Mapping the Mind: a conversation between LeDoux and Kandel Eric Kandel

22 08 2014

Here is a fascinating interview with Kandel, a Nobel laureate and professor of biochemistry and biophysics at Columbia University. In this conversation between LeDoux and Kandel you can learn how do our brains remember: http://vimeo.com/103749284

Enjoy!

 





Are Neuropsychiatric Disorders caused by Autoimmune Sydndroms??

15 05 2014

Did you know that recent high quality, cutting edge research indicates that neuropsychiatric disorders may be caused by definable autoimmune syndromes?  The theoretical implications of this line of research may significantly impact the way we understand, diagnose and treat persons with neuropsychiatric disorders!

Here are two reviews in this issue that you may find interesting:

The Emerging Link Between Autoimmune Disorders and Neuropsychiatric Disease

Neuroinflammation and psychiatric illness

 

 

 





THE UNCONSCIOUS: A bridge between psychoanalysis and cognitive science – Researchers and clinicians in dialogue

23 03 2014

This year the Joseph Sandler Research Conference was devoted to a central topic of the interdisciplinary dialogue between contemporary psychoanalysis and other scientific disciplines: the unconscious. In order to see the lectures of the leading researchers and practitioners that participated in this interesting conference click HERE.

I would like to thanks Ms. Irith Raveh, Founder and Chairperson at Israel Forum of Neuropsychoanalysis, that sent me the links to these great lectures.





Brain Awareness Month – What do we know and don’t know about the brain

12 03 2014

Brain Awareness

By Thomas Insel

This is the time of March Madness, Daylight Savings Time, and what Emily Dickinson famously called the “month of expectation.” March is also Brain Awareness Month, an annual celebration with school visits, community lectures, and lab tours to introduce the public to the mind-blowing world of neuroscience. A list of Brain Awareness events can be found at http://www.dana.org/brainweek/ , where you will also find that March 10 -16 is the peak for related public events around the world.

Since NIMH began focusing on mental disorders as brain disorders nearly two decades ago, educating people about the brain has been a priority for us. We often say that with the powerful tools of neuroscience, we can now use the brain to understand the mind, fulfilling the original vision that Freud had for a scientific psychology. But we have to remain humble about our understanding of the brain, because even our most powerful tools remain pretty blunt instruments for decoding the brain. In fact, we still do not know how to decipher the basic language of how the brain works.

A few numbers can help to define the challenge. The human brain is thought to have close to 86 billion neurons, each making on average about 10,000 connections. In contrast to most animals, our brains are largely made up of a heavily folded cortex, accounting for 80 percent of brain mass and about 100,000 miles of axons that provide the highways between neurons.1

How many different kinds of neurons are there in the brain? We really don’t know.  Unlike the heart or kidney, which have a small, defined set of cell types, we still do not have a taxonomy of neurons, and neuroscientists still argue whether specific types of neurons are unique to humans. But there is no disputing that neurons are only about 10 percent of the cells in the human brain. Most of our brain cells are glial cells, once thought to be mere support cells, but now understood as having a critical role in brain function. Glial cells in the human brain are markedly different from glial cells in other brains, suggesting that they may be important in the evolution of brain function. As one hint to their function, astrocytes, which are one form of glial cell, have been reported recently to “eat” synapses in the brain, providing a critical new mechanism for brain plasticity.2

How does the brain work? Again, we really don’t know. We have a very detailed understanding of how the heart pumps and the kidney filters, but how the brain encodes, stores, and retrieves information is still largely a mystery. We have known for over a century that most of the cortex is organized horizontally into six precise layers, and much of the cortex has vertical mini-columns, but how this matrix of horizontal and vertical structures computes information is not really clear.

Neuroscientists talk a lot about brain circuits. In fact, the word “circuit” is probably misleading. We do not know where most circuits begin and end. And unlike an electrical circuit, brain connections are heavily reciprocal and recursive, so that a direction of information flow can be inferred but sometimes not proven. We believe there are “emergent properties” of the brain that convert electrical signals into memories or dreams, but how this happens is still a mystery. Recent studies have shown that diffuse waves of synchronization across the brain may be critical for attention or learning, but we are just learning about these slow waves of activity, and whether they occur at the “speed of thought” is still debated.3

Of course, the spectacular images from MRI and PET scans have already given us maps for perception and fear and language and many other functions. As scanners have improved their resolution from 1.5T (tesla) to 3T to recent 7T magnets, and the protocols and analytic approaches have evolved, we now can map the cortical real estate associated with complex tasks like decision-making and face recognition. But these approaches, even with the best current technology, are still a 30,000-foot view of the action. Jay Giedd here at NIMH estimates that each gray matter voxel—the individual 3D pixels of 1 cubic mm that make up the scan—contains about 90,000 neurons, 400 meters of dendrites, and 4.5 million synapses. Each scan has over 650,000 voxels. And the actual measure is not neural activity per se but local blood flow, which changes slowly relative to the speed of thought.

In a sense, functional MRI (fMRI) is providing an image of something like the power grid of a city. fMRI slowly maps where and when different parts of the brain wake up, based on blood oxygen metabolism. By contrast, the street map of the brain is being mapped by the Human Connectome Project. Supported by the NIH Blueprint for Neuroscience Research , over 100 neuroscientists at ten sites in the United States and Europe are building something like a Google map for the human brain.  Scientists at Massachusetts General Hospital have created new MRI scanners with greatly enhanced resolution for looking at the geometric structure of the human brain.4 One remarkable claim from that work (still controversial) is that the fiber connections which heretofore looked like a bowl of spaghetti might actually have a relatively simple grid structure, allowing comparisons of connectomes between people. This kind of comparison is already underway at Washington University and the University of Minnesota where the Human Connectome Project  is obtaining the wiring diagrams of 1200 healthy adults, including 300 twin pairs. Thus far, data from the first 226 volunteers have been released on the Connectome website, with 10 gigabytes of data available for each subject. That’s right, this project is releasing the data as it becomes available to scientists everywhere—over 700 users are already mining the Connectome data to see how a Google map of the human brain might answer their questions.

Whether March for you means basketball, changing clocks, or expectations, I hope you will check out some of the Brain Awareness events. Brain science has become one of the most exciting frontiers of science. When I was a kid, the scientific frontier was “outer space.” Today it seems to be “inner space” that fascinates the boldest and brightest young minds (or should we say young brains). We are still at the beginning of what could be an era of brain exploration, with great promise for understanding more about how each of us thinks and dreams and loves, but perhaps even greater promise for helping people with mental disorders.

References

1 Lent R, Azevedo FA, Andrade-Moraes CH, Pinto AV. How many neurons do you have? Some dogmas of quantitative neuroscience under revision.  Eur J Neurosci. 2012 Jan;35(1):1-9. doi: 10.1111/j.1460-9568.2011.07923.x.

2 Chung WS et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways . Nature. 2013 Dec 19;504(7480):394-400. doi: 10.1038/nature12776. Epub 2013 Nov 24.

3 Salazar RF, Dotson NM, Bressler SL, Gray CM. Content-specific fronto-parietal synchronization during visual working memory Science 2012 Nov 23;338(6110):109-100. doi: 10.1126/science.1224000.

4 Wedeen VJ et al. The geometric structure of the brain fiber pathways .Science. 2012 Mar 30;335(6076):1628-34. doi: 10.1126/science. 1215280.





How the anatomical structure of the brain impacts its functional networks?

20 01 2014

Today I want to offer an interesting paper by Andreas et al (2013) that sought to  determine how the anatomical structure of the brain impacts its functional networks. I think that their interesting findings (see abstract below) may contribute to a better understanding of brain functioning in healthy people and people with neurodegenerative disorders such as Alzheimer’s disease and psychiatric disorders such as schizophrenia and bipolar disorder. Enjoy!

Andreas Horn, et al., “The structural–functional connectome and the default mode network of the human brain,” NeuroImage, 2013; DOI: 10.1016/j.neuroimage.2013.09.069

Abstract

An emerging field of human brain imaging deals with the characterization of the connectome, a comprehensive global description of structural and functional connectivity within the human brain. However, the question of how functional and structural connectivity are related has not been fully answered yet. Here, we used different methods to estimate the connectivity between each voxel of the cerebral cortex based on functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data in order to obtain observer-independent functional–structural connectomes of the human brain. Probabilistic fiber-tracking and a novel global fiber-tracking technique were used to measure structural connectivity whereas for functional connectivity, full and partial correlations between each voxel pair’s fMRI-timecourses were calculated. For every voxel, two vectors consisting of functional and structural connectivity estimates to all other voxels in the cortex were correlated with each other. In this way, voxels structurally and functionally connected to similar regions within the rest of the brain could be identified. Areas forming parts of the ‘default mode network’ (DMN) showed the highest agreement of structure–function connectivity. Bilateral precuneal and inferior parietal regions were found using all applied techniques, whereas the global tracking algorithm additionally revealed bilateral medial prefrontal cortices and early visual areas. There were no significant differences between the results obtained from full and partial correlations. Our data suggests that the DMN is the functional brain network, which uses the most direct structural connections. Thus, the anatomical profile of the brain seems to shape its functional repertoire and the computation of the whole-brain functional–structural connectome appears to be a valuable method to characterize global brain connectivity within and between populations.





Biological Psychiatry – 3G

29 12 2013

Here is a very recommended article for those who are interested in the mental health field:

The third wave of biological psychiatry

Henrik Walter1,2

1Research Division of Mind and Brain, Department of Psychiatry and Psychotherapy, Charité Universitaetsmedizin Berlin, Berlin, Germany
2Berlin School of Mind and Brain, Humboldt University, Berlin, Germany

Abstract

In this article I will argue that we are witnessing at this moment the third wave of biological psychiatry. This framework conceptualizes mental disorders as brain disorders of a special kind that requires a multilevel approach ranging from genes to psychosocial mechanisms. In contrast to earlier biological psychiatry approaches, the mental plays a more prominent role in the third wave. This will become apparent by discussing the recent controversy evolving around the recently published DSM-5 and the competing transdiagnostic Research Domain Criteria approach of the National Institute of Mental Health that is build on concepts of cognitive neuroscience. A look at current conceptualizations in biological psychiatry as well as at some discussions in current philosophy of mind on situated cognition, reveals that the thesis, that mental brain disorders are brain disorders has to be qualified with respect to how mental states are constituted and with respect to multilevel explanations of which factors contribute to stable patterns of psychopathological signs and symptoms.

Keywords: mental disorder, cognitive neuroscience, neuroimaging, genetics, philosophy of mind, philosophy of psychiatry, RDOC, DSM-5

WHAT IS BIOLOGICAL PSYCHIATRY?

As a first approximation we can say that it ties psychiatry closely to the biology of the brain. Under such a broad characterization today nearly everyone would qualify as a biological psychiatrist, as only very few would deny such a connection. However, there are stronger and more controversial claims, for example the ontological claim that psychiatric disorders are disorders of the brain, or, on the therapeutic level, that the best therapies are biological ones like medication or deep brain stimulation. However, many biological psychiatrists would not share these stronger claims, so this characterization seems too narrow.

To better understand the characteristics of the third wave, it will be helpful to take a short look at the first and second wave in the history of psychiatry (Shorter, 1998). The first wave in the second half of the nineteenth century can be best understood as a new research agenda. It was not so much characterized by the idea that the mental and the nervous system are closely linked – this was already believed by ancient philosophers – but rather by the ambition to uncover the relation between mind and brain by doing systematic research linking neuropathology and mental disorder and by using the experimental method in animals and humans. Wilhelm Griesinger (1817–1868), one of the most important figures of this first wave, famously declared: mental disorders are disorders of the brain. Note, that this was not primarily intended as a reductionist claim, but rather as a statement intended to delineate his ideas against the two prevailing approaches of that time: the moral approach on the one hand, and the somatic approach, linking mental disorder to body processes in the lung, liver or other organs, on the other hand. Nevertheless, Griesingers claim was not at all uncontroversial as theorists felt that such a brain approach would not do justice to the intricate psychopathological phenomena psychiatrists dealt with. For example, Karl Jaspers, the philosopher-psychiatrist, called 1913 the localationist models of two main protagonists of the first wave, Theodor Meynert and Carl Wernicke, “brain mythologies.”

In the early twentieth century, there was a decline in the biological approaches through various developments. Emil Kraeplin, one of the most influential psychiatrists at his time, started as an opponent to biological psychiatry, and developed his diagnostic system on systematic observations of symptoms and course of mental disorders, laying the groundwork for the later DSM. Also, psychological models, inspired by psychoanalysis and behaviorism became increasingly fashionable and had a large impact on therapy.

The second wave of biological psychiatry started only in the second half of the twentieth century and was, according to Shorter, driven by two new discoveries. The first was genetics, which could show that severe mental disorders, in particular schizophrenia, have a strong genetic component. The second was the discovery of efficient medication for various mental disorders (1949 lithium, 1952 chlorpromazin, 1957 imipramin, 1958 haloperidol, 1963 diazepam). They quickly became a major pillar of psychiatric treatment and contributed strongly to the opening and later disappearance of the large mental asylums in the second half of the last century. Soon, the concept of a neurochemical imbalance of neurotransmitters became the favored explanatory model for psychiatric disorders. Interestingly, at the same time as psychiatry for the first time used effective medications, the movement of antipsychiatry emerged. It was part of a more general political protest against tradition starting in the 1960s and declared “mental illness as a myth” (Szasz, 1961). It also was quite effective in discrediting one of the most effective treatments for severe depression, electroconvulsive therapy, supported among other things by the impressive movie “One flew over the cockoo’s nest” (1975) by Milos Forman. So although the second wave was in effect quite successful there was always some opposition against it on one hand, but on the other hand those insights and practices that were helpful for patients are now integrated into daily practice.

So what is the third wave of biological psychiatry? I want to suggest that this wave has started in the last two decades of the twentieth century and is now in full progress. Again, it has been driven by methodological and technological progress. Since the declaration of the last decade of the twentieth century as the decade of the brain by the president of the United States, neuroscience has developed into one of the largest research programs worldwide. According to my view, there were two developments particularly relevant in the transition of the second wave into the third wave. The first is the progress in the molecular neurosciences. The journal Molecular Psychiatry, founded in 1997, is now one of the fields most prestigious and most cited journals. It became increasingly clear that the effects of psychiatric drugs are not primarily exerted via the level of neurotransmitters in the synaptic cleft, but that there is up- and down-regulation of receptors, effects on intracellular cascades, and even regrowth of neurons in the hippocampus. The picture of the neurobiological changes underlying psychiatric disorders and treatment thus became much more complex and differentiated and it became apparent that different levels of brain organization are important which interact in a complex way. The second development was the birth of cognitive neuroscience and neuroimaging. This field studies information processing in the brain by combining the methods of experimental psychology with tools to record brain activity or to stimulate the brain. In fact, neuroimaging, in particular functional magnetic resonance imaging (fMRI) has contributed much to public “brain awareness,” by (although wrongly) suggesting that we can literally watch “the brain at work.” With the first human study published in 1991, fMRI has today become a major research tool in psychology as well as in psychiatry. This development could not have taken place without a large increase in computational power. In fact, computational neuroscience which tries to develop mathematical models of brain function, has become an important tool in explaining neurocognitive processes and recently the program of computational psychiatry has begun to evolve (Montague et al., 2012). Further methods and technologies have become available to investigate the interplay of genetics, experience and environment in the etiology and neural explanation of psychiatric disorders like imaging genetics, epigenetics, optogenetics, or deep brain stimulation. Also big science, combining large – omic datasets like the (epi)genom, metabolom, proteome, or connectom with clinical data is becoming more important in psychiatric research and allows for new ways of discovery. The underlying model is that of systems medicine, understood as an interdisciplinary field of study that looks at the dynamic systems of the human body as part of an integrated whole, incorporating biochemical, physiological, and environmental interactions that sustain organismic life. In brain science, the paradigm of localationist thinking is substituted increasingly by thinking in functional systems and brain connectivity patterns (Buckholtz and Meyer-Lindenberg, 2012).

At this moment, we are at a critical stage of the third wave. In fact, progress in the first decade of this century has been so impressive that researchers as well as media have been overenthusiastic with regard to the power of the new methods. In particular neuroimaging results, probably due to their seemingly simple and straightforward presentation, have ignited the imagination of researchers, lay people and the media. Results are reported, similar to genetic results, in a oversimplified causal language (“love is in the ACC,” “the God spot,” “gene for schizophrenia discovered,” etc.). Such oversimplified messages are well for drawing attention to headlines, but way over what really can be inferred from most studies. Consequently, neuroscience has recently been criticized for its overambitious claims, and the field of “critical neuroscience” has flourished in the last 5 years immensely with an increasing number of books, papers and blogs (for a respectable example compare Slaby and Choudhury, 2011). Actually, in neuroscience in general, as well as in cognitive neurosciences and neuroimaging in particular self-critical articles concerning methods have begun to be increasingly published (e.g., Kriegeskorte et al., 2009Button et al., 2012) which is a healthy self-correcting development.

According to the third wave of biological psychiatry, mental disorders are relatively stable prototypical, dysfunctional patterns of experience and behavior that can be explained by dysfunctional neural systems at various levels. As with any understanding of disease in general the notion of a “dysfunction” inevitable involves normative judgments of what is regarded as normal, functional, healthy on the one hand, and as abnormal, dysfunctional, pathological on the other hand. Further below I will come back to normative issues. But before I do so, let’s look at the concept of mental disorder within biological psychiatry.

WHAT ARE MENTAL DISORDERS?

Modern psychiatry has taken a lot of effort to make the description of psychopathology reliable by introducing standardized ways of exploring, describing and rating psychopathological patterns over time. In America, psychiatric disorders are diagnosed using the DSM-IV (published 1994), the Diagnostic Statistics and Manuals of Mental Disorders, the official handbook of the American Psychiatric Association (APA), sometimes referred to as the “bible” of psychiatry. According to DSM-IV mental disorders are diagnosed by carefully checking if subjects fulfill a certain number of psychopathological criteria for a certain amount of time. DSM-IV is agnostic on etiopathogenesis, i.e., the causal genesis of disorders, but rather has put emphasis of establishing a reliable, intersubjective schema for diagnoses on the psychopathological level. But what about validity, i.e., what is measured or rather intended to be measured with DSM-criteria? What kind of things are mental disorders? Kendler et al. (2011a) have distinguished four types of kinds that mental disorders could be. Essentialist kinds are based on an essence, e.g., an underlying cause, from which the defining features (the typical symptoms) do arise. Although this theory fits to some cases like progressive paralysis in syphilis or Mendelian defects in cholesterol metabolisms, it is now widely acknowledged that this model neither fits most chronic diseases as atherosclerosis, hypertension or autoimmune disease, nor psychiatric disorders. Rather, it is generally accepted that psychiatric disorders arise from a multitude of causes that are probabilistically related to signs and symptoms. Even in cases, where family and twin studies unambiguously have demonstrated that most of the variance is explained by genetics factors (e.g., up to 80% in schizophrenia) there is no single gene causing this disorder. Recently discovered risk variants explain only a tiny portion of variance, usually less than 1%, although, using imaging genetics, they can be shown to have much stronger effects on the brain level (Walter et al., 2011). A second approach is to understand psychiatric disorders as socially constructed kinds which are brought about solely by the human activity of describing and classifying but not by an underlying structure independent of human constructs. Although this still is a popular thesis in the camps of cultural relativists and anti-psychiatry, this theory is rarely taken serious today. Instead, it is now widely acknowledged that cultural influences and social factors play important roles in the expression of symptoms, e.g., in the content of delusions. But it is also clear that for certain prototypical diseases (e.g., schizophrenia, bipolar disorder, depression, and some anxiety disorders) there are invariant patterns in experience and behavior despite eminent cultural differences. Many people think that what matters most is how we handle mental problems. So maybe psychiatric disorders are best understood as practical kinds. This approach holds that psychiatric disorders do not carve nature at its joints but just are those kinds which are most useful for certain purposes, ranging from medical ones (diagnoses and treatment) to sociological or even political ones (this is the point of departure of anti-psychiatry). This model is grounded in pragmatist philosophy and instrumentalism and has some appeal. In fact, the philosophy of DSM is very close to this approach with its agnostic and atheoretical framework. Although the practical kind of view avoids metaphysical discussion (like: What is schizophrenia really?), it gives us no advice as how classifications should be build and goes against many realistic intuitions that are the basis of successful applications not only in medicine. Instead, Kendler et al. (2011a) argue for a concept that is based on a model originating in the philosophy of biology, dealing with the problem how species are classified and on recent developments in the theory of neuroscience: the concept of mechanistic property clusters (MPC). According to this view, the items to be classified rest on properties that need not to be shared by all members of a class, rather they should be understood as a cluster within an abstract space of features or properties in a multidimensional space. Some of those features may be more essence like, some more practical. Importantly, the MPC-view encourages the thought that there are robust explanatory structures to be discovered underlying psychiatric disorders. These explanatory multidimensional structures (genes, cell receptors, neural systems, psychological states, environmental inputs, social-cultural variables) are interacting in a complex and intertwined way, are sometimes fuzzy, but nevertheless stable. Importantly, it cannot simply be read from the superficial structure of items if they belong to the same kind. Rather, their membership is explained by the causal mechanisms that regularly ensure that their properties are instantiated together (a historical account). The interaction typically is inter-level, but can also be on the level on symptoms, thus mutually re-enforcing the pattern, e.g., in depression insomnia predisposes to tiredness and guilt predisposes to suicidal ideation. As MPC kinds are defined in part by the mechanisms that underlie and sustain them, the reductionist intuitions of old wave biological psychiatry are partially satisfied. However, the kind cannot be fully explained and thus understood if inter-level interactions, which are often hidden to the subject as well as to the external observer, are not taken into account. For example, it has been empirically shown that subjective explanations for depressive episodes by patients do not correlate with objective risk factors for depression (Kendler et al., 2011b) – a finding that makes it likely that explanations based on just a selection of levels (subjective experience and remembered behavioral events) do not explain depression well. The same can be said for simplified biological models of depression as a neurotransmitter deficit that ignores many of the other levels. Although the MPC-model does not tell us in advance what the relevant causal mechanisms are, it is consistent with the new biological wave in psychiatry which we will now characterize by describing a controversy around the introduction of DSM-5.

DSM-5 AND ITS CRITICS

On May 18th 2013 DSM-5 was launched at the meeting of the APA. When the APA started to work on DSM-5, it was hoped that it would be able to integrate new dimensional approaches (constellation of symptom dimensions, rather than categories of disorders) and more of the exploding neurobiological research results from the molecular and cognitive neurosciences. However, this hope was frustrated. Shortly before publication, the APA-DSM task force decided against these ideas, as it felt it would be too early and that research was not far enough to deliver sound evidence that could be integrated. Moreover, another feature of DSM-5 steered much controversies. Diagnostic criteria for some disorders were changed and new disorders were included. For example, the former exclusion criterion for the minimum duration of a depressive episode (normally 2 weeks, but after the death of a significant other at least 2 months) was skipped, which was criticized as the medicalization and pathologization of the normal human experience of grief. Diagnoses like binge eating disorder, mild cognitive disorder, and disruptive mood regulation disorder in childhood were introduced. These decisions were heavily criticized, most prominently by the psychiatrist who led the development of DMS-IV, Allen Frances. In fact, Frances had been arguing for years that DSM-5 was on the wrong track by introducing more and more disorders without taking into account that these will be overdiagnosed in practice and will create millions of new patients as well as justification for medication that is not indicated. In concert with the practices that advertisement for medication in the U.S. is allowed (not in most European states) this would lead to severe individual and societal side effects of overmedication, so the prediction of Frances and many other critics. Notably, he did not shy away to accuse himself of having performed similar mistakes by introducing three diagnoses in DSM-IV which he now regards as a mistake: attention deficit hyperactivity disorder (ADHD), child bipolar disorder and the Asperger-syndrome (a form of high-functioning autism). In his book “Saving Normal” (Frances, 2013) he argues that DSM-IV has been and DSM-5 will even be more leading to overdiagnoses, to pathologizing normal children and to the treatment of only slightly dysfunctional persons at the expense of taking care of the severely ill.

Here I will not discuss his arguments and the truth of his prognosis in detail, although it is highly likely that some of his predictions will become true, but rather point to an event surrounding the introduction of DSM-5 that makes the claims of the third wave of biological psychiatry clearer.

THOMAS INSEL’S ATTACK ON DSM-5

The date of the launch of DSM-5 at the APA meeting on May 18th was long known to everybody in the field. So it was probably not by pure chance that just 3 weeks earlier, on April 29th a blog was posted by Thomas Insel, a renowned neuroscientist himself (working in particular on oxytocin and vasopressin in animal research) and since 2002 director of the National Institute of Mental Health, the world’s largest research institute investigating psychiatric disorders. He declared that “the weakness (of DSM-5) is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment” (Insel, 2013). This is a harsh judgment. And he also drew consequences: “That is why National Institute of Mental Health (NIMH) will be re-orienting its research away from DSM categories.” This is quite a severe conclusion: just before the official diagnostic textbook of the APA is published after more than a decade of work, the largest research organization on mental health declares that it will orient its research away from DSM categories. Why? “(I)t is critical to realize that we cannot succeed if we use DSM categories as the “gold standard.” The diagnostic system has to be based on the emerging research data, not on the current symptom-based categories. Imagine deciding that ECGs (=electrocardiograms, H.W.) were not useful because many patients with chest pain did not have ECG changes. That is what we have been doing for decades when we reject a biomarker because it does not detect a DSM category. We need to begin collecting the genetic, imaging, physiologic, and cognitive data to see how all the data – not just the symptoms – cluster and how these clusters relate to treatment response” (Insel, 2013).

So, in a nutshell: psychiatry has not been able to develop any objective laboratory test for clinical use because the current development of such tests is based on superficial criteria (symptoms), but not on the causal explanatory structures that underly them. If these structures exist he is right: it is difficult to make progress if you are measured by the fit with a descriptive, possibly faulty diagnostic system.

But there are further, homemade, problems within scientific psychiatry. Shitij Kapur, the Dean of the Institute of Psychiatry in London, and coauthors, among them Thomas Insel, gave three possible explanations for slow progress (Kapur et al., 2012). First, many studies in biological psychiatry are underpowered, i.e., they perform p-value chasing with small numbers of subjects (or animals). A good example is psychiatric genetics, but the same argument has been put forward for neuroscience in general (Button et al., 2012). Secondly, many studies are only approximately replicated, i.e., with different methods, different scanners, different paradigms, making it difficult to judge whether an effect is really stable. Thirdly: many stable effects, i.e., effects with large effect sizes are only found in extreme comparisons, i.e., by comparing patients with healthy controls. However, for clinical purposes it would be much more interesting to compare different patient populations. Kapur et al. (2012) also suggest methods to improve the situation, including to increase power, share data, and to report data more accurately. Most importantly, they argue for a stratified medicine (and psychiatry), i.e., for the identification of biomarkers or cognitive tests that stratify a broad-illness phenotype into a finite number of treatment-relevant subgroups. To put it into their metaphor of jacket producing: not to hope for a jacket with one-fits all (the usual approach) but also not hoping for a personally tailored jacket (like in the overambitious project of personalized medicine) but rather to go for a series of chest sizes of jackets for different groups.

RESEARCH DOMAIN CRITERIA: COGNITIVE SYSTEMS, NEURAL CIRCUITS, AND DIMENSIONS OF BEHAVIOR

A paradigmatic example of how the third wave of biological psychiatry is trying to get a grip on mental disorder and their underlying mechanisms is the initiative of research domain criteria (RDoC) developed by the NIMH which has been suggested as an alternative to investigate mental disorders and develop new classifications that are based on observable behavior and neurobiological measures. According toMorris and Cuthbert (2012) it developed out of two initiatives that targeted schizophrenia, in particular the MATRICS (measurement and treatment research to improve cognition in schizophrenia) and the CNTRICS (cognitive neuroscience treatment research to improve cognition in schizophrenia). RDoC can be regarded as a generalization of these initiatives being constructed for application to all mental disorders. It is based on three central assumptions: (1) mental disorders are presumed to be disorders of brain circuits. (2) Tools of neuroscience, including neuroimaging, electrophysiology and new methods for measuring neural connections can be used to identify dysfunctions of neural circuits. (3) Data from genetics research and clinical neuroscience will yield biosignatures that will augment clinical signs and symptoms for the purposes of clinical intervention and management. It also includes developmental processes and interaction with the environment as orthogonal dimensions that should inform hypotheses and conclusions derived from the RDoC organization structure. This structure is organized as a 2-dimensional schema. One dimension includes constructs that represent five core domains of mental functioning: Negative valence systems, positive valence systems, cognitive systems, systems for social processes and attention/arousal systems. Each of these domains includes subconstructs (around five). For example the negative valence systems include: active threat (“fear”), potential threat (“anxiety”), sustained threat, loss and frustrative non-reward. To take another example: the cognitive systems domain comprises attention, perception, working memory, declarative memory, language behavior, and cognitive (effortful) control. The second dimension consists of units of levels of organization on which the constructs can be measured. These levels are defined as follows: genes, molecules, cells, circuits, physiology, behavioral, self-reports, and paradigms. The “circuits” unit of analysis refers to measures that can index the activity of neural circuits, either through functional neuroimaging or through recordings previously validated as circuit indices (e.g., fear-potentiated startle). “Physiology” refers to well-established measures that have been validated by assessing various constructs, but that do not measure brain circuit activity directly (e.g., heart rate, cortisol). “Behavior” may refer either to systematically observed behavior or to performance on a behavior task such a working memory. The advantage of this conceptualization in comparison to a purely symptom and course based system like DSM is that it is based on research on different levels, allows to characterize patients dimensionally, not categorically (diagnosis present or not) and that it is open to new evidence. Clearly, it cannot simply substitute DSM, which is based on long clinical experience, but it will inform classification based on multilevel science and might, in the long term, identify subgroups of patients that show characteristic constellations within this matrix that are helpful for categorization, treatment or management of patients. In the above mentioned blog Thomas Insel has announced that the NIMH will try to fund studies which follow such a transdiagnostic, systematic approach instead of studies that try to find neural correlates of categories that are simply based on the (superficial) clustering of signs and symptoms.

EVALUATING THE THIRD WAVE OF BIOLOGICAL PSYCHIATRY: A VIEW FROM INSIDE

By now the general approach or framework of the third wave of biological psychiatry should have become clear. It is focusing on a research-inspired, multi-level approach to understand what psychiatric disorders are, what mechanisms underly signs and symptoms and how an understanding of those mechanisms might help in classification, diagnosis, prognosis, and treatment. Note, that the approach does not entail the claim that biological approaches in a narrow sense are the best therapeutic approaches. It is as such neutral to the question what intervention will prove best to treat whatever there is. For example it may very well be that psychotherapeutic approaches will emerge as the best way to treat certain types of disorders. In fact, psychotherapists see no general problem in integrating their approach into such a framework as psychological mechanisms and principles that are effective in psychotherapy can be conceptualized as part of cognitive neuroscience itself (Walter et al., 2009Disner et al., 2011). Also, the role of psychosocial and cultural factors can be integrated effortlessly as the MPC approach by Kendler et al. (2011a),b makes clear: if social factors or societal and cultural mechanisms are part of the causal machinery that contributes to the instantiation of typical clusters of signs and symptoms that characterize psychiatric disorders they are part of the underlying explanatory structure.

However, probably many or at least some people will still view this approach skeptically. Indeed, there are several problems and limitations. To name just four of them: first, it could still be argued that the framework favors the neurobiological over other factors, as it entails the idea that psychiatric disorders are brain disorders. It will make no difference if you call psychiatric disorders “disorders of the brain” or “disorders of brain circuits” and thus do not justice to the mental within the concept of mental disorders. Second, the third wave does not include a solution to the normativity problem, namely the question when a constellation of psychological signs and symptoms is already a disorder or when it is still part of “normal experience,” so it will still promote a medicalization of life problems. Third, even if we somehow could solve the first two problems, it might be argued that a focus on the brain will lead to inefficient resource allocation because the outcome for patients is not worth the effort be put in. History has shown that all general claims that we will in the near future know “the” causes of mental disorders have failed, and the continuous failure of neurobiology (with some exceptions) to sufficiently explain or predict mental disorders shows that it cannot account for such complex phenomena. Therefore, we should rather focus on the well-known psychosocial factors contributing to the development or sustainment of psychiatric disorders which are much more relevant in practice.

A recent critique of the thesis that “addiction is a brain disease” can be interpreted as a condensed combination of these worries. It argues that addiction would only be a brain disease if it has (i) neural correlates, (ii) these correlates are pathological and (iii) that pathology is sufficient for the person to have a disease, in almost any accessible environment Levy, 2013. As addicts are able to quit in certain environments, addiction would not qualify as a brain disease. This is a very clever argument as it uses one feature of the multilevel approach, namely the role of environmental factors, to argue against the “disorder of brain circuits thesis.” Indeed, there is a grain of truth in this argument, but only insofar as it helps to distinguish “organic or neurological” from “mental or psychiatric” disorders. For example, neurodegenerative diseases like M. Huntington or Alzheimer will progress in almost any environment, whereas drinking might stop. However, there are two problems with this argument: first of all, it confuses behavior (drinking) with the disorder (alcohol addiction). It is well known that people suffering from alcohol addiction who manage to quit, still are addicted life-long and have a high propensity for relapse – exactly this might be explained by the brain disorder thesis. Secondly, the argument puts the stake much too high. Using the same kind of argument it could be argued that phenylketonuria, a genetically transmitted severe metabolic disorder is not really a metabolic disorder as it can be effectively treated by a diet, i.e., the pathology is not sufficient for a person to have a disease in almost any accessible environment.

Finally, some may argue, that also the third wave of biological psychiatry, like the preceding waves, will tend to devalue an approach to psychiatry that focues on the personal level. For example, the concept of MPC is based on the idea that regards minds as brains and brains as kind of machines that are causally effected by different levels. This approach, so the argument may go, ignores the personal level even if it may pay lip service to the subjective by for example including “subjective reports” in the RDoC grid.

There are several ways to response to these critiques from within, some of which I will mention here. First, admittedly, there is a common misunderstanding on the role of neurobiological findings in psychiatric disorders. Very often, it is either said, implicitly assumed, or implied that the mere fact that there is a neurobiological correlate of a mental dysfunction is already a proof that the “causes” of the respective disorder are biological in the same way as for neurological disorders. But this clearly is a misconception. Because every mental state has a correlate in the brain, we should be able to find at least in principle neurobiological correlates of any mental state, pathological or not. So the question is not, whether there is a neurocognitive correlate or mechanism, but whether it is pathological, how it came into being, whether it is persistent, whether and how it can be influenced, and so forth. In fact, the neurobiological misunderstanding even goes further in many cases as often it is wrongly concluded that the existence of a “brain signature” (to use a more neutral term) would already imply that the disorder cannot be controlled or changed by psychological means, or even that it is inborn or genetically caused, implications which clearly are non-sequitures, but widely believed.

Second, the normative problem indeed has to be addressed – not only by biological psychiatry, but also by any other approach to psychiatry, and not only for psychiatric but also for all concepts of disorders – and consequently it has been discussed in medicine in general. As it is in no way specific for psychiatry, let alone biological psychiatry, I will not discuss it here in detail but just make some remarks. It is clear that the sheer discovery of neural correlates or mechanisms of a disorder cannot prove a state as pathologically. This can be done only by spelling out a concept of normal functioning. If a biological approach claims to be able to define mental disorders without reference to norms it must fail. Normativity in the context of mental disorders comes at least in three guises, “statistical,” “biological design” or “value-preference laden” (Graham, 2013, p. 59). For example, most definitions of mental disorders include a criterion of suffering or of clinical relevance, that only can be spelled out with respect to a norm that cannot be read simply from biological facts. I will return to this issue later. Although it has to be admitted that the third wave of biological psychiatry does not take a specific stance to the normativity problem, it should be noted that this can be only used as a critique against variants of biological psychiatry that explicitly claim that normality can be inferred simply from biological measures.

Thirdly, why has neurobiology failed to deliver better results for explanation, diagnosis, prognosis or treatment? Some answers relating to methodological problems have been already discussed above (Kapur et al., 2012). However, a further explanation for only modest progress is often not mentioned. These are the ethical constraints under which biological psychiatric research has to operate which does make progress difficult. In contrast to other medical disciplines psychiatric research can access the “organ of the mind,” the brain, only indirectly. There is no known ethically justifiable way to directly access brain tissue to investigate assumed molecular mechanisms. In contrast, the heart, the liver, the kidney and many other organs can be accessed directly in therapy and research by taking biopsies or measuring metabolites in the blood. There are only a few exceptions to this barrier, for example the possibility to measure certain molecules non-invasively with magnetic resonance spectroscopy, or with research windows related to invasive therapeutic procedures in epilepsy surgery or deep brain stimulation. Direct access to the brain in animal research also has its problems, because rodents and humans differ in many respects and animal experiments are confronted with ethical issues, too. So the “failure” of biological psychiatry is not necessarily related to its concepts or theoretical approach, but partly may be explained by important and relevant ethical barriers we have implemented in human research for good reasons.

Fourthly, does a biological psychiatry approach imply disrespect for persons? First note, that this critic in its most general and radical form is not confined to biological psychiatry but to any psychiatric approach that claims that there are mental disorders in the first place. This antipsychiatric argument claims that mental illness in general is a myth by confusing sickness with life difficulties and by stigmatizing people with mental problems as having a disorder and thus not giving them the credit and responsibility for what they do and chose to be. In a more specific and much less radical, but more frequent variant (not claiming the non-reality of mental disorders) a biological approach of psychiatry is accused of resulting in an overenthusiastic reliance on medication and an insufficient use of understanding the life stories and real-world problems of patients. Without doubt, overmedication is a problem in certain strands of psychiatry and admittedly this may be due to the fact of an oversimplified picture of mental disorders (“For depression you need to substitute serotonine like insuline in diabetes”). However, many of these implications are not inherent to the concepts of the third wave of biological psychiatry but rather are based on older conceptions that postulated a close connection between etiology and therapy, that has been abandoned today in current practice. For depression for example there was a distinction between endogenous depression (from within, medication, no talking cure), neurotic depression (originating in childhood, talking cure, no medication) and reactive depression (understandable reaction after a life event).

The aforementioned responses to a critique to biological psychiatry were given from within psychiatry and psychiatric research in itself. Many of these issues revolve about the “disorder” part of mental disorders. However, I think that a more comprehensive way of assessing the prospects of biological psychiatry can only be found when we turn to the “mental” part of a theory of mental disorders. In order to do so we can turn to a rich resource that has reflected on the concept of the mental for a long time: philosophy of mind.

RECONSIDERING BIOLOGICAL PSYCHIATRY: A PHILOSOPHY OF MIND PERSPECTIVE

If we want to understand what mental disorders are then we should take the question what “the mental” is more seriously. Traditionally, there has been a close link between philosophy in general and psychiatric theorizing. Here, I will restrict myself to recent philosophy of mind approaches, as they are targeting similar problems as biological psychiatry: what is the connection between mind and brain? The idea behind consulting philosophy is simple: if we better understand how mental states are related to brain states we might better understand how disordered mental states relate to disordered brain states. Take for example the thesis of identity theory that assumes that mental states are identical with brain states. If this is true, it seems to follow straightforwardly that disordered mental states simply are disordered brain states. Or take the problem of reductionism and mental causation: if we were really able to show that mental states can be reduced to brain states, this would leave us with only two possibilities: either we have to eliminate mental states, because they are nothing more than a convenient, folk psychological way to talk about hidden brain states or we have to conclude that mental states are epiphenomenal, i.e., have no causal powers. This seems like a conclusion only few people would like to embrace. Or take the idea of dualism. Do we have to assume a special substance that does all the work in explaining mentality that is in a separate ontological realm outside of physical reality?

However, if we dwell too deep into the heart of philosophy of mind, the danger is great, that we will end up with metaphysical debates that might too easily be dismissed as theoretical talk with no direct relevance for psychiatry. Instead, I will refer here to two examples of the relevance of philosophy of mind for psychiatry: one specific approach of a theory of mental disorder by a philosopher (George Graham) and one family of problems discussed in contemporary philosophy of mind, namely if mental states extend beyond the brain in a relevant sense.

A comprehensive and accessible version of linking philosophy of mind and mental disorders has been given by Graham (2013). In his theory he explains what mental disorders are, according to which (normative) criteria we classify them as clinically relevant and how they differ as mental disorders from proper brain (=neurological) disorders. According to Graham a mental disorder is a disability, incapacity or impairment in one or more basic or fundamental mental faculties of psychological capacities of a person that has harmful or likely harmful consequences for its subject. It is a disorder because it is harmful and undesirable for the subject, whether the subject himself appreciates this or not. In more concrete terms this means that the person is worse off with than without the disorder, that the disorder has a non-voluntary and personally uncontrollable nature and that the disorder cannot be excised or extirpated by the mere addition of other psychological resources. For example, the delusion of a paranoid person will not be alleviated by giving more information about the content of his delusion and the sadness of a depressed person will not be cured by cheering him up. Mental disorders are mentaldisorders because they are brought about by a mix of mental forces and brute a-rational neural mechanisms, or at least Graham argues so. The crucial point here naturally is what Graham means by mental forces. He explicitly states that he is not a dualist. Rather, he tries to argue what the “mental” in mental disorders refers to. The mark of the mental is that states of mind are constituted by either or both of two elements, i.e., consciousness and intentionality. Only if the causal mechanisms bringing about or sustaining a mental disorder work through conscious and/or intentional states, so Graham claims, they should be categorized as mental disorders. Mental symptoms that arise from brute brain affections (like stroke, neurodegeneration, or infection) are neurological disorders even if they present with (secondary) mental symptoms. Also, the mental is decisive for the criteria when a mental state of mind should be regarded as a disorder and not as a variant of normal mind life: namely when they impact a person’s reason-responsiveness or rationality considerably without totally destroying it.

In Graham’s theory the mental plays a prominent role in several respects: first, because the mechanisms causing or sustaining mental disorders are supposed to work through those brain mechanisms that implement mental (intentional and/or conscious) states and thus through mental qua mental. Second, the normative criteria for clinical relevance (and thereby the criteria for separating normality from disorder) rely on the impairment of intentionality and rationality, i.e., marks of the mental. Thirdly, he argues that mental disorders (like panic attacks, schizophrenia, depression) should and can be distinguished from proper neurological brain disorders (like stroke, Parkinson, Alzheimer) by the fact that the latter are brought about by pure mechanical, brute, a-rational affections of the brain that moreover are not sensitive to psychological (mental) treatment. In contrast, the “mental” in mental disorders has a double role: first it is characterized by an impairment of intentionality and rationality and second, because these marks of the mental are not totally absent but within the symptoms there is still a sense of rationality and intentionality preserved.

A problem in Graham’s theory is his explication of mental forces. Sometimes, he seems to imply that rationality or intentionality have a causal power of their own, although he denies that. But the worth of his approach for biological psychiatry seems for me that he insists on the relevance of the role of the mental in understanding, explaining and identifying mental disorders against pure brain disorders and non-pathological mind states on the other. In fact, many proponents of biological psychiatry now accept an interplay of neurobiological and psychological (mental) factors. However, if the mental is identical with the neural what does this claim of interaction amounts to? So let us turn then to the important question, if the mental can really be reduced to the neural.

In philosophy and in cognitive sciences there exist a number of proposals that doubt that cognitive processes (for our purpose: mental states) are best understood as only internal processes that happen within a cognitive system (in our case: the brain). Internal approaches, so the basic idea, ignore that cognitive processes are situated, i.e., that they essentially depend on (weak version), or even may be constituted by (strong version), their embodiment and the interaction with the natural, technological and social environment. There is not yet a consistent or complete theory of situatedness, rather there are several strands of research and theorizing that can be subsumed under the catchword “the 4Es”: the embodied, extended, embedded and enacted mind (Lyre andWalter, 2013). The main idea is that in order to understand what cognition (the mental) is, it is necessary to take into account that cognitive capacities of a system may depend on the fact that those systems (our brains) are (i) embodied, i.e., coupled to our bodily constitution and that it therefore is necessary to regard the bodily realization of cognitive abilities as an integral part of the cognitive architecture; (ii) situationally embedded, i.e. are dependent in a specific way on their environment, i.e., cognitive systems exploit the specific circumstances of their environmental context in order to increase their performative abilities, (iii)extended, i.e., extend over the boundaries of our body into the technological or social environment and thus are constituted not only by internal factors but also by external, environmental factors and (iv)enacted, i.e., arise only by the active interaction of an autonomous systems with its environment (Walter, 2010).

The thesis of embodiment has a long tradition in phenomenological philosophy, e.g., in the writings of Merleau-Ponty. The thesis of the extended mind has more recently been introduced into the debate by a paper published in 1998 (Clark and Chalmers, 1998). They introduce an example of an external device for memory (a cognitive process) that has since then been discussed extensively in the literature. The example refers to the notebook of Otto, an Alzheimer patient with memory problems who uses his notebook instead of his normal physiological memory in order to remember certain things. The argument is that if the entries into the notebook play the same role in Ottos life and in the explanation of his behavior as neurally implemented memory contents in healthy adults, it would be arbitrary or neural chauvinism if we would not regard them in the same way as genuine parts of the material substrates of his normal memories and beliefs. The general form of the argument inherent in this example is called the parity principle: if a part of the world functions in a way that, would it happen in our brain, we would have no hesitation in recognizing as part of a cognitive process, then that part of the world is part of the cognitive process. To make this part of the process more plausible it is easy to modify the example such that the notebook is constructed as a brain-computer-interface, e.g., as a digital device coupled more directly to the brain, for example in a technological advanced form of the actually existing google glasses.

Why could the 4E thesis be relevant to understand the nature of mental disorders? Because they regard processes external to the brain as constitutive for mental processes and thus also as constitutive for disordered, pathological mental processes. An example, where this might be relevant is ADHD. ADHD might be only correctly diagnosed as a mental disorder if the external world is such that adolescents grow up in an environment that favors attentional distraction and punishes hyperactivity. In a similar vein, anorexia nervosa, a severe and often deadly mental disorder in Western countries seems to be much less frequent or even non-existent in environments in which a slim figure and control of eating and weight is not promoted, like in poor countries in Africa. These facts seem to draw into doubt that every currently acknowledged mental disorder is best categorized as a pure brain disorder – which is not to deny that internal processes of the brain play an important role if specific circumstances hold.

The main point which I would like to make here is that biological psychiatry has to take into account theories about how the mental is constituted. The new wave of biological psychiatry might be able to incorporate these issues into its conceptualization of mental disorders – but only if it comes along with a consistent theory of the mental that should take into account arguments and insights of philosophy of mind.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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The Human Brain Project

15 10 2013

A 10-year, billion pound neuroscience project which aims to revolutionise our understanding of the human brain has begun. To learn more about this amazing project click Here

 





The Neuroscience of Sleep

2 09 2013

This time I want to offer you an opportunity to hear a great lecture by Russell Foster about the The Neuroscience of Sleep. To see his speech click HERE. Enjoy!





The BRAIN Initiative on The Charlie Rose Brain Series

22 07 2013

Please see the Charlie Rose Show Brain Series that discusses the greatest mysteries in science and one of the greatest challenges in medicine: The BRAIN. In this show you can see and hear the GREAT: Eric Kandel of Columbia University, Thomas Insel of the National Institute of Mental Health, Story Landis of the National Institute of Health, Cornelia Bargmann of Rockefeller University and William Newsome of Stanford University. ENJOY!

 

 

 

 





Psyche and Soma in the 21th Century

3 06 2013

Here is a recent paper by Siri Hustvedt that was published at Seizure, Volume 22, Issue 3 (2013, pp 169–173). I hope and belive that you will find this thought provoking paper interesting and relevant.

Philosophy matters in brain matters

Abstract

Purpose

Although most neuroscientists and physicians would argue against Cartesian dualism, Descartes’s version of the psyche/soma divide, which has been controversial since he proposed it in the seventeenth century, continues to haunt contemporary neurological diagnoses through terms such as functionalorganic, andpsychogenic. Drawing on my own experiences as a person with medically unexplained seizures, I ask what this language actually means if all human experience has an organic basis.

Methods

Close reading of a textbook chapter on psychogenic seizures.

Results

I expose the author’s unreflective embrace of psyche and soma as distinct entities, his inherent bias against illnesses labeled psychogenic, and the implicit sexism of his position. I further argue that even when a patient’s symptoms are not alleviated, heightened self-consciousness and narrative framing can strengthen his or her sense of agency and have therapeutic benefits.

Conclusion

The ethical treatment of patients requires a respect for their stories.

Keywords

  • Cartesian dualism;
  • Functional;
  • Organic;
  • Psychogenic seizure;
  • Agency;
  • Narrative

In a novel I am writing now, one of my characters says, “All dying people are Cartesian dualists.” This overstatement hides a piece of the truth. Illness can make almost every person vulnerable to a mind/body split. If the ill person can still think clearly, he often suffers an acute feeling that his body has betrayed him, that it has gone its own way without him. The thinking, speaking ego, what I like to call the internal narrator, appears to exist independently of the afflicted body and becomes a floating commentator on the goings-on, while the symptoms of disease wreak havoc on the poor mortal body. Subjective experience often includes a self that observes illness, even though the very idea of the self remains a philosophical and scientific conundrum.

René Descartes’s dualism—his assertion that human beings are made of two stuffs, spirit and matter—is unfashionable these days and has, in fact, been highly controversial since his own time. In her Philosophical Letters of 1664, the natural philosopher, Margaret Cavendish wrote, “I would fain ask them…where their Immaterial Ideas reside, in what part or place of the Body?” Neuroscientists, many of whom, I dare say, have read little Descartes, repeatedly echo Cavendish’s complaint about Cartesian dualism (one I share), and yet, it is important to state that as of now there is no consensual theoretical model for the brain-mind. The neural correlates of consciousness, NCC—which might help explain the chattering internal narrator inside each one of us—have not been found. The terms neural correlates, underpinnings, andrepresentations do not close the psyche/soma gap, they expose it. What we have are overwhelming amounts of data, much of it from scans, but from other research as well, and that data is racing far ahead of any overarching theory of brain function.

But why is this important? And what does it have to do with doctor-patient ethics and medically unexplained symptoms? Medical knowledge is continually evolving and is always dependent on new research. But as Thomas Kuhn pointed out in The Structure of Scientific Revolutions, the course of that research also rests on paradigms, primary assumptions that lie beneath all scientific investigation, and sometimes those paradigms shift. There is increasing recognition that the terms functional and organic may be misconstrued from the start and rest upon an artificial psyche-soma divide. As I pointed out by quoting Cavendish, materialist monism is hardly new. In his introduction to Outlines of Psychology (1895), Wilhelm Wundt carefully articulates the debates between metaphysical and empirical psychology and comes down clearly on the empirical side, arguing that from his point of view “the question of the relation between psychical and physical objects disappears entirely”.Bio-physicists, such as Hermann von Helmholtz in the nineteenth century, were materialists, as was Jean Martin Charcot, the French neurologist who never ceased hoping he would discover during autopsy the brain lesions that caused hysteria.  And Sigmund Freud who coined the term conversion for hysterical phenomena never stopped insisting that for him psychoanalysis was a “biological psychology.” In Borderlands in Psychiatry, published in 1943, Stanley Cobb, echoing Wundt, wrote:

I solve the mind-body problem by declaring there is no such problem …I would insist that the old dichotomies ‘functional or organic,’ ‘mental or physical’ are not only wrong, but lead to bad habits of thinking because they lead to static and obsolete ideas and do not allow for modern pluralistic and dynamic ideas of matter and structure…Anyone who stops to think realizes that no function is possible without an organ that is functioning and therefore no function takes place without structural change.”

This is indubitably true. Every phenomenal thought and feeling is accompanied by brain changes.

In my 2004 edition of Campbell’s Psychiatric Dictionary, the word psychogenic carries the following definition: “Relating to or characterized by psychogenesis; due to psychic, mental or emotional factors and not to detectable organic or somatic factors.” The definition may be saved from dualism by the worddetectable, but probably not. Nevertheless, it is interesting to ask whether the distinction between psychological and physiological should be erased from medical vocabularies or whether they continue to serve some useful purpose.

I am one of countless people in the world beset by an undiagnosed and medically unexplained symptom of a neurological character. I wrote a book about it called The Shaking Woman or A History of My Nerves that was published in 2009. The book is an interdisciplinary investigation of my symptom, which draws on insights from philosophy, the history of medicine, psychiatry, psychoanalysis, neurology, and neuroscience research. Early in the book, I describe the first shaking episode that occurred two years after my father’s death in May of 2006. I had been asked to give a speech in memory of my father at a ceremony held on the campus of the college where he had been a professor for over forty years.

Confident and armed with index cards, I looked out at the fifty or so friends and colleagues of my father’s…launched into my first sentence, and began to shudder violently from the neck down. My arms flapped. My knees knocked. I shook as if I were having a seizure. Weirdly, my voice wasn’t affected. It didn’t change at all. Astounded by what was happening to me and terrified that I would fall over, I managed to keep my balance and continue, despite the fact that the cards in my hands were flying back and forth in front of me. When the speech ended, the shaking stopped. I looked down at my legs. They had turned deep red with a bluish cast.

My mother and sister were thrown back by the mysterious bodily transformation that had taken place within me. They had seen me speak in public many times, sometimes in front of hundreds of people. Liv [my sister] said she had wanted to go over and put her arms around me to hold me up. My mother said she had felt as if she were looking at an electrocution. It appeared that some unknown force had suddenly taken over my body and decided I needed a good sustained jolting. Once before, during the summer of 1982, I’d felt as if some superior power picked me up and tossed me about as if I were a doll. In an art gallery in Paris, I suddenly felt my left arm jerk upward and slam me backward into the wall. The whole event lasted no more than a few seconds. Not long after that, I felt euphoric, filled with supernatural joy, and then came the violent migraine that lasted for almost a year, the year of Fiorinal, Inderal, cafergot, Elavil, Tofranil, and Mellaril, a sleeping-drug cocktail I took in the doctor’s office in hopes that I would wake up headache-free. No such luck. Finally, that same neurologist sent me to the hospital and put me on the antipsychotic drug Thorazine. Those eight stuporous days in the neurology ward with my old but surprisingly agile roommate, a stroke victim, who every night was strapped to her bed with a restraint sweetly known as a Posey, and who every night defied the nurses by escaping her fetters and fleeing down the corridor, those strange drugged days, punctuated by visits from young men in white coats who held up pencils for me to identify, asked me the day and the year and the name of the president, pricked me with little needles—Can you feel this?—and the rare wave from the Headache Czar himself, Dr. C., a man who mostly ignored me and seemed irritated that I didn’t cooperate and get well, have stayed with me as the blackest of all black comedies. Nobody really knew what was wrong with me. My doctor gave it a name—vascular migraine syndrome—but why I had become a vomiting, miserable, flattened, frightened ENORMOUS headache, a Humpty Dumpty after his fall, no one could say.

Perhaps because I had had one seizure before, and had suffered from violent migraines with vomiting since childhood, not to speak of my unhappy stint in Mount Sinai, I did not rush to a neurologist. My headaches had often been preceded by auras, with their sparkling lights, black holes, supernaturally clear vision but also fogs, lifting feelings that gave me a sensation of being pulled upward, and just once, a Lilliputian hallucination, during which I saw a little pink man and pink ox on the floor of my bedroom. A single episode of shaking did not cause me undue alarm. It appeared to be another curious adventure in a life marked by neurological instability. I had febrile convulsions as an infant and since my mid-thirties have had paraesthesia or what I refer to as “the body electric.” Because I had at the time of my first convulsive fit and still have an abiding interest in neuroscience, I asked myself what on earth had caused it. Because it appeared to have been triggered by the speech about my father, I began to suspect a diagnosis of conversion disorder or hysteria. The shaking fits happened again. They did not happen every time I spoke in public, only once in a while, and then while climbing hard and fast on a rocky mountain trail in the Pyrenees, out of sight of my companions who were far behind me, I felt light-headed, strange and, still panting from my exertion, I sat down on a rock to catch my breath and felt my whole body go into violent shaking yet again. I felt wobbly, drained and unwell for the rest of the day. I began to doubt my own diagnosis. Maybe my shaking wasn’t hysterical. After all, the good news about psychogenic seizures is that they can’t kill you.

During my medical saga, I saw a psychiatrist, a psychoanalyst, and a neurologist. My brain MRI showed nothing. The benzodiazepine lorazepam did nothing to quiet my shakes, but the Beta-blocker propranolol has been effective, although occasionally I have felt a buzzing, humming sensation in my body, which I take as a warning that without propranolol, I would probably be flapping like crazy. None of the doctors—they were all doctors—believed that I was having conversion episodes and yet, none of them could say exactly what I had either.

After I published my book, I received letters from physicians and researchers all over the world. (The book was translated into several languages.) There were two kinds of letters: those from doctors who were interested in some of the points I had made and either elaborated upon them or complemented me on my insights and those in which I was offered a diagnosis. It is fascinating to note that I did not receive two diagnoses that were the same. I especially remember a letter from a medical researcher who was convinced my shaking was being caused by a particular bacteria. Testing for the bacteria turned out to be so elaborate and limited to a few specialists that I never pursued it. So how to label my shakes: functional, organic, psychic, somatic, psychosomatic?

The practical use of the word organic turns on visible location—a brain lesion or abnormal electrical brain discharges that explain the symptom—but its use also unearths ideas about what is real and unreal. The bias is: if you can see it and name it, it’s real. If you can’t, it’s not. New technology has altered visibility. Oxygenated blood flow can be seen on scans, but blood flow is hardly a lesion. In popular culture it has become common to talk about depression as “a chemical imbalance”, as if balancing a person’s neurochemicals, whatever that might mean, can resolve the complex reality of depression. Schizophrenia has also become “an organic brain disease”, although its cause is unknown. The reduction of psychiatric illness to brain processes comforts patients and their families because the evocation of neural networks appears to confirm the physical reality of their illnesses. Cultural and medical hierarchies about the psychic or physical nature of disease infect our attitudes toward them. Unfortunately, chemical imbalance and organic brain disease don’t mean much, despite the fact that the brain is obviously at the bottom of these ailments.

Epilepsy is classified as an organic disease, psychogenic non-epileptic seizures or PNES as a functional disorder because no physical site of injury can be found. Nevertheless the two are often confused. EEG’s may be ambiguous, and not all epileptic patients have revelatory MRIs. The neurologist who suspects PNES must become a medical detective, relying on a clue from her patient, such as a seizure triggered by some powerful emotional event. Then again, there are epileptic patients who can seize after a shock or a strong emotional experience, too. The doctor may note the failure of medication to stop the fits. Of course, medication sometimes also fails to cure genuine epileptic seizures. And because some epileptic patients also have PNES, the picture can grow pretty murky.

The Treatment of Epilepsy: Principles and Practice, 4th edition, 2006, has a chapter on PNES. The author of this chapter adopts a confident authoritative tone, no doubt intended to buck up budding neurologists who might be worried about misdiagnosis. In a section labeled PSYCHOPATHOLOGY, he declares PNES a psychiatric disorder and rehashes the DSM criteria for somatoform disorders, factitious disorders, and malingering. Somatoform disorders are “the unconscious production of physical symptoms caused by psychological factors.” He then emphasizes that the patients are not faking, unlike the factitious folks and malingerers. He makes no comment on the controversies that surround the DSM’s metamorphosing categories or its lack of etiology. He mentions that sexual trauma or abuse may play a role in psychogenic seizures, and then, at the very end of this small section, the reader is told, “From a practical point of view the role of the neurologist and other medical specialists is to determine whether organic disease exists. Once the symptoms are shown to be psychogenic in nature, the exact psychiatric diagnosis and its treatment are best handled by a psychiatrist.”To be brief: send the patient to the other ward.

Under the following section called MANAGEMENT, the reader is told how important it is for the neurologist to communicate the psychogenic diagnosis using words such as “psychological,” “stress induced,” and “emotional… The physician communicating the diagnosis must be compassionate (remembering that most patients are not faking), but firm and confident (avoiding “wishy-washy” and confusing terms).” The author is clearly unfazed by any philosophical difficulties involved in opposing organic to psychogenic. He does not bother to say that emotion and stress are also organic processes, albeit not ones connected to specific, locatable brain damage. His discussion is inherently dualistic.

Rounding up his chapter, he names several “fashionable” syndromes that may be thought of as partly or “entirely psychogenic”. The words entirely psychogenic are followed by parentheses, inside of which we find the emphatic explanatory phrase “without any organic basis.The implication is that they are somehow non-organic, but how can that be? Are psychogenic seizures unreal, ungrounded, and immaterial? Are they brought on by supernatural, spiritual forces? The syndromes he mentions include fibromyalgia, fibrositis, chronic fatigue syndrome, and irritable bowel. Note the use of the word fashionable. The word fashionable is a put-down that effectively turns these syndromes into flimsy, effeminate, short-lived phenomena, similar to this year’s skirt lengths or a new rage for open-toed shoes. Fibromyalgia, fibrositis, irritable bowl, and chronic fatigue are all diagnosed far more in women than in men, but this may in part be due to prejudice. One study has shown that fibromyalgia appears to be under-diagnosed in men.

The ethical implications of my semantic analysis of these passages are not difficult to extrapolate. It is not that distinguishing between epileptic and non-epileptic seizures isn’t important or that their etiologies aren’t different. Of course they are. It is that the author’s supposedly neutral language is colored by a philosophically naïve, hierarchical conception of the physiological over the psychological. He does not even tip his hat to the truism that organic brain processes accompany all subjective psychological experiences. Nor does he cite research on the neurobiology of emotion and its implications for psychiatric illness.

During emotional shocks or trauma, the body goes into a state of emergency, and there is considerable evidence that repeated shocks create lasting physiological changes. Although the mechanisms are unclear and the results mixed, there is increasing evidence that both cortisol levels and hippocampal volume are affected, to give just two examples.And epigenetic studies are beginning to uncover the effects of stress on gene expression. I will cite a single example, a 2010 paper in Biological Psychiatry “Epigenetic transmission of the impact of early stress across generations.” The study exposed male mice to repeated and unpredictable maternal separation, which had the effect of altering the profile of their DNA methylation—the modification of a DNA strand after it has been replicated. Comparable changes in methylation were seen in their offspring even though they were reared normally. To make it short, stress altered the pattern of gene expression not only in the parent, but in the next generation. That traumatic stressors appear to play a role in conversion disorder is well known but poorly studied, and yet the burgeoning research being done in affective neuroscience warrants, at the very least, a careful reevaluation of what we mean by functional illness.

Lurking beneath our author’s use of the word fashionable, alas, is an implicit sexual bias that dismisses incompletely understood syndromes as all-in-your-head feminine complaints. The widely-held belief that psychogenic or conversion phenomena are up to ten times more common in women than in men, a statistic cited in the DSM, only increases the odds that sexism plays a role in the characterization of psychogenic illness. The truth is that conversion seizures have been recorded in the largest numbers among combat soldiers, most of whom, until recently, have been men. The trenches of World War I were seething hotbeds of psychogenic illness. My guess is that the horror of helplessness in soldiers who were literally stuck in a hole as they watched their fellows being blown to bits, goes a long way in explaining why “shell shock” became the illness of the Great War. And it is not over. Many veterans of Iraq and Afghanistan also suffer from conversion seizures.

The problem is getting the Veteran’s administration to recognize their suffering as real. A letter posted on line in 2007 by a veteran of both Iraq and Afghanistan may stand as exemplary. The man had myriad symptoms—headaches, a recurrence of odd smells, shortness of breath, fatigue, and seizures. After an EEG, he was told that his seizures were non-epileptic, the result of conversion disorder. I quote: “… the head of neurology, Dr. Sams, came in and stated that everything was in my head and it was all PTSD related”. The patient was discharged and told to get physical therapy. It is not odd that he was puzzled. “… if it is mental”, he writes, “then why am I going to physical therapy for it?”.

It is highly unlikely that the neurologist author of the textbook chapter on PNES would admit to naïve dualism, sexism, or bias against emotionally produced illness, but I suggest they are all present nevertheless. Historical context provided by medical history may serve as a corrective to these underlying prejudices. In the first of the fifteen lectures he gave at Harvard in 1907, collectively titled The Major Symptoms of Hysteria, Pierre Janet confronted the ambiguous character of what would now be called psychogenic ailments. The symptoms of the disease are, he says, “exceedingly numerous” and “its limits…very vague.” He acknowledges that contemporary authors do not agree about what falls under the term hysteria, but then goes on to articulate a far broader ambiguity that every doctor and every patient should bear in mind, “This indecision generally surprises young people. You think that, in science, things are perfectly definite, and you are very much astonished to find indecision in your masters. In reality definiteness does not exist in natural phenomenon; it exists but in our systematic descriptions. It is the men of science who cut separate pieces out of a whole that nature has made continuous… Physicians, it is true, may agree in certain cases, when there is a distinctly visible objective phenomenon characterizing such and such a lesion…but unfortunately we have nothing of the kind at our disposal to define diseases of the mind” (my italics).

Janet was a neurologist and a philosopher. His Kantian inheritance is clear in his statement that it is we who cut the world into pieces. We cannot leap out of our minds, become omniscient, and see the world as it is. Objectivity in science is not an absolute, but one determined by consensus, as Janet points out, an agreement about a lesion, for example. And yet, those same “objective” categories change over time. In 1907, hysteria had not yet been handed over to psychiatry. Charcot, with whom the younger Janet worked at the Salpétrière hospital in Paris, regarded hysteria as a natural phenomenon, period, with an unknown physical cause. Hysterics were not insane. For Janet, hysteria had a psychobiological character caused by a mental dissociation of particular functions from others, through what he called “a retraction of the field of personal consciousness.” What is missing, he argues, is “the faculty that enables the subject to say, ‘It is I who feel, it is I who hear.” Specifically addressing hysterical tremor, Janet writes, “In some rare cases, you can find behind the tremors, as behind the tics, the existence of a fixed idea separated from the consciousness.” Janet’s idée fixe was an idea that had been unconsciously transformed into a somatic symptom.

Whatever its cause, a conversion seizure is involuntary and real. With scans, it is now possible to see visible asymmetries in the brains of conversion patients that resolve themselves when the affliction ends. This, of course, does not explain what conversion is even in neurobiological terms; it simply points to organic changes. In The Shaking Woman, I quote a paper in Neurology by Trevor Hurwitz and James Pritchard in 2006 published a century after Janet’s lectures at Harvard: “conversion reactions are fixed beliefs of somatic dysfunction arising from psychological distress that control cortical and subcortical pathways to produce patterns of loss or gain of function that are not organic in the conventional sense.” This is no more precise than Janet’s description in 1907, and a good deal less thoughtful. They also lift the term “fixed belief” from a much earlier era of psychiatry, probably from Janet. I also quote a 1998 paper in Psychiatry Research, in which the authors are more straightforward: “…the question of how special psychological processes transmute into neurobiology has yet to be answered.” I point out that this is exactly what Freud asked and hoped to answer in 1895 when he was working on his Project. How do we ethically frame the murky territory of non-epileptic seizures?

The veteran, who after an EEG, is summarily told his symptoms are “all in his head” and sent off to physical therapy without further ado, has clearly been treated unethically. The problem is not the diagnosis of conversion necessarily, although I wonder about the man’s olfactory hallucinations and whether his physicians may have missed something. The problem is that his subjective experience of suffering has been dishonored by cavalier treatment and, frankly, ignorance about the organic character of what is now called PTSD. The most terrible thing that can happen to a patient is to be robbed of the dignity of his own narrative.

Every illness has a story because every illness is a dynamic, not a static phenomenon that exists in time. Therefore static, mechanistic models, whether in neurology or psychiatry, inevitably distort the character of any illness. Patients must be allowed to tell their stories, and they must be listened to as experts on the nuances of their own symptoms. Their case histories are valuable as documents of an unfolding story, and no two narratives will be identical, but there is also a therapeutic value in telling itself, which is related to the all important question of agency. Every illness chips away at this aspect of the self. The disease or symptom creates feelings of helplessness, vulnerability, and a general sense that one lacks control over one’s own life. But even when a disease or symptom persists without resolution, a sense of personal agency can be strengthened.

In Injured Brains of Medical Minds: A View from Within, edited by Narinder Kapur, a compilation of physician’s self reports on their neurological disorders, a general practitioner, John Lisyak, who developed epilepsy late in his life, meditates on questions of illness and agency. “Understanding”, he writes, “does not necessarily change the reactions but it makes a difference to their severity.”21 After stopping his medicine because he had been free of seizures for three years, he had another tonic–clonic convulsion that was followed by a depression. “However”, he writes, “because of the knowledge I had gained this depression was not accompanied by the feelings of hopelessness. And even the ‘funny’ smell that returned together with the emotional dread wasn’t nearly as disturbing because I understood what was happening”. His symptoms are identical. He uses the words depression and dread to describe them, but he acknowledges that his feelings have nevertheless been transformed by an increased understanding of the nature of his disease.

Knowledge creates a change in him, a change that I would argue is psychobiological and related to a greater sense of agency that arrives with understanding and narrative mastery. When I learned to accept my migraines as permanent fixtures in my life and to practice biofeedback in the face of them, my life changed and my pain lessened. The change is not just “mental”. It is physical or psychobiological. There are increasing numbers of neuroimaging studies on depression, for example, which demonstrate that the abnormal activity of the prefrontal cortex seen in depression becomes normal after remission, when a patient has been treated with either fluoxetine or placebo. Placebo is of course a top-down effect that involves beliefs, beliefs that trigger relief both through the release of endogenous opioids in the brain and by non-opioid mechanisms.Exactly how belief, an idea, transmutes into physiological processes wasn’t understood by Janet and it is not understood now.In all events, there is increasing evidence for similar prefrontal normalization after talk therapy, which may involve precisely the understanding Lisyak cites as having altered his relation to his epilepsy. And this brings us back to the internal narrator and Descartes’ cogito ergo sum—that powerful subjective, if illusory, feeling of an “I” that exists beyond the body.

What human beings have that animals do not is a highly developed reflective self-consciousness that makes it possible for us to alienate ourselves in symbols. We can represent ourselves to ourselves in language. We can say “I” and that “I” can tell a story, and how the story of an illness is told is crucial to how it is lived. I cannot emphasize this enough. Looking back on his life, John Lisyak remembers, “not being able to do what other children could. The village fair”, he writes, “that filled everyone with wonder and excitement made me feel uneasy, and I was never happy to go on the Ferris wheel”. Nor was I. I simply couldn’t understand why the rides that caused intense nausea, dizziness, and disequilibrium in me seemed so pleasant to other children. The neurological hypersensitivity—visual, auditory, tactile, olfactory—that arrives with migraine and/or epilepsy is not all bad. I, for one, am not willing to trade in my childhood sensitivities and raging pains, my many auras followed by headache, or even my peculiar epileptiform, maybe, maybe not pseudo-seizures, for a more normal trajectory because these events are not only part of my story, they have been crucial to my life as a writer of both fiction and nonfiction. I have sometimes wondered if I would have become a writer if I had not had my particular neurological disposition. But my pathological hypersensitivity (let us call it by its right name) has also served me well because I have been able to frame this quality of my being to my advantage through a self-narrative that recognizes strength in what is often regarded as weakness. Moreover, my insatiable reading in many disciplines and my subsequent thinking about the question “what are we?” have brought me what can only be called compensatory joy. If you can’t cure yourself, you can certainly learn as much as possible about what ails you.

Philosophy matters because it informs diagnosis. I think it may be time for “functional” and “organic” to go the way of humors and be replaced by other more subtle understandings of biological processes. In the face of so much that remains unknown about brain function, intellectual humility matters and, as a physician, intellectual humility may involve explaining to a patient that you don’t know what is wrong with him or her. It may mean being wishy-washy and ambivalent, rather than firm and confident. It may mean recognizing implicit prejudices in yourself against psychogenic and/or emotional, psychiatric illnesses as somehow effeminate and less “real” than a brain lesion. As a young woman with debilitating migraines, I was at times treated with condescension and exasperation by neurologists and medical professionals. Although some empathy in one’s doctor is certainly desirable, an ethical position requires respect, above all, the simple recognition that the patient in front of you has an inner life as full and complex as your own.

Acknowledgements

This manuscript is based on a talk given by the author at an international ethics conference entitled “Brain Matters 3: Values at the Crossroads of Neurology, Psychiatry, and Psychology” organized by Dr Paul Ford. Organizational support and funding for the conference was provided by the Cleveland Clinic Foundation’s Epilepsy Center and Neuroethics Program. Additional funding came from a National Institute od Neurological Disorders and Stroke conference grant (Award# R13NS080513). See http://www.clevelandclinic.org/brainmatters3 for full program.