS however, specialized INB sprays target the superior concha to directly access the olfactory bulb.  Comprised of millions of nerve endings, the olfactory bulb sends out those nerve endings through the holes in the cribriform plate to test the air for smells and provides a pathway from the nasal cavity to the brain.  As such, the nasal cavity is a rare location with open access to the nervous system.  INB drugs can bypass the difficult BBB treat CNS disorders.⁵

Reaching the Brain through the Nose

To reach our goal, INB drugs do not target the vasculature, but rather the top of the nasal cavity – olfactory bulb and cribriform.  If absorbed systematically, the drug would still have to pass through the BBB reducing the neuronal availability and potentially cause toxicity.  INB drugs avoid systemic circulation by entering the brain through the more permeable epithelial membrane above the superior concha.  Any INB drug reaches the CNS through two main pathways.  The epithelial pathway uses paracellular transport around the olfactory epithelium, across the cribriform plate and into the subarchnoid space.  The CSF carries the drug particle throughout the brain or clears into the systemic circulation.⁶  Using the epithelial pathway requires a small, hydrophilic molecule.  An olfactory pathway uses the nerve endings to internalize the drug and ferry it to the olfactory bulb and into the olfactory region of the brain.  These molecules must trigger endocytosis to promote transport.

While easier to reach than through the blood, the nasal cavity still possesses a number of factors that can affect absorption.  As stated before, small molecular weight drugs are ideal as absorption is limited at 1000 daltons.  The secretion and removal of mucus can affect absorption clearing drug from the site of absorption.  Few enzymes exist in the area, but degradation remains a concern for drug stability, especially for proteins.  Finally, rhinitis can alter absorption.⁵  Still, the nasal cavity remains a valid alternative to administer drugs to the CNS, especially if the drug is orally ineffective, blocked by the BBB, or requires a rapid onset of action.  Several modifications can protect from these protections and improve INB delivery.

To improve uptake through the olfactory bulb, either the drug or the formulation can be modified.  Prodrugs take advantage of local enzymes and increase lipophilicity.  Excipients transiently open up mucosal pores to increase absorptions.  Chitosan is a natural polysaccharide that binds to the mucosal membrane and loosens the tight junctions between epithelial cells allowing more drug to enter.⁵  PLGA nanoparticles can increase absorption by attaching a lectin ligand, triggering receptor-mediated endocytosis.⁷  Currently, several drugs are being designed and studied to use these methods to treat a variety of CNS disorders.  Mouse models show an increase in brain distribution through INB relative to normal intravenous administration, opening the door to potential treatments for Alzheimer’s disease and autism.

Potential Treatments through INB

Alzheimer’s patients face a dark diagnosis with little positive light.  Chi Zhang and his group in Shanghi hope to make the outlook a little brighter.  Basic fibroblast growth factor (bFGF) simulates the growth of neurons, but remains blocked by the BBB.  Intravascular delivery of the peptide shows that only 1% reaches the brain.  INB offers an alternative route but must overcome mucusal clearance and protein degradation.  Incorporating bFGF into PEG-PLGA nanoparticles coated with Solanum tuberosum lectin, Zhang’s group showed increased residence time, CNS concentration of bFGF in Alzheimer-model rats and corresponding improvement in memory tests.  Direct bFGF administration to the brain through the nose decreases plasma concentrations resulting in fewer toxicities.⁷

Each day, more children receive diagnoses of autism spectrum disorders, but few treatments exist.  Evdokia Anagnostou and her Toronto-based lab want to administer intranasal oxytocin as a potential cure.  Children with ASD have poor social skills, tend to perform repetitive behaviors, and have reduced levels of oxytocin in the blood.  Medical oxytocin could hopefully ameliorate many autism symptoms.  Because oxytocin degrades in the intestines by chymotrypsin, it cannot be given orally.  Intravascular injection of oxytocin shows positive effects, but is too invasive for children.  INB produced better CNS distribution with easier administration.  While early in the process, children treated with INB oxytocin showed promising improvements in autism-related behaviors.⁸

Conclusion

Getting medication into the brain remains a difficult task as many molecules fail to reach the desired destination.  The BBB protects the neurons but makes treatment more difficult.  As the population grows and ages, more patients will be diagnosed with neurodegenerative diseases, like Alzheimer’s.  A targeted nasal spray to the olfactory bulb could potentially deliver therapeutic compounds for a variety of CNS disorders.  INB is a rapid acting route that avoids the restrictive BBB and potentially toxic systemic side effects.  More studies must determine the safety of this route on a larger scale and show more examples of efficacy.  We should learn more about local side effects of penetration enhancers on an important protective membrane or sensitivity in the nasal cavity leading to rhinitis.  Overall, INB offers a safer, less invasive route of administration directly to the brain and can potentially help the patients with the frightening diseases of the CNS.

References

1.     Patel M, Goyal B, Bhadada S, Bhatt J, Amin A. Getting into the brain: Approaches to enhance brain drug delivery. CNS Drugs. 2009;1:35-58.

2.     Illum L. Nasal drug delivery: New developments and strategies. DDT. 2002;7(23):1184-1189.

3.     Merkus F, van den Berg P. Can nasal drug delivery bypass the blood-brain barrier? questioning the direct transport theory. Drugs R D. 2007;8(3):133-144.

4.     Goldsmith M, Abramovitz L, Peer D. Precision nanomedicine in neurodegenerative disease. Asc Nano. 2014;8(3):1958-1965.

5.     Tayebati S, Nwankwo I, Amenta F. Intranasal drug delivery to the central nervous system: Present status and future outlook. Curr Pharm Design. 2013;19:510-526.

6.     Illum L. Nasal drug delivery - possibilities, problems and solutions. J Controlled Release. 2003;87(187):198.

7.     Zhang C, Chen J, Feng C, et al. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat alzheimer's disease. Int J Pham. 2014;461:192-202.

8.     Anagnostou E, et al. Intranasal oxytocin in the treatment of autism spectrum disorders: A review of literature and early safety and efficacy data in youth. Brain Res. 2014.

An Explanation for Inception

If you watched the movie "Inception" and become confused as to what in the world was going on, this quick video can explain the different levels of dreams.  It offers a creative metaphor for the layers of dreams.  One problem: it still doesn't help explain the ending of Inception.

Enjoy!

INCEPTION_FOLDER from chris baker on Vimeo.

Football and Brain Trauma

National Geographic has an interesting article on the dangers of football.  Along with the article, an interactive graphic allows you to see the magnitude and location 537 helmet impacts on a football player from the University of North Carolina.  Of the collisions, 417 produced greater that 10g's and two actually caused concussions.  The scientists hope to replicate the study with more students from different schools and even NFL players.

From NatGeo: Red = Collision greater than 80g and Black = Concussion

The powerful visual underscores the dangers of football at any level.  Seemingly insignificant head collisions add up to severe potential for brain damage later in life.  So many former NFL players suffer from early onset dementia that many decided to donate their bodies to science to get a better understanding of what actually happens to the brain.

Hopefully these studies can help us prevent more problems in the future through acceptance of rule changes and better technologies.

Cambridge Brain Science Intelligence Tests

Partnered with the New Scientist Magazine and the Discovery Channel, Cambridge Brain Science produced this awesome series of intelligence tests.  The tests are designed to examine the 12 Pillars of Wisdom, including planning, reasoning, memory, and attention.  The test very specific brain functions with simple tasks.  Try them.  They take about 30 minutes to complete with a short questionnaire at the end.  I took the test at the wrong time with distractions, at the end of the day, and on four hours of sleep.  If I can find enough time, I would like to try again.

Teachers and psychologists often discuss Multiple Intelligences.  Intelligence has always been difficult to describe and to determine.  Our basic IQ tests suffer from hidden biases and flaws.  Multiple intelligences divides knowledge into several categories such as Visual/Spatial, Verbal/Linguistic, Logical/Mathematical, Bodily/Kinesthetic, Musical/Rhythmic, Interpersonal and Intrapersonal.  Because people excel in different areas, we find it difficult to label intelligence.  This idea basically determines your likes and dislikes and assumes that you will be intelligent with the things you like and less intelligent with the things you don't.  You can take this test to learn about your Multiple Intelligences.

Robert Sapolsky on Our Metaphorical Brains

Robert Sapolsky, a Stanford professor, studies primates and what makes us human.  In an online commentary from the New York Times, Sapolsky explains how our brain differs from other animals.  The structure of our brains grow out of the same building blocks as everything else.  The neurons of all animals follow the same structure and work the same way.  Our main advantage is shear numbers.  


We have 100 billion neurons which create a seemingly infinite number of synapses and pathways.  Some scientists hope to build a connectome to show how each neuron communicates with another.  We have almost finished the complex connectome of model nematode, C. elegans.  The human connectome shows several orders of magnitude more complexity and is years away.  But even without visualizing every connection in the brain, we can understand the importance of these synapses to human capabilities.  Sapolsky notes our unique language center (Broca's Area), fine motor area, and neuron-dense frontal cortex.  Specifically, our frontal cortex controls emotional reactions, personalities, decision-making, and planning abilities.



However, Sapolsky points to our use of metaphors and symbols to describe reality.  He describes a person eating rotten food.  That person's neurons in their insula will remember the disgusting food and the need to vomit.  The same neurons will fire when a person smells the same food or think about eating similarly disgusting food.  Interestingly, those neurons will fire when we hear a story which "makes us sick" or react to something that it morally disgusting.  We didn't invent anything new, but built upon the existing model.  


We see the same situation in pain response.  Neurons fire when our body senses pain, but the same neurons fire when the see someone else in pain.  We feel their pain, sometimes almost literally.  The effects of clinical depression disappear when medicines block the actions of neurotransmitters associated with pain.  Perhaps depression manifests because of extreme empathy.


In many ways, our brains confuse the literal and the metaphorical reality.  The same neuronal circuitry fire in each case - disgust, pain, cleanliness, temperature, or touch.  Because evolution doesn't have to make new structures, our language symbols latched onto the neural networks already associated to the literal response.  Unfortunately, this rigging can confuse our decision-making and create subconscious biases.  Or we can use these responses to alter (control?) other people.  People have found all kinds of tricks to put people into an appropriate frame of mind to get what they want.


We still have much to learn about the brain itself.  We have even more to learn about the evolutionary changes to the brain which made us human.