Preface

"Babylon in all its desolation is a sight not so awful as that of the human mind in ruins."

Scrope Berdmore Davies1

"I can face death, but I cannot face watching myself disappear from within.I don't know who I am anymore."

Claude Jutra2

Each annual meeting of the Society for Neuroscience (SfN) is, for me, once more a reminder just how reductionist the field of neuroscience has been, continues to be, and apparently is destined to remain.

Anyone who has gone to this conference, or any similar type of large meeting, cannot help but be overwhelmed by the sheer quantity of the information on display. During the three and a half days of the main SfN meeting, some 30 000 participants will present over 15 000 posters along with almost 13 000 talks of various lengths. These numbers were the projected figures for the 2014 conference in Washington, DC, but other SfN conferences of the recent past will have been much the same in size. Future conferences will likely be even larger.

Most of the talks at the meeting occur in the so-called "mini"- and "nano"-symposia which feature 15-minute-long presentations, each usually containing a small body of data and its preliminary interpretation. However, the poster sessions really show the true dimensions of the conference: seven 4-hour-long sessions, each filling an area the size of several football fields.

Each poster, or mini-talk, contains a snippet of information - almost all of it, as noted, preliminary - a lot of which will turn out to be conceptually flawed in design or experimentally incorrect. Much of the time, as the lack of later publications bears out, the work is simply not reproducible. This outcome is in accord with studies by various scholars who have noted a lack of reproducibility in experimental data of all kinds, perhaps particularly often in the biomedical sciences.

Multiply these numbers by the additional numbers of people and presentations at conferences in neurology or more specialist neurological diseases, multiply again by the number of years these conferences have all been going on, and one likely gets billions of words and millions of tons of paper in a virtual tidal wave of information, which, combined with endless time spent by a great variety of otherwise quite talented scientists, actually produces what, at the end of the day, amounts to relatively little useful information about neurological diseases. Further, very little of this information is actually sorted, compiled, or cross-checked internally or externally with the previous decades of results from all of the similar meetings.

What then are the outcomes for neurological disease remediation? First, the field still does not understand the etiology of most neurological diseases, and, as a consequence, it has only a very limited means of translating what it thinks it knows into treatments that actually halt the progression of - never mind "cure" - these diseases.

The problem here is therefore obviously not one of quantity, or even in many cases of quality. Rather, the problem is that the field still cannot answer some really fundamental questions about the diseases in question and therefore cannot come up with treatments that make a lot of sense mechanistically or, at the very least, do what they are intended to do. Maybe what this really means is that the field of neurological disease research is not asking the right questions, or that it does not know how to interpret the answers.

For me, the question is not how to (over) simplify the nervous system and its diseases, but rather how to understand them in their entirety. Admittedly, the task of understanding the former has proven quite difficult. The second goal clearly depends on accomplishing the first.

As other authors have pointed out in different contexts, attempts to "atomitize" a subject of study into ever smaller bits without any context to their inter-relationships can be enormously detrimental (see, for example, Gould and Lewontin, 1979). Further, should the field really expect that a system as complex as the nervous system will break down in a simple way, or should it expect that its pieces will, in some measure, reflect its overall innate complexity? Almost for sure, it is the latter. At least, this is the perspective I will take in the pages that follow. I should acknowledge here that my bias against overusing reductionist approaches when considering neurological disease origins in as complex a system as the human central nervous system (CNS) is very much the polar opposite to the tack taken by Dr. Christof Koch, one of the foremost theorists on human consciousness (see Koch, 2012). The latter subject is surely as complex as the breakdown of the CNS in neurological diseases, but there may be some common ground (see Chapter 14).

As will be discussed in this book, the origin, function, and diseases of the nervous system are, by their very nature, complex, and are highly interconnected amongst the various types of cells and regions affected. The concept of biosemiosis, or biological signaling, is in this context highly relevant, and it will be highlighted in much of the discussion that follows. Moreover, the diseases upon which this book will focus are "progressive," meaning that they continue to get worse in terms of nervous system pathology and functioning over time. They are also age-related and somewhat sex-dependent, are complicated by the added complexities of genetic variations, individual microbiomes, and a host of other likely contributing factors.

How all of these aspects combine to produce any neurological disease is actually something that neurological disease research has not really begun to understand. If the nervous system is constructed as a complex system both developmentally and functionally, which it decidedly is, then it is surely so when it malfunctions. In brief, those of us in what can broadly be described as the neurological disease "field," a term that will be used throughout the book, are in rather dire need of a conceptual frame shift.

Many scientists are hard at work to accomplish such a shift, but they are swimming against a powerful tide of overwhelming amounts of data, which, as noted earlier, are often incorrect. How, then, is one to sort the wheat from the chaff, the valid from the invalid?

This book is intended to help the process along. Inevitably, in so doing, it will annoy some of my neuroscience colleagues as it may seem to imply that all their myriad experiments - often with amazingly spectacular methodologies - are not going to get the field to any answers without reframing the questions. Techniques are, after all, merely the equivalent of tactics in a military setting, simply, in this case, the means to accomplish the larger strategic goal of understanding these diseases. The strategic goal is aimed at an end state of prevention (or of effective treatment, as the second-best option).

Understanding this end state is actually critical to our collective wellbeing, because these various diseases are threatening to overwhelm the medical systems of the developed nations. (As for the developing countries, their medical systems are in many cases in poor enough shape as is, and hardly need the added burden of increased neurological diseases.)

My hope is that Neural Dynamics of Neurological Disease will spark debate. Time will tell if this hope has been realized. While desirable, indeed essential, from my perspective, such an outcome is decidedly a long shot. Scientific journals and meetings such as the SfN have become major industries, and are often mired in dogma, with an apparently dominant philosophy that "more equates to better."

It is clear from the work of Prof. John Ioannidis and others that more is not necessarily better if the data are incorrect or interpreted incorrectly and/or are not verified by replication, or at least convergent forms of information. Thus, of the approximately 28 000 talks and poster presentations at SfN, some two-thirds (or more) will be incorrect, and virtually none will be replicated. This is a vastly larger problem than most of those in the field realize, and I will touch upon it further in Chapter 8.

It is reasonable to assume that much of what follows in this book will be controversial, not so much because the data are contested (although in many cases they are) but because the way I have chosen to put them together in particular categories leads to certain conclusions. Other authors, ordering the subjects in different ways, might reach very different outcomes. In this sense, the process of writing a book is a lot like museum curatorship in that what one chooses to put on display versus what one leaves in the basement will provide very different narratives. When writing about neurological diseases, how one collates and arranges the key subjects and lesser items shapes the presentation, and thus the conclusions. And, needless to say, all authors have their own assumptions, prejudices for or against certain hypotheses and data, and ways of viewing any particular field of study.

Given this, it seems only fair at the outset for me to state my own assumptions. These are listed in a sequence from what I hope will be the least controversial, "motherhood" sorts of assertions to those that perhaps deviate to a lesser or greater extent from mainstream concepts of the nervous system in disease. Each will be bolstered by the relevant literature in the appropriate places in the book's chapters.

One point to be addressed first, however, is the...