I love the Dana Press, and I always love books in this series, this one with a foreword from Alan Leshner and contributions from some of the best in the research in neuroscience. The first one is cannabis, from my old mate Sir Robyn Murray at King’s College in London, where I last met him some time ago. The issue of cannabis and schizophrenia has been much debated, and he takes on the moving parts here, namely does it cause it, in which individuals, is this just an exacerbation of risk, is the weed more potent now, or bred to be more prepotent in terms of the balance of chemicals? Robyn does this with his usual and expected British style and some hint of wit beneath his academic exterior, as his profile photo supports. Dependence and cognitive impact are still up in the air, and he addresses the controversy here as well. One thing we do know is that using synthetic cannabinoids makes you 30 times more likely to end up in the ER, and so the idea in life that anything highly processed, is worse than the natural product. So the dose-dependent relationship to harm is a work in progress, with Europe watching the evolving USA-based science and legal issues with interest: to legalize or not? Is usage rising? Falling? A great topic.

Zak writes on the neuroscience of narrative, on how we focus and engage with characters in print and in movies both, how we are immersed in narrative. I often wondered why I cared not what happened to Oscar Pistorius, until I realized that I had paid attention to his case, but bonded with his victim: a short but powerful piece in this book. For a change of pace, let’s talk about adrenocorticotrophic hormone and oxytocin and Oscar Pistorius and movies. So what is the connection? Well let’s say we want to make a movie that enthrals people and makes them sad to see it end. How does that happen from a neuroscience point of view? Well, the makers of the movie have to do things: firstly, arouse our attention and focus us clearly on the movie and secondly, make is feel empathy with the characters, giving us enough to immerse us fully in their lives and care what happens to them. Let’s think of Oscar Pistorius and his ITV interview a few weeks ago. We were aroused to watch, but we did not engage or feel sorry for him as we wept. Why? Well, firstly the ACTH aroused our interest if we are interested in such things, but given we empathise strongly with Reeva Steenkamp, his victim, we do not release oxytocin in response to Oscar, and so although we might be riveted by ACTH, there is no empathy for his plight and crocodile tears. So a movie writer needs to think in terms of ‘surprising familiarity’ where we really care about the lives onscreen, but as importantly, keep our focus

Koob then puts forward the latest views on stress, worth summarizing: let’s give you the laymen’s guide to what the neurochemistry of stress and inflammation is, since some are not quite clear on it. 1. Stress is anything that challenges the psychological homeostasis of the body. 2. Maintaining this homeostasis requires responses from the nexus provided by the hypothalamic-pituitary-adrenal axis. 3. A peptide called corticotropin-releasing-factor initiates the HPA axis’ neuroheumeral response, liberated from the paraventricular nucleus of the hypothalamus. 4. This is the primary controller of the HPA axis. 5. The CRF travels to the pituitary gland and binds to receptors in the anterior pituitary and that releases adrenocorticotropic hormone into the bloodstream. 6. ACTH travels to the cortex of the adrenal glands (supra-renal..above the kidneys) to release the glucorticoids which synthesize glycogen to provide energy to the brain and decrease immune function by blocking ‘pro-inflammatory’ proteins. Acute high-dose glucocorticoid responses thus impart a PROTECTIVE effect. So why fight, flight or freeze?  The extended amygdala encodes negative emotional states. This area includes the amygdala and nucleus accumbens. These areas receive input from the hypothalamus and the prefrontal cortex. The connections from here to the hypothalamus and other midbrain structures are extensive. We will show an enhanced freeze response to a conditioned fear stimulus, enhanced startle response to a startle input, and avoidance of places we might be exposed in. I mentioned CRF before: this is a major component of the extended amygdala. So CRF mobilizes the behavioural response to what the glucocorticoid mobilized as a physiological response to the stressor, not just the physiological and hormonal responses. CRF will make us hyperactive and happy in a familiar cosy environment, but freeze with fear in a novel, stressful environment or experience. Now, interestingly, glucocorticoids stimulate CRF production in the amygdala, but inhibit it in the hypothalamus. This is an attempt to protect us from prolonged stress by shutting down the HPA axis. There is another important neurotransmitter system involved here though. So the dynorphic-kappa opiod system is part of the extended amygdala. It produces aversive, negative or bad mood states in humans. These dynorphins are widely distributed in the CNS. They regulate things such as pain, motor, temperature, cardiovascular function, respiration, feeding, stress responses. They are not alone: other factors in this system include norepinephrine, vasopressin, substance P, pro-inflammatory cytokines, hypocretin, and others. However, these mediate responses to stresses, but other neurochemical systems oppose these above: Neuropeptide Y, nociceptin, and endocanabinoids. So you can see that stress is pro-pain and inflammation here, and opposed by NY for instance, and you can see why cannabis oil might work here too! Neuropeptide Y is interesting in my special ops soldiers: they have high levels to help them cope with stress, but dying early from cardiac issues is common enough, in their early 50’s.  So what about PTSD? You will guess at high levels of glucorticoid receptor sensitivity. This, as you will now have seen, results in excessive suppression of the HPA axis via negative feedback loops. If you are deployed as a soldier with high levels before, in early childhood, that will predispose you to high levels of PTSD: so early childhood stresses can predispose you to conk in during combat stress for instance. About 33% of PTSD is predicted this way. High CRF receptor signalling also predicts similar responses in the individual (you can measure this in the spinal fluid). Clinical diagnosis of PTSD will also include increased dynorphin release in the same way (kappa-opiods I mentioned before). So high levels of Neuropeptide Y can protect our special ops boys, but lead to later cardiac death, probably in relation to arrhythmia, so essential to train them into respiratory sinus arrhythmia to keep them alive after retirement! If the amygdala is busy in fMRI studies, then the ventromedial (go-no go) prefrontal cortex is quiet on the subject, as is the inferior frontal gyrus. The loss of inhibition of these areas means increased response to fear, greater attention to threatening stimuli, delayed or decreased extinction of traumatic memories and emotional dysregulation. This is why we think if Borderline Personality in a similar way in response to childhood stresses. In mild stress the PFC inhibits the amygdala, but in prolonged stress or extreme stress, the PFC goes offline.

So this is the dense information in just one small chapter: this is the attraction of this type of book: rapid learning with tight writing to showcase the work of each author.

Tau proteins are part of our brains, so what happens when they go ‘toxic’. Ken Kosik takes this on for this series. Unlike the previous paragraph, documenting the complexity of Tau is beyond anything like this book or this review. Referring to the relative space into which proteins fold, the author notes it is astronomical.  Tau in fact is an ‘intrinsically disordered protein’, just so you know. This means they are capable of multiple structural changes and actions, which makes them versatile in the extreme, and thus can also go horribly wrong. Prions are just one example. When Tau gets unfolded and sticky……not good.

Kaplan and Anzaldi look at Purpose in Life: the connection between and optimal sense of existence and meaning, and physiological health. Of course, one is immediately alerted to a man I also once met Viktor Frankly, the famous author of Man’s search for meaning. A well -known phenomenon of the camps under German wartime extermination of the perceived untermensch was the need to find a compelling reason to stay alive amidst German cruelty. Research will show that the major avenues to death are mitigated by a positive sense of meaning and self-preservation, namely combating inflammation, preserving neuronal tissue, preventing stroke and dementia in other words. We know the role the inflammatory cytokines play in the aetiology of all sorts of preventable illness, so not too surprising to surmise, or indeed induce, that working via the CNS backwards from the happiness zones in the mind that this will positively impact on disease-inducing processes that rely on inflammation of the cell, and disruption of the immune system.

When it comes to hope in the major illnesses, Sullivan sees blue sky in Schizophrenia, which although only affects 1% of our population, along with Bipolar Affective Disorder accounts for high levels of permanent disability and the brainstorm that bars one from a good life. The issues is that this is a multifactorial condition, with a recent finding of yet another 80 zones on the genome that might play a role. That makes the count now in the hundreds: a multifaceted target that means firing a single drug at all the target zones could just be impossible. Sullivan’s blue sky? Genetics. Nothing else there folks…

Predicting what treatment in what person is the holy grail, and the controversial Charlie Nemeroff is here up next to talk about this.  The issue here is the seeking after of the holy biomarkers, so that personalized medicine is possible, and of course, measuring to manage this is vital: what biomarkers would predict what person would respond in contrast to the Star-D studies’ finding that few really do, or that drugs therefore don’t work reliably in anyone. Can we predict which ones will respond to which pills?

Cicero works in the neurobiological basis of drug addiction. Multiple patients I see have tremendous issues with complex pain, and complex medication seems to be fraught with issues as recent reviews on this website into Pohl’s work in Nevada and Markowitz’s work in Sausalito Bay as highlighted by Doidge. There is no end in sight to the risk of addiction. More history of the state of the nation in addiction in the USA than anything else, the education of the dangers here is clear.

Ely and Cusack deal with another sad addiction: Binge eating, and the brain processes underneath and how to intervene. Not too much new here it seems.

Ioannides deals with psychological research, and recent investigations deal with the real issue of reproducibility. Namely, if something is good science, it should be replicable to demonstrate it was not just chance. So for a long time, the idea of a 95% confidence interval would mean if you redid an experiment 100 times, you would expect the results to re-occur at 95 of those occasions. In reality, less than 50 do. That makes the evidence base look more like chance, and ‘chance’ in psychological research means: NO cigar. And although failure to reproduce doesn’t necessarily mean the original was bogus, sometimes No Cigar is actually No Cigar. Sorry Sigmund. We have to get greater rigour into our science or risk being seen as art, or irrelevant.  If nearly 2/3 of the original findings were found to be false-positives, with worse impact on social psychology, better outcomes in the more concrete divisions, such as cognitive psychology, then a lot of work has to be done to ensure outcomes that matter.

What is age, and what is sinister in terms of cognitive loss along the elderly pathway?  Howieson argues that it is difficult to determine what is healthy and normal ageing, since on autopsy many of the changes seen can be attributed to pathological brain changes, so this is always going to be a difficult one. Again, the default treatment for prevention include…… nutrition and exercise to combat the effects of inflammation and pathological ageing processes.

The book finishes off with a few book reviews.

So the book has few answers, but the state of the nation in these fields is set out here, as it will be in future additions, and always a good read to come up to date with current experts and where they are going with all of this.

 

© 2016 Roy Sugarman

 

Roy Sugarman PhD,Director Applied Neuroscience: Performance Innovation Team, EXOS USA.