Tag Archives: neuroscience

The Alzheimer’s-insulin link is really interesting.

I’m convinced that in physiology, everything is connected.  That is, one of your body’s systems can’t be altered without avoiding the ripple effect that change will have on every other system–however miniscule it might be.  This point reinforced itself while I attended a seminar talk that I found appealing for its fusion of past and present topics of interest to me, Alzheimer’s disease and metabolic disorders.  I decided to write a short synopsis of the story behind that talk (it was given by Laura Baker, mentioned below):

The study of progressive cognitive decline—specifically, Alzheimer’s disease—is one of the most frustrating areas of research in neuroscience at both the scientific and personal levels.  Approximately 5 and a half million Americans live with the disease, and as our population continues to age, that number is expected to increase exponentially.  All current drug therapies, most of which enhance the brain’s cholinergic system, have no more than a modest* effect.  But Drs. Laura Baker and Suzanne Craft from my university, Wake Forest, are exploring a promising new focus in Alzheimer’s disease research that may lead to new treatment strategies to improve cognitive function or delay the onset of disease symptoms: brain insulin signaling.

Researchers have uncovered a strong link between dementia and a deficiency of insulin in the brain.  Insulin is critical for many cells to function properly, including neurons.  Most of us associate insulin with its role in diabetes, in which it is either completely absent (type 1 diabetes) or its signaling action in cells is defective (type 2)**.  The latter condition is referred to as insulin resistance.  As peripheral cells become resistant to insulin, more will be released into the bloodstream by the pancreas to compensate for its impaired actions.  Increased release of many hormones usually means that higher levels will reach the brain, but not so with insulin.  Insulin must be transported into the brain across the blood-brain barrier, and long-term elevation of circulating insulin causes down-regulation of insulin receptors and transporters at this junction.  Thus, over time, less insulin is able to enter the brain.  This is likely a major factor behind the observation that adults with type 2 diabetes have at least double the risk of developing Alzheimer’s later in life.

Insulin’s ability to improve memory acutely is well known, as is its contribution to the formation of new synapses.  In the brains of deceased Alzheimer patients, scientists have noted a reduction in both insulin receptors and the activity of enzymes involved in insulin signaling compared to healthy brains.  Others have even established an important link between brain insulin deficiency and the accumulation of β-amyloid proteins, the proximal cause of neuronal death in Alzheimer’s disease.  Under normal conditions, insulin will help transport the toxic proteins out of the cell, preventing the formation of intracellular plaques that are a hallmark of the disease.  As evidence for the role of insulin in progressive cognitive decline continues to mount, it seems more and more appropriate that Alzheimer’s disease is sometimes referred to as type 3 diabetes.

Drs. Baker and Craft, along with collaborators at the University of Washington, believe that enhancing levels of insulin in the brain may be one answer to the challenges of treating Alzheimer’s disease.  However, this would require insulin to circumvent the blood-brain barrier because of the dangers of chronic high circulating insulin, in addition to reduced transport into the brain over time.  An innovative way to accomplish this is through the intranasal inhalation of an insulin spray.  Olfactory sensory neurons are directly exposed to the external environment, allowing drugs to be transported directly into the brain by traveling through nerve channels.   Craft and Baker recently published their results from a clinical trial that tested the intranasal delivery of insulin into Alzheimer patients, showing that insulin improved delayed memory, preserved the ability of patients to carry out daily functions, and indicated that neuron metabolism was improved compared to patients who received placebo.  Longer and larger clinical trials are currently underway, which they hope will demonstrate that intranasal insulin is a viable new treatment for Alzheimer’s disease.

For further reading, see Cholerton B, Baker LD, Craft S. Insulin, cognition, and dementia. European Journal of Pharmacology (in press), 2013.

*Jargon for “minimal or none; nothing, basically.”

**Type 2 diabetes can also manifest as a relative shortfall in insulin release, especially in obese patients.  Meaning insulin is there, and it works, but there’s not enough of it.


Lit Review: Hallucinations, by Oliver Sacks

Finally, something worth posting here.  I wrote another book review for our newsletter.  I didn’t enjoy writing about this book as much as the previous one I reviewed because there wasn’t too much wrong with it.  Not that there was a ton I disagreed with in Consciousness, but there were some pretty controversial topics covered in it that were more fun to discuss.  Anyway…


Oliver Sacks

Alfred A. Knopf (New York), 2012

“Thus the matter of belief is, in all cases, different in kind from the matter of sensation and perception, and error is in no way analogous to hallucination.  A hallucination is a fact, not an error; what is erroneous is a judgment based upon it.”

–Bertrand Russell, Theory of Knowledge (1913)

            One astonishing revelation of the human mind uncovered by the study of neuroscience is the fragility of our perception of reality: a mild imbalance in the activation of certain neuronal circuits from drug use or psychiatric disease is often sufficient to evoke profound alterations in sensation and perception.  We call the precepts that form in the absence of external reality hallucinations.  Despite the stigmas associated with them, drug users and the mentally ill are far from the only people who experience hallucinations.  In fact, hallucinogenic experiences are a nearly universal phenomenon.  As Dr. Oliver Sacks illustrates in his most recent book Hallucinations, they can provide deep insight into how the human brain functions.

            Dr. Sacks has a gift for crafting a compelling narrative out of the human nervous system, and he accomplishes this in Hallucinations by combining medical history, scientific background, fascinating (and sometimes downright bizarre) case studies of his patients, as well as his own personal experience.  Perhaps because he experienced it himself, Dr. Sacks begins by describing a common (yet little recognized) condition called Charles Bonnet Syndrome (CBS) that afflicts older people suffering from visual impairment.  CBS is marked by the experience of a wide spectrum of intensely vivid, complex visual hallucinations.  Patients report seeing anything from faces, common objects, repetitive patterns, and even rows of text or sheet music.  Often times a “scene” composed of hallucinatory people and objects will play in the patient’s visual field. 

            Patients with CBS are not united by dementia or mental illness, as many doctors mistakenly diagnose.  Rather, they suffer from deficits in the visual field.  The visual damage that yields CBS hallucinations can arise in the eye (due to macular degeneration, for example) or in the brain, especially in areas of the cortex associated with the visual pathway.  Dr. Sacks describes the pioneering research of British psychiatrist Dominic ffytche, who, using fMRI, discovered a “striking correspondence” between the particular hallucinatory experiences of CBS patients and specific portions of the visual pathway that become activated while the patient is hallucinating.  For instance, hallucinations of faces were associated with activation of the fusiform gyrus and the superior temporal sulcus, brain areas known to be specialized for the representation of faces and facial features, respectively. 

            As the remainder of Hallucinations uncovers, there are hallucinations for every perceptual experience—those of sound, smell, touch and taste, as well as complex, multimodal hallucinations involving a combination of the senses—and their origin is in the brain.  Dr. Sacks devotes chapters to describing visual auras seen by sufferers of migraines and epilepsy, and even recounts his own experiences while under the influence of hallucinogenic drugs to hilarious effect.  The recurring theme of the book is that the vast majority of people who experience hallucinations are not crazy; the patients Dr. Sacks describes are instead treated as privileged observers of singular neurological phenomena.

Dr. Sacks ascribes an almost romantic quality to hallucinations, frequently citing patients who describe their experiences as comforting and even inspiring.  Among the more interesting segments are his discussions of how hallucinatory experiences may have contributed to works of art and literature, including myths and certain religious beliefs.  “Hallucinations,” writes Dr. Sacks, “beyond any other waking experience, can excite, bewilder, terrify, or inspire, leading to the folklore and the myths (sublime, horrible, creative, playful) which perhaps no individual and no culture can wholly dispense with.”  As Dr. Sacks brilliantly illuminates in Hallucinations, the brain often separates our sense of what is real and what is illusory with a fuzzy line.

Lit Review: Consciousness: Confessions of a Romantic Reductionist

A truncated version of this post first appeared in issue 14 of The Neurotransmitter

Consciousness: Confessions of a Romantic Reductionist

Christof Koch

MIT Press (Cambridge, MA), 2012

Bart: What is the mind?  Is it just a system of impulses or is it… something tangible?

Homer: Relax.  What is mind?  No matter.  What is matter?  Never mind!

– The Simpsons, “Good Night,” 1987.

The nature of the mind is a philosophical topic as old as philosophy itself.  Plato, Aristotle, Descartes, Kant, and other historical thinkers shared ideas about the mind that remain influential today.  Many of these ideas laid the foundation of modern neuroscience, as scientists established that the mind is a product of the brain.  To understand the mind we must therefore understand the brain, and this has proven to be one of the greatest challenges science has ever encountered.

There was intense debate late into the twentieth century about whether it was even possible to study the physical relationship between the mind and the brain.  Out of this debate emerged a new problem dealing with consciousness: what must happen in the brain for our awareness of the world to arise?  And more importantly, why do these internal brain events cause us to experience the world around us?  This so-called Hard Problem of Consciousness attracted scientists from the burgeoning field of cognitive neuroscience in the 1980s and 90s, with Christof Koch of the California Institute of Technology among them.  While working closely with his friend and mentor Francis Crick—the co-discoverer of the double helical structure of DNA—Koch became one of the pioneering neuroscientists in the study of consciousness during a time when most considered it a fringe subject.  In his book Consciousness: Confessions of a Romantic Reductionist, Koch offers a personal account of his life’s work and his goal of understanding the origins of the mind.

The opening chapters of Consciousness relay some anecdotes that helped shape Koch’s scientific quest.  Here he manages to portray himself as someone many in science can relate to: an earnest, romantic nerd.  The content of some passages may border on the mundane, but the tone of Koch’s writing is kept refreshingly personal, reminding readers he is a flesh-and-blood creature with real motives and desires.  These chapters are indeed a large reason for the book’s subtitle Confessions of a Romantic Reductionist.  Koch’s “confession” is that he was drawn to the study of consciousness by his desire to justify his instinctual belief that life is meaningful. “By giving the study of consciousness my all and failing in this endeavor, I was going to demonstrate to my own satisfaction that science is inadequate to the task of fully understanding the nature of the mind-body divide.”  He concludes his confession with an enticing spoiler: “In the end, this is not how it turned out.”

Religion played a very influential role in motivating Koch to become a scientist, and he emphasizes its importance to his childhood in the book’s endearingly candid second chapter.  The liberal, though devout, Catholic tradition in which he was raised provided a framework for fulfilling his curiosity about the natural world that was both intuitive and comforting.  But as Koch grew older it became more difficult for him to reconcile his religious beliefs with the naturalistic stance of his profession.  He admits to an internal conflict between faith and reason that persisted well into his career, and was resolved only in recent years by abandoning his belief in God.  However, a pervasive theme in Consciousness is Koch’s view that there must be something grander in the laws of the universe that science has not yet fully illuminated.  He projects a sense that his religious conviction is not quite fully lost, and whatever remnant he retains is in part driving his research.  As he says, “I lost my childhood faith, yet I’ve never lost my abiding faith that everything is as it should be!  I feel deep in my bones that the universe has meaning that we can realize.”

Despite his apparent reluctance to fully divorce himself from his Catholic background, Koch is still foremost a scientist and demands evidence.  “Let the conversation turn to consciousness, and everybody chimes in, on the assumption that they are all entitled to their own pet theory in the absence of pertinent facts.  Nothing could be further from the truth,” he forcefully asserts, as if to reassure wary, scientifically minded readers.  The central argument Koch makes is that modern neuroscience now possesses the tools to investigate consciousness, therefore elevating its status from fringe or pseudoscience into a legitimate scientific field of inquiry. Koch’s and Crick’s own research focus is in what they termed the “neural correlates of consciousness”—the minimum neuronal activity sufficient to generate a specific conscious percept—and they probed the primary visual pathway in search of these.  He makes it clear, however, that they are far from the only scientists at work.  Much attention is given to Naotsugu Tsuchiya’s work with fMRI and the technique of continuous flash suppression.  Later chapters describe case studies by neurologists on peculiar perceptual defects like prosopagnosia (face-blindness) and akinetopsia (motion-blindness), as well as the brain’s subconscious “zombie agents” that control much of our lives from beyond our awareness.  The discussion of consciousness progresses from practical to theoretical when Koch introduces neuroscientist Giulio Tononi and his Integrated Information Theory, praising it as the most promising fundamental theory of consciousness yet.

Perhaps the most fascinating parts of Consciousness are in its seventh chapter, in which Koch “throws caution to the wind” and expounds upon one of the more abstract concepts to emerge with the study of the mind: free will.  The question of whether humans are truly agents of free will has tormented philosophers for centuries.  The intuitive answer to most is of course we have free will, meaning the power to behave and make decisions of our own volition.  René Descartes was a strong proponent of this view, as was Koch as a younger man.  Remarkably, data from modern neuroscience refute this classical notion of free will.  Koch points to the work of physiologist Benjamin Libet, who famously showed that EEG can detect activity in the motor cortex, called a readiness potential, up to half a second before a person feels the decision to initiate a movement.  Further compelling work by psychologist David Wegner seemed to confirm these results, and convinced Koch to adopt a new position on free will.  Nevertheless, he stops short of believing that behavior is fully determined by physical laws using what some readers may consider specious reasoning.  He cites the chaotic orbit of Pluto, which makes it impossible to predict its future position along its orbit, along with the quantum uncertainty principle as proof that natural laws are inadequate to account for all human behavior.  What Koch does not mention is that Pluto’s orbit is chaotic largely because its tiny mass (in relation to the other planets of the Solar System) precludes it from clearing its orbit, leaving it forever vulnerable to the perturbations of as-yet unseen, distant objects.   Nor does he offer any insight into whether quantum indeterminacy does or does not measurably affect behavior.  Even so, Koch is by no means a minority figure as a prominent holder of a compatibilist view of free will (Daniel Dennett readily comes to mind), and his thoughtful treatment of the subject is among the best qualities of Consciousness.

Koch’s discussions of the science avoid sounding pedantic and mostly tie into the theme that small chunks of gray and white matter are responsible for encoding very specific pieces of conscious content.  Readers lacking an introduction to basic neuroscience may struggle with these segments of the book, but Koch lucidly conveys the significance of these discoveries to his target audience, with a palpable sense of excitement.  One shortcoming of the book, however, is the deficiency of new perspective Koch offers with respect to the science he describes.  It often seems as though the opinions he expresses are non-committal or incipient, especially toward his personal feelings on the relationship between science and religion, but this may simply be his inner scientist revealing itself to readers.  Broaching subjects as personal as these, considered off-limits to formal scientific discourse, certainly requires a degree of bravery, just as embarking on a quest to understand the nature of consciousness once did.  On this topic, Koch is perfectly clear: thanks to the tools of modern neuroscience, we are much further along in the study of consciousness than Plato, Descartes, Kant, and Homer Simpson ever were.  Overall, Consciousness: Confessions of a Romantic Reductionist is an engaging, succinct introduction to the study of the mind by someone who should be easily relatable to many young scientists and students of neuroscience.


PET Scanning Reveals Neurodegenerative Condition in Retired NFL Players

A version of this post first appeared in issue 14 of The Neurotransmitter

Junior Seau was one of the most decorated and beloved players in the National Football League (NFL) over an iconic professional career that spanned twenty seasons.  As a linebacker, a bruising defensive position tasked with tackling offensive ball carriers, Seau’s honors included twelve Pro Bowl selections, the NFL’s 1994 Man of the Year Award, and being named to the NFL 1990s All-Decade Team.  He developed a reputation for his ferocious play and passionate on-field leadership, often playing through injury and performing a distinctive fist-pumping dance after big plays [1].  Most would agree that Seau was a wonderful representative of the NFL before retiring in January 2010.

On May 2, 2012, at the age of 43, Junior Seau committed suicide by a self-inflicted gunshot wound to the chest.  His ex-wife reported that he had suffered from depression and insomnia in the last years of his life [2].  Suspecting that brain damage related to his long playing career contributed to his suicide, Seau’s family donated his brain tissue to the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH) for analysis.  On January 10, 2013, his family announced that NIH neuroscientists had definitively concluded that Seau suffered from chronic traumatic encephalopathy (CTE) [3], a degenerative neurological condition associated with concussion-related brain injury.

Seau’s post-mortem CTE diagnosis is one of several high profile cases that have brought recent media attention to a disturbing trend among retired professional football players.  Studies of former NFL players reveal a persistently higher rate of personality and mood disorders (e.g. major depression), mild cognitive impairment (MCI), and severe dementia compared to the general population.  In fact, retired NFL players sustaining three or more concussions during their careers may be three times more likely to be diagnosed with depression and five times more likely to be diagnosed with MCI later in life [4, 5].  Dozens of similar cases in former athletes who had suffered repetitive brain injuries are linked to CTE after death [6, 7].

CTE manifests as a steady deterioration in mood, personality, motor function, and cognition.  It is confirmed by a variety of findings at autopsy, particularly the widespread accumulation of phosphorylated tau protein tangles (similar to Alzheimer’s disease), axon damage, inflammation, and other brain abnormalities, including neuronal loss [6, 7].  Clearly, CTE can be a devastating consequence of repeated traumatic brain injury, and it is quite alarming that so many people are at risk due to the popularity of contact sports [8].  That retired NFL players are disproportionately more at risk for CTE should be cause for further unease among current players and league officials.  After all, American football is not merely a contact sport, according to legendary coach Vince Lombardi—it’s a collision sport.

Despite the risk for CTE among former athletes, there is no established method for its early detection.  All cases of CTE are currently diagnosed at autopsy.  However, in a clinical research article from the February 2013 issue of The American Journal of Geriatric Psychiatry, Dr. Gary W. Small and his UCLA colleagues describe a promising method for the non-invasive early detection of CTE and similar brain pathologies [9].

Dr. Small’s group previously invented a new tracer ligand for use in positron emission tomography (PET) that is capable of detecting tau tangle deposits in living brains, and can track and predict cognitive decline in people without dementia [10, 11].  A PET scanner detects the energy released by the decay of a special radioactive isotope (called a tracer) that is injected into the bloodstream and selectively binds to a tissue of interest.  The energy released by the bound tracer is then rendered into an image and color-coded for signal intensity.  In their latest study, Dr. Small’s research team applied this PET imaging technique to the brains of five living, retired NFL players with a history of cognitive or mood symptoms.

The former players, ranging in age from 45 to 73 and having sustained between one and twenty concussions during their playing careers, completed a battery of neuropsychological tests prior to PET scanning.  The tests revealed that the players indeed have significantly higher depression scores than control subjects, as well as a trend toward lower global cognitive ability.  These results closely reflect the players’ clinical presentation, as three were diagnosed with MCI, and another with dementia.  All exhibited symptoms of major depression.

More distressing, however, are the PET scans of the players’ brains: all had very high tracer signal intensity compared to controls that was especially concentrated in the thalamus, midbrain and amygdala, indicating large tau deposits in these regions (see Figure 1).  These binding patterns are consistent with the tau build-up observed in autopsy studies of CTE [6].  Perhaps the most striking feature of the study is the illustration of a relationship between PET signal intensity and the number of concussions each player sustained throughout his career (Figure 2).  Although none of the correlations reached statistical significance due to the small sample size of players tested, the plots below show a clear trend toward an increase in tracer binding with more concussions suffered.

This study may have a considerable impact in medicine and sports.  The PET tracer developed by Dr. Small’s team could facilitate the early detection of trauma-related brain diseases like CTE.  As the authors note, the early detection of this condition is a crucial first step toward the development of medical interventions that may hinder the onset or progression of symptoms.  No such early detection method is currently in practice.  This study should also help raise further awareness of the substantial long-term consequences of traumatic brain injuries in many at-risk athletes.  The NFL is now placing a much greater emphasis on player safety [12], having recently adopted new playing rules, medical guidelines and equipment standards to reduce the health risks of the game.  Researchers at Wake Forest University and Virginia Tech are aiding this initiative by conducting research on football helmets to reduce the number of concussions suffered [13].  The effectiveness of these measures remains to be seen, but the goal remains that at the end of their careers, players can truly leave all of the game on the field.


Figure 1 – Coronal and transaxial PET scans of retired NFL players show extremely high signals in cortical and subcortical brain regions compared to the control subject [9].


Figure 2 – Plots showing PET tracer binding according to number of concussions sustained suggest a positive relationship between greater number of concussions and higher PET tracer signal in several brain regions [9].


[1] http://www.utsandiego.com/news/2012/may/02/chargers-greats-feats-on-field-and-off-spoke-for/?print&page=all

[2] http://usatoday30.usatoday.com/sports/football/story/2012-05-31/Junior-Seau-suicide-last-days-sleep-issues/55316506/1

[3] http://abcnews.go.com/US/junior-seau-diagnosed-brain-disease-caused-hits-head/story?id=18171785&singlePage=true

[4] Guskiewicz KM, et al. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery, 2005; 57:719-726.

[5] Guskiewicz KM, et al. Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc, 2007; 39:903-909.

[6] McKee AC, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy following repetitive head injury. J Neuropathol Exp Neurol, 2009; 68:709-735.

[7] McKee AC, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain, 2013; 136:43-64.

[8] Centers for Disease Control and Prevention: National Center for Injury Prevention and Control. Non-fatal traumatic brain injuries from sports and recreation activities—United States, 2001-2005. MMWR Weekly, 2007; 56(29):733-737.

[9] Small GW, et al. PET Scanning of Brain Tau in Retired National Football League Players: Preliminary Findings. Am J Geriatr Psychiatry, 2013; 21(2):138-144.

[10] Shoghi-Jadid K, et al. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer’s disease. Am J Geriatr Psychiatry, 2002; 10:24-35.

[11] Small GW, et al. PET of brain amyloid and tau predicts and tracks cognitive decline in people without dementia. Arch Neurol, 2012; 69:215-222.

[12] Cf. http://www.nflevolution.com/

[13] http://www.news-medical.net/news/20130130/Wake-Forest-expands-football-helmet-research-to-reduce-sports-concussion-risks.aspx