Psychosocial Stress, Inflammation, and Adhesion Molecules

I have been re-reading a book by Joseph LeDoux (NYU), Synaptic Self: How Our Brains Become Who We Are (2002), in which he argues that synapses in the brain are the foundation of personality, the basis of our sense of self:

My notion of personality is pretty simple: it‟s that your “self,” the essence of who you are, reflects patterns of interconnectivity between neurons in your brain. Connections between neurons, known as synapses, are the main channels of information flow and storage in the brain. Most of what the brain does is accomplished by synaptic transmission between neurons, and by calling upon the information encoded by past transmission across synapses. (p. 3-4)

This is relevant to some of the work I have been doing for Dr. Cress at the University of Arizona Cancer Center. Dr. Cress has been working for many years on the function of integrins in cancer metastasis, specifically in prostate cancer.

Here is how integrins are defined at Wikipedia, which is as precise as any you will find.

Integrins are transmembrane receptors that are the bridges for cell-cell and cell-extracellular matrix (ECM) interactions. When triggered, integrins in turn trigger chemical pathways to the interior (signal transduction), such as the chemical composition and mechanical status of the ECM, which results in a response (activation of transcription) such as regulation of the cell cycle, cell shape, and/or motility; or new receptors being added to the cell membrane. This allows rapid and flexible responses to events at the cell surface, for example to signal platelets to initiate an interaction with coagulation factors.

There are several types of integrins, and a cell may have several types on its surface. Integrins are found in all metazoa.^[3]

Integrins work alongside other receptors such as cadherins, the immunoglobulin superfamily cell adhesion molecules, selectins and syndecans to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin, collagen, and laminin.

Integrins are heterdimic adhesion receptors, meaning they have two different parts, the α (alpha) and β (beta) subunits. There are at least 18 α and eight β subunits are known in humans and other vertebrates (Takada, Ye, & Simon, 2007).

Dr. Cress has been work with the A6B4 integrin (alpha 6 beta 4) and its role in metastatic prostate cancer. A6 is one of three laminin-binding molecules in humans (the others are A3 and A7), although other researchers suggest there are five laminin-binding integrins, A1, A2, A3, A6, A7 (Alberts, Johnson, & Lewis; 2007; Molecular Biology of the Cell. 5th edition). This graphic explains the functions of the different integrins and their combinations.

Integrins are also expressed in the brain, especially in synapses and in the lamination of axons, which allows information to more quickly and efficiently through the brain (and through neural cells throughout the body). Schwann cells in peripheral nerves interact with axons and extracellular matrix (ECM) as part of their work in ensheathing and myelinating axons and they express B4 (beta 4 integrin) [Feltri, et al, 1994], and specifically A6B4. 

In digging around for additional information on synapses and brain function, I found a related article by LeDoux - this is the abstract (crucial section is in bold):

STRUCTURAL PLASTICITY AND MEMORY
Raphael Lamprecht and Joseph LeDoux

Much evidence indicates that, after learning, memories are created by alterations in glutamate-dependent excitatory synaptic transmission. These modifications are then actively stabilized, over hours or days, by structural changes at postsynaptic sites on dendritic spines. The mechanisms of this structural plasticity are poorly understood, but recent findings are beginning to provide clues. The changes in synaptic transmission are initiated by elevations in intracellular calcium and consequent activation of second messenger signalling pathways in the postsynaptic neuron. These pathways involve intracellular kinases and GTPases, downstream from glutamate receptors, that regulate and coordinate both cytoskeletal and adhesion remodelling, leading to new synaptic connections. Rapid changes in cytoskeletal and adhesion molecules after learning contribute to short-term plasticity and memory, whereas later changes, which depend on de novo protein synthesis as well as the early modifications, seem to be required for the persistence of long-term memory.

Source: Nature Reviews Neuroscience; January 2004; 5(1):45-54. doi:10.1038/nrn1301 

Rho GTPaseas mediate extracellular stimulation-induced actin cytoskeleton rearrangements. Stimulation of the postsynaptic neuron leads to actin-dependent morphological changes mediated by Rho GTPases105–108. 1) Activation of adhesion molecules, such as integrin or cadherin, which have been shown to be involved in synaptic plasticity, regulates Rho GTPase inactivation by RhoGAPs. 2) Calcium influx through membrane channels can induce activation of tyrosine kinases (TKs), such as the cell adhesion kinase-β/proline-rich tyrosine kinase 2 (CAKβ/Pyk2), that in turn activate Src. The later modulates p190 RhoGAP activity and thereby controls Rho GTPase inactivation. 3) On the other hand, Rho GTPase activators, RhoGEFs, are also regulated by extracellular stimulation. Ephrin A activates, through the receptor tyrosine kinase EphA, a Rho GEF called ephexin. EphA has been implicated in memory formation133. 4) Rho GTPase controls actin polymerization through downstream effectors such as Rho-associated kinase (ROCK). ROCK activates LIM-domain-containing protein kinase (LIMK), which in turn inhibits the actin depolymerizing factor cofilin. This event can contribute to actin polymerization. ROCK, LIMK and cofilin have been shown to be involved in synaptic plasticity. 5) Cdc42 and Rac, other members of the Rho GTPase family, induce actin polymerization by regulating downstream effectors. GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; N-WASP, neuronal Wiskott-Aldrich syndrome; SCAR, suppressor of cAR.

The text above is the caption for the image. Here is another quote from near the end of the paper, which is minimal and could be the topic of an entire paper:

Adhesion molecules and synaptic plasticity 

The formation of new synaptic contacts is a dynamic process that involves ongoing morphological alterations and modulation of adhesion between the pre- and postsynaptic neurons [115,116]. These processes require coordinated activity between molecules that regulate cytoskeletal rearrangements and morphology, and those that control adhesion between the pre- and postsynaptic membranes.Adhesion molecules, mostly integrins, cadherins, neurexin and the immunoglobulin superfamily, are membrane-bound molecules that have hetero- or homophilic interactions with proteins in the extracellular matrix and synaptic membranes to control the adhesion between the pre- and postsynaptic membranes. Adhesion molecules, which also have an intracellular component, can initiate signalling pathways that couple the dynamics of extracellular connectivity with intracellular events that control morphology. For example, cadherin regulates dendritic spine morphogenesis and function. Blockade of cadherin function leads to elongation of the spine, bifurcation of its head structure and alterations in the distribution of postsynaptic proteins [117]. Moreover, neuronal activity induces the movement of β-catenin (which mediates the interaction of cadherin with the actin cytoskeleton) from dendritic shafts into spines to become associated with cadherin and to influence synaptic size and strength [118]. Adhesion molecules such as cadherin also associate with molecules that regulate cytoskeletal rearrangements, such as proteins that control the Rho GTPase pathway [119].

Adhesion molecules could therefore contribute to the morphological alteration and stabilization of connectivity between neurons, a process that is hypothesized to underlie memory consolidation. Consistent with this hypothesis is the role of adhesion molecules in the formation and stabilization of LTP and LTM. Integrin-mediated adhesion helps to stabilize early-phase LTP (E-LTP) into late-phase LTP (L-LTP). For example, inhibition of integrin with a peptide that contains the integrin recognition sequence 10 min before, immediately after and 10 min after LTP induction caused a gradual decay of synaptic strength over 40 min [120]. The peptide had no effect when applied 25 min after LTP initiation, indicating that integrin has a role in stabilization of synaptic connectivity. Furthermore, N-cadherin is synthesized and internalized to new assembled synapses during the induction of L-LTP, and blocking N-cadherin adhesion prevents the induction of L-LTP but not E-LTP [121]. This event depends on glutamate receptor activity. In chicks, memory is impaired 24 h after a visual categorization task when antibodies against the cell adhesion molecule L1 are injected before, 5.5 h or 15–18 h after training (but not later) [122]. In addition, intraventricular injection of antibodies against neural cell adhesion molecule (NCAM) in rats 6–8 h after passive avoidance training, but not later, impaired retention of the avoidance response [123]. These observations indicate that adhesion molecules are essential for memory consolidation during a period of hours after acquisition.

The level and distribution of adhesion molecules is also correlated with synaptic plasticity and learning. In Aplysia, repeated application of 5-hydroxytryptamine (serotonin; 5-HT), which leads to long-term facilitation of the sensory–motor connection, induces the internalization of the adhesion molecule apCAM (Aplysia cell adhesion molecule) [43]. This could destabilize the interaction between sensory neurons, permitting the growth of new sensory axons.ApCAM could be redistributed to the area where new synapses are formed. In rats, N-cadherin is induced in the piriform cortex and hypothalamus 2 h after fear conditioning [124]. N-cadherin was not induced in control animals that were presented with the conditioned stimulus and unconditioned stimulus in a non-associative manner.

On the whole, these observations indicate that adhesion molecules have a central role in mediating neuronal connectivity and morphogenesis, and in the progressive stabilization of synaptic connectivity that leads to memory consolidation. (LeDoux, 2004, pages 50-51)

I did some more digging and found that A3, A5, A8, and B1 (McGeachie, Cingolani, & Godaare, 2011) are all expressed in synaptic formation and function and in the growth and activity of dendrites. If the alpha versions of the integrins are not functioning properly, learning and memory are inhibited, but there are differences for each of the alpha integrins and for the beta integrin:

Interestingly, behavioural tests revealed specific deficits in hippocampal-dependent working memory, while spatial memory was unaffected. Although ITGβ1 is likely to be the major subunit for ITGα3, ITGα5 and ITGα8 in the hippocampus (Hynes, 2002), ITGα3/+;ITGα5/+;ITGα8/+ mice showed behavioural deficits (see above) that are different from those of ITGβ1 conditional knockout mice. Such divergent results may reflect the differences arising from global reduction in ITGα3, ITGα5 and ITGα8 versus a more specific ablation of ITGβ1 mainly in CA1 pyramidal neurons.

[In the quote above, ITGα3, and so on, is used to represent integrin (ITG) alpha 3.] 

Inflammation from Psychosocial Stress

We know that psychosocial stress causes inflammation. University of Arizona researcher/professor Charles Raison (2006) found that depressed patients have higher levels of proinflammatory cytokines, acute phase proteins, chemokines, and cellular adhesion molecules (an important finding for my thesis). It has also been shown that therapeutic administration of the cytokine interferon-α (a cancer treatment drug that inhibits tumor cell growth) leads to depression in up to 50% of patients (Bonaccorso, et al, 2002).

Stress appears to down-regulate immunity through at least three mechanisms:

(A) Stress hormones are influenced by negative events and negative emotions: catecholamines (adrenaline and noradrenaline), adrenocorticotropic hormone (ACTH), cortisol, growth hormone, and prolactin, as examples

(B) Immune modulation by these hormones proceeds through two pathways: 

1. Directly, through binding of the hormone to its cognate receptor at the surface of a cell 
2. Indirectly — for example, by inducing dysregulation of the production of cytokines, such as interferon-γ (IFN-γ), interleukin-1 (IL-1),IL-2,IL-6 and tumour-necrosis factor (TNF)

Cytokines such as IFN-γ have many functions and affect different target cells. Therefore, there are secondary effects of many stress hormones on the immune response

(C) Communication between the CNS and the immune system is bidirectional - examples: 

1. IL-1 influences the production of corticotropin-releasing hormone (CRH) by the hypothalamus. In turn, CRH can affect the HPA axis and thereby trigger increases in stress hormone levels, which results in dysregulation of immune function 
2. Lymphocytes can synthesize hormones such as ACTH, prolactin and growth hormone

Glaser, R., & Kiecolt-Glaser, J. K. (2005). Stress-induced immune dysfunction: implications for health. Nature Reviews Immunology, 5(3), 243-251.

Here is the abstract (edited for relevance) from an excellent review article: Psychosocial stress and inflammation in cancer by Powell, Tarr, and Sheridan (2013) that provides some useful information about how stress (i.e., trauma) can compromise the immune system. [Bold area is my emphasis.]

Stress-induced immune dysregulation results in significant health consequences for immune related disorders including viral infections, chronic autoimmune disease, and tumor growth and metastasis.  Both human and animal studies have shown the sympathetic and neuroendocrine responses to psychosocial stress significantly impacts cancer, in part, through regulation of inflammatory mediators. Psychosocial stressors stimulate neuroendocrine, sympathetic, and immune responses that result in the activation of the hypothalamic–pituitary–adrenal (HPA)-axis, sympathetic nervous system (SNS), and the subsequent regulation of inflammatory responses by immune cells. Social disruption (SDR) stress, a murine model of psychosocial stress and repeated social defeat, provides a novel and powerful tool to probe the mechanisms leading to stress-induced alterations in inflammation, tumor growth, progression, and metastasis.

The following is from the first section of the same paper and it provides an overview of the chemical pathways involved in stress-induced inflammation.

[S]tudies using a mouse model of repeated social defeat, termed social disruption (SDR) stress, have shown that stress alone can trigger the generation, egress, and trafficking of immature, inflammatory myeloid derived-cells that are glucocorticoid (GC) insensitive (Curry et al., 2010, Engler et al., 2004a and Engler et al., 2005). In addition, these GC insensitive cells produce high levels of IL-6 and other inflammatory cytokines and chemokines (Powell et al., 2009, Stark et al., 2002 and Wohleb et al., 2011). As a consequence, these stress-induced changes at the cellular level translate to significant immune (enhanced inflammatory responses and immunity to microbial, viral, and allergen challenge) and behavioral (prolonged anxiety-like behavior) changes (Bailey et al., 2007, Bailey et al., 2009b, Bailey et al., 2009a, Dong-Newsom et al., 2010, Kinsey et al., 2007, Mays et al., 2010, Mays et al., 2012, Powell et al., 2011 and Wohleb et al., 2011). Indicative of the important role of the SNS in stress-induced immune alteration, these changes are reversed by the blockade of sympathetic signaling prior to stressor exposure (Wohleb et al., 2011).

The stress response in vertebrates stems from internal or external stimuli that trigger the “fight or flight” and "defeat/withdrawal" responses expressed in sympathetic nervous system (SNS) and the hypothalamic–pituitary–adrenal (HPA)-axis activation. Years of research has shown that specific central nervous system (CNS) pathways function as translators of social stimuli into peripheral biological signals that regulate inflammatory responses.

For instance, stress activates neuroendocrine and autonomic pathways like the HPA axis, and the SNS resulting in the release of GC, catecholamines, and pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α. The release of these sympathetic, neuroendocrine, and immune factors has a profound influence on immunity, behavior, and physiology in both humans and rodents and triggers peripheral biological responses that, in turn, signal back to the CNS to complete a bi-directional communication circuit. This is evident in models of repeated social defeat, like SDR, that enhance immune responses to microbial, viral, and allergic challenges and promote and prolong anxiety-like behavior in rodents (Kinsey et al., 2007, Bailey et al., 2009a, Bailey et al., 2009b and Mays et al., 2010). Social disruption stress-induced prolonged anxiety-like behavior coincides with a unique pattern of c-Fos activation in brain regions associated with fear and threat appraisal. For example, repeated social defeat, termed social disruption (SDR) causes increased c-Fos activation in the prefrontal cortex, amygdala, hippocampus, paraventricular nucleus, bed nucleus of the stria terminalis and the lateral septum (Wohleb et al., 2011). [Powell, Tarr, and Sheridan, 2013, p. 3]

When the HPA and SNS circuitry are activated, the release of neurotransmitters and stress hormones generates compensatory physiologic changes that impact behavior and the function of the immune system. In humans, chronic or repeated exposure to stress appears to lead to increases in the expression of inflammatory biomarkers, worsened disease states, and affective/emotional disorders (Glaser and Kiecolt-Glaser, 2005; Gouin et al., 2012).

In several studies, stressed individuals exhibit reduced anti-inflammatory glucocorticoid regulation and increased inflammatory nuclear factor (NF)-κB signaling (Miller et al., 2008). In these situations, psychosocial stress represents a challenge to homeostasis that manifests as physiological alterations in the body (Glaser and Kiecolt-Glaser, 2005).

This may be something to look at in terms of how trauma impacts the brain and body, a microbiological model of traumatic stress, inflammation, and the alteration of adhesion molecules, all of which leads to impaired learning and impaired memory.

As of now, there are no known interventions at the cellular level for altering integrin function. However, the are many ways to control and eliminate inflammation. Among the most well-researched (I could provide citations for these, but it's late, so I might add them later):

1) Curcumin/turmeric
2) Resveratrol
3) Exercise
4) Stress-reduction techniques, such as meditation
5) Avoiding smoking, drinking, and processed foods

We have some control over how our bodies manage and adapt to stress. We are not merely victims of our biology.

Neuroimmune Mechanisms Contributing to Addiction Neurobiology - Brain Function and Alcohol Use Disorders

From the National Institute on Alcohol Abuse and Alcoholism (NIAAA), this is an all-day conference on the role of the neuroimmune system in addiction neurobiology.

The field of psychoneuroimmunology has been around for a couple of decades (the term was coined in 1975 Robert Ader and Nicholas Cohen at the University of Rochester), but we are only now beginning to really grasp the implications of immune system function of mental health.

Neuroimmune Mechanisms Contributing to Addiction Neurobiology

Tuesday, September 02, 2014
Runtime: 05:07:43

Description:
The purpose of this workshop is to highlight recent progress in the understanding of neuroimmune mechanisms contributing to brain function and alcohol use disorders. It will bring together scientists from both alcohol and other research fields to highlight recent science advances, identify research gaps, and discuss possible challenges in this area.

Full Program:

8:30 AM - Welcome/Opening Remarks - George Koob, Ph.D., Director, NIAAA

8:40 AM - Introduction: Neuroimmune, Brain Function, and Alcohol Use Disorders - Changhai Cui, Ph.D., Program Director, Division of Neuroscience and Behavior, NIAAA

8:50 AM - Neuroimmune regulation in alcohol consumption: from gene to behavior - Adron Harris, Ph.D., Director, Waggoner Center for Alcohol & Addiction Research, University of Texas at Austin

9:20 AM - Mechanisms of Ethanol Activation of Neuroimmune Signaling and Neurodegeneration - Fulton Crews, Ph.D., Professor, Department of Pharmacology, Director, Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill

9:50 AM - Innate Immune Factors Modulate Ethanol Interaction with GABAergic Transmission in the Central Amygdala - Marisa Roberto, Ph.D., Associate Professor, Committee On The Neurobiology Of Addictive Disorders, Scripps Research Institute

10:20 AM - Break

10:35 AM - Microglia in learning dependent synaptic remodeling - Wen-Biao Gan, Ph.D., Professor, Skirball Institute of Biomolecular Medicine, New York University

11:05 AM - Neural-glial interactions in addiction: modulation by early-life experience - Staci Bilbo, Ph.D., Associate Professor, Psychology & Neuroscience, Arts & Sciences, Duke University

11:35 AM - Immune signaling, emotions/stress, and addiction - Rajita Sinha, Ph.D., Director of Interdisciplinary Stress Center, Yale University School of Medicine

12:05 PM - Lunch Break

1:05 PM - Panel Discussion - Antonio Noronha, Ph.D., Director of Division of Neuroscience and Behavior, NIAAA - Panelists: Drs. Dorit Ron, Kathy Grant, Cynthia Kane, Dipak Sarkar, Gyongi Szabo

2:05 PM - Closing Remarks

M. J. Friedrich - Research on Psychiatric Disorders Targets Inflammation

This is an interesting overview of the current research on how inflammation can play a role in depression, schizophrenia, and autism. I suspect there is much more research to be done in this realm, but I believe they need to stop using pharmacological interventions targeted at a specific molecule or hormone in the immune response (such as the tumor necrosis factor [TNF] antagonist infliximab, which only showed limited efficacy in treatment resistant depression, and then only for those who had high levels of inflammation before the trial).

Rather, the use of a general anti-inflammatory agent, such as curcumin or omega-3 fats, among many others, might offer greater benefits in that they target several different immune system products. Further, improving the health of the microbiome can be the most effective method to reduce inflammation, which is as simple as a healthy diet.

Full Citation:
Friedrich, MJ. (2014, Aug 6). Research on Psychiatric Disorders Targets Inflammation. JAMA; 312(5): 474-476. doi:10.1001/jama.2014.8276.

Research on Psychiatric Disorders Targets Inflammation

M. J. Friedrich

New York—Activation of the immune system is the body’s natural reaction to infection or tissue damage, but when this protective response is prolonged or excessive, it can play a role in many chronic illnesses, not only of the body, but also of the brain.

“Psychiatric and neurodevelopmental disorders are being thought of more and more as systemic illnesses in which inflammation is involved,” noted Eric Hollander, MD, of Montefiore Medical Center and Albert Einstein College of Medicine, New York City. The cause of increased inflammation in these conditions isn’t always clear, but it has become a hot topic of investigation.

Hollander, who spoke at the annual meeting of the American Psychiatric Association held here in May, was among several investigators who discussed how immune-inflammatory mechanisms can go awry and contribute to the development of depression, schizophrenia, and autism, insights that are leading to novel experimental approaches for these and other disorders.

CYTOKINES IN DEPRESSION

“The notion that inflammation plays a role in neuropsychiatric disorders really caught fire in the context of depression,” said Andrew Miller, MD, of Emory University School of Medicine, Atlanta.

This idea came from early studies showing that patients with depression, regardless of their physical health status, exhibited cardinal features of inflammation, including increases in inflammatory cytokines in the blood and cerebral spinal fluid. The inflammatory cytokines interleukin-6 and tumor necrosis factor (TNF), as well as the acute-phase reactant c-reactive protein (CRP), are the most reliable biomarkers of increased inflammation in patients with depression, said Miller.



Studies suggest that proinflammatory processes may be activated in people with autism spectrum disorders. A medicalized parasite, the eggs of porcine whipworms, tamps down the body’s proinflammatory response and is being studied as a possible treatment for reducing symptoms of autism.  CNRI/www.sciencesource.com
Interestingly, there seems to be a special relationship between inflammation and treatment-resistant depression (TRD), which occurs in about one-third of all depressed patients, said Miller. Patients who don’t respond to antidepressant therapy tend to show an increase in inflammatory markers. Data indicate that these inflammatory molecules can sabotage and circumvent the mechanisms of action of conventional antidepressant therapy.

Given the association of inflammatory cytokines with TRD, researchers set out to test the therapeutic potential of inhibiting inflammatory cytokines in this subset of patients. Administration of a TNF antagonist has been shown to improve depressed mood in patients with other disorders, such as psoriasis and Crohn disease, suggesting that this approach might help reverse depressive symptoms in otherwise healthy patients with TRD.

In a recent proof-of-concept study, Miller and his colleagues gave infusions of the monoclonal antibody infliximab, a TNF antagonist, to 60 adults with major depression that was at least moderately resistant to medication (Raison CL et al. JAMA Psychiatry. 2013;70[1]:31-41). Based on the hypothesis that an anticytokine strategy might be effective only in patients with high inflammation before treatment, the researchers also measured CRP and other inflammatory biomarkers at baseline and throughout the study.

Infliximab did not prove to be more effective than placebo in treating TRD in the study. In fact, overall, those treated with placebo did better than those who received infliximab, said Miller. However, when patients were stratified on the basis of inflammatory biomarkers, those patients with high baseline measurements (plasma CRP concentrations >5 mg/L) had the best response to infliximab.

These results indicate that a simple test for a peripheral blood biomarker of inflammation like CRP might predict which patients would respond to immune-targeted therapy for depression, said Miller. “It’s one of the first studies in psychiatry connecting a biomarker to treatment response,” he noted.

In a subsequent study, Miller’s team compared gene expression profiles of the participants who responded to infliximab with those who did not respond. Within 6 hours after the first infusion of infliximab, the researchers were able to distinguish responders from nonresponders (Mehta D et al. Brain Behav Immun. 2013;31:205-215).

Miller’s group has also been working to identify the brain regions and pathways that are targeted by inflammatory cytokines, such as interferon-alpha—work that may lead to more personalized treatment options for patients with depression, he said (Capuron L et al. Arch Gen Psychiatry. 2012;69[10]:1044-1053).

ANTI-INFLAMMATORY TREATMENT IN SCHIZOPHRENIA

A role for the inflammatory process is also being explored in schizophrenia, noted Norbert Müller, MD, PhD, of Ludwig Maximilian University of Munich, Germany.

The influence of infectious agents on the pathogenesis of schizophrenia, as well as on other psychiatric disorders, has been discussed for decades, and prenatal and postnatal infections are considered risk factors for schizophrenia. Research in prenatal infections indicates that the culprit is not a specific infectious agent, but rather the maternal immune response (Krause D et al. World J Biol Psychiatry. 2010;11[5]:739-743).

Data from a 30-year population-based register study indicate that inflammation coming from either infection or autoimmunity is a risk factor for schizophrenia, not only during development but also later in life (Benros ME et al. Am J Psychiatry. 2011; 168[12]: 1303-1310). The risk seems to increase in a dose-dependent manner, with the risk increasing along with the number of infections, for example, said Müller.

Because of the apparent involvement of inflammatory processes in schizophrenia, the use of anti-inflammatory compounds for the disorder has received increasing attention. A number of studies carried out in the past decade using cyclooxygenase-2 (COX-2) inhibitors in addition to antipsychotic medication have shown a therapeutic effect for the disorder.

Müller noted that timing seems to influence response to this anti-inflammatory therapy because no benefit was seen in a study involving patients who had a long duration of disease (Rapaport MH et al. Biol Psychiatry. 2005;57:1594-1596). Rather, the most compelling data was for anti-inflammatory therapies carried out in the early phase of the disorder: a recent meta-analysis showed an advantage of COX-2 inhibitors only among patients who had a short duration of the disorder (Nitta M et al. Schizophr Bull. 2013;39[6]:1230-1241).

“From an immunologic point of view, this fits very well,” said Müller. “If you have chronic inflammation, it’s more or less impossible to treat effectively with a short-term anti-inflammatory therapy,” he said.

Müller’s group is also beginning to use interferon γ to activate the cellular arm of immunity (type 1 response), which appears to be blunted in most patients with schizophrenia. The work is only in early stages but so far has shown some promise.

INFLAMMATORY MECHANISMS IN AUTISM

A hyperactive immune system is also postulated to play a role in people with autism spectrum disorder (ASD). Increases in proinflammatory cytokines have been found both in the cerebrospinal fluid of patients with ASD and in postmortem brain tissue from deceased patients with autism, said Montefiore’s Hollander.

The association between immune dysfunction and ASD has led researchers to test several novel treatments that target inflammatory mechanisms to alleviate some symptoms of ASD.

One of these mechanisms involves the gut microbiome. “We can think about certain bacteria and parasites in the gut as helping to dampen the chronic inflammatory response, and that a lack of favorable gut parasites allows proinflammatory cytokines to prevail,” said Hollander.

When the microbiome is deprived, as the “hygiene hypothesis” contends has happened in developed countries, it may lead to a lack of control of the immune system. This could help explain why developed countries have higher rates of autoimmune conditions, although other factors—such as underdiagnosis—could also contribute to the lower rates in low- and middle-income countries.

Hollander and his colleagues have focused on trying to beef up the microbiome in people with ASD by introducing a medicalized parasite, Trichuris suis ova (TSO), the eggs of a porcine whipworm. Trichuris suis ova is safe in humans, does not multiply in the host, is not transmittable by contact, and is cleared from the system spontaneously.

Trichuris suis ova works by tamping down the proinflammatory response to increase its survival within the host. It has been studied with some success in autoimmune diseases such as Crohn disease and inflammatory bowel disease and appears to achieve its effects by shifting the balance of T-regulator and T-helper cells and their respective cytokines, said Hollander.

Hollander’s group has been carrying out a small preliminary study of TSO in 10 high-functioning adults with ASD who were able to give informed consent. All participants had a family or personal history of some kind of a seasonal or food allergy or a family history of autoimmune problems.

The aim of identifying this subset of people with ASD was to stratify the study population according to signs of immune dysfunction. In this way, researchers can study a more homogeneous group of people within what is considered a very heterogeneous illness, said Hollander.

In a 28-week, double-blind, randomized, crossover study, the patients received TSO for 3 months (2500 eggs every 2 weeks) followed 4 weeks later by placebo treatment for 3 months. After the first 12-week phase of TSO or placebo, the patients entered a 4-week washout before beginning the second 12-week phase.

The researchers used several measurements to assess symptoms, including stereotypy (self-stimulatory behavior), repetitive behavior, and rigidity or craving for sameness. In their interim analysis of this pilot study, they demonstrated the feasibility and safety of using TSO in an adult population with autism and have found a potential benefit from treatment in all these domains.

Hollander’s team is in the process of launching a new study of this same approach in a pediatric population with ASD, based on the idea that early intervention in developmental disorders is optimal.

In a different therapeutic approach, Hollander and his colleagues studied 10 children with ASD who had a history of symptom improvement when they had fevers. All the children spent alternate days soaking in a hot tub at 102°F (to mimic fever) or at 98°F (control condition).

The children showed improvements on the days when their body temperature was raised to 102°F, compared with the days they were bathed at 98°F. Benefits were seen particularly in restricted and repetitive behavior as well as social behavior, said Hollander.

The mechanism of action is under investigation, but researchers conjecture that raising the body’s temperature either through fever or a hot tub bath releases anti-inflammatory signals that can bring about the observed behavioral effects.

Future studies need to be done to replicate many of these findings. But researchers suggest the data represent a step toward personalizing therapies for psychiatric and neurodevelopmental disorders and provide promise for the development of inflammatory biomarkers and treatment approaches for patients who are responsive to immune-targeted therapies.

2014 – The Year in Books (so far)

Halfway through the year, almost, and there have already been some seriously good books published that will appear on a lot of top-ten lists in December. Some of those books are below, but there also a lot of books below no one will have heard of about side of their respective fields, books from academic publishers or other sources not likely to be found at your local bookstores.

Below is a list of the books I have picked up this year (which is not likely to be very mainstream), and I am including the publisher's ad copy for their books. I would love to review each of these, but I seriously do not have that kind of time. Perhaps, if time allows, I will offer some individual reviews of a few of these books.

2014 – The Year in Books (so far)

Jeremy Rifkin – The Zero Marginal Cost Society: The Internet of Things, the Collaborative Commons, and the Eclipse of Capitalism

 

In The Zero Marginal Cost Society, New York Times bestselling author Jeremy Rifkin describes how the emerging Internet of Things is speeding us to an era of nearly free goods and services, precipitating the meteoric rise of a global Collaborative Commons and the eclipse of capitalism.

Rifkin uncovers a paradox at the heart of capitalism that has propelled it to greatness but is now taking it to its death—the inherent entrepreneurial dynamism of competitive markets that drives productivity up and marginal costs down, enabling businesses to reduce the price of their goods and services in order to win over consumers and market share. (Marginal cost is the cost of producing additional units of a good or service, if fixed costs are not counted.) While economists have always welcomed a reduction in marginal cost, they never anticipated the possibility of a technological revolution that might bring marginal costs to near zero, making goods and services priceless, nearly free, and abundant, and no longer subject to market forces.

Now, a formidable new technology infrastructure—the Internet of things (IoT)—is emerging with the potential of pushing large segments of economic life to near zero marginal cost in the years ahead. Rifkin describes how the Communication Internet is converging with a nascent Energy Internet and Logistics Internet to create a new technology platform that connects everything and everyone. Billions of sensors are being attached to natural resources, production lines, the electricity grid, logistics networks, recycling flows, and implanted in homes, offices, stores, vehicles, and even human beings, feeding Big Data into an IoT global neural network. Prosumers can connect to the network and use Big Data, analytics, and algorithms to accelerate efficiency, dramatically increase productivity, and lower the marginal cost of producing and sharing a wide range of products and services to near zero, just like they now do with information goods.

The plummeting of marginal costs is spawning a hybrid economy—part capitalist market and part Collaborative Commons—with far reaching implications for society, according to Rifkin. Hundreds of millions of people are already transferring parts of their economic lives to the global Collaborative Commons. Prosumers are plugging into the fledgling IoT and making and sharing their own information, entertainment, green energy, and 3D-printed products at near zero marginal cost. They are also sharing cars, homes, clothes and other items via social media sites, rentals, redistribution clubs, and cooperatives at low or near zero marginal cost. Students are enrolling in free massive open online courses (MOOCs) that operate at near zero marginal cost. Social entrepreneurs are even bypassing the banking establishment and using crowdfunding to finance startup businesses as well as creating alternative currencies in the fledgling sharing economy. In this new world, social capital is as important as financial capital, access trumps ownership, sustainability supersedes consumerism, cooperation ousts competition, and “exchange value” in the capitalist marketplace is increasingly replaced by “sharable value” on the Collaborative Commons.

Rifkin concludes that capitalism will remain with us, albeit in an increasingly streamlined role, primarily as an aggregator of network services and solutions, allowing it to flourish as a powerful niche player in the coming era. We are, however, says Rifkin, entering a world beyond markets where we are learning how to live together in an increasingly interdependent global Collaborative Commons.

Michio Kaku – The Future of the Mind: The Scientific Quest to Understand, Enhance, and Empower the Mind

 

The New York Times best-selling author of PHYSICS OF THE IMPOSSIBLE, PHYSICS OF THE FUTURE and HYPERSPACE tackles the most fascinating and complex object in the known universe: the human brain. 

For the first time in history, the secrets of the living brain are being revealed by a battery of high tech brain scans devised by physicists. Now what was once solely the province of science fiction has become a startling reality. Recording memories, telepathy, videotaping our dreams, mind control, avatars, and telekinesis are not only possible; they already exist.
 
THE FUTURE OF THE MIND gives us an authoritative and compelling look at the astonishing research being done in top laboratories around the world—all based on the latest advancements in neuroscience and physics.  One day we might have a "smart pill" that can enhance our cognition; be able to upload our brain to a computer, neuron for neuron; send thoughts and emotions around the world on a "brain-net"; control computers and robots with our mind; push the very limits of immortality; and perhaps even send our consciousness across the universe.
   
Dr. Kaku takes us on a grand tour of what the future might hold, giving us not only a solid sense of how the brain functions but also how these technologies will change our daily lives. He even presents a radically new way to think about "consciousness" and applies it to provide fresh insight into mental illness, artificial intelligence and alien consciousness.

With Dr. Kaku's deep understanding of modern science and keen eye for future developments, THE FUTURE OF THE MIND is a scientific tour de force--an extraordinary, mind-boggling exploration of the frontiers of neuroscience.

Peter Zachar – A Metaphysics of Psychopathology (Philosophical Psychopathology)

 

In psychiatry, few question the legitimacy of asking whether a given psychiatric disorder is real; similarly, in psychology, scholars debate the reality of such theoretical entities as general intelligence, superegos, and personality traits. And yet in both disciplines, little thought is given to what is meant by the rather abstract philosophical concept of "real." Indeed, certain psychiatric disorders have passed from real to imaginary (as in the case of multiple personality disorder) and from imaginary to real (as in the case of post-traumatic stress disorder). In this book, Peter Zachar considers such terms as "real" and "reality" -- invoked in psychiatry but often obscure and remote from their instances -- as abstract philosophical concepts. He then examines the implications of his approach for psychiatric classification and psychopathology. Proposing what he calls a scientifically inspired pragmatism, Zachar considers such topics as the essentialist bias, diagnostic literalism, and the concepts of natural kind and social construct. Turning explicitly to psychiatric topics, he proposes a new model for the domain of psychiatric disorders, the "imperfect community" model, which avoids both relativism and essentialism. He uses this model to understand such recent controversies as the attempt to eliminate narcissistic personality disorder from the DSM-5. Returning to such concepts as real, true, and objective, Zachar argues that not only should we use these metaphysical concepts to think philosophically about other concepts, we should think philosophically about them.

Stephen Finlay – Confusion of Tongues: A Theory of Normative Language (Oxford Moral Theory)

Can normative words like "good," "ought," and "reason" be defined in entirely non-normative terms? Confusion of Tongues argues that they can, advancing a new End-Relational theory of the meaning of this language as providing the best explanation of the many different ways it is ordinarily used. Philosophers widely maintain that analyzing normative language as describing facts about relations cannot account for special features of particularly moral and deliberative uses of normative language, but Stephen Finlay argues that the End-Relational theory systematically explains these on the basis of a single fundamental principle of conversational pragmatics. These challenges comprise the central problems of metaethics, including the connection between normative judgment and motivation, the categorical character of morality, the nature of intrinsic value, and the possibility of normative disagreement. Finlay's linguistic analysis has deep implications for the metaphysics, epistemology, and psychology of morality, as well as for the nature and possibility of normative ethical theory. Most significantly it supplies a nuanced answer to the ancient Euthyphro Question of whether we desire things because we judge them good, or vice versa. Normative speech and thought may ultimately be just a manifestation of our nature as intelligent animals motivated by contingent desires for various conflicting ends.

Howard Rachlin – The Escape of the Mind

The Escape of the Mind is part of a current movement in psychology and philosophy of mind that calls into question what is perhaps our most basic, most cherished, and universally accepted belief--that our minds are inside of our bodies. Howard Rachlin adopts the counterintuitive position that our minds, conscious and unconscious, lie not where our firmest (yet unsupported) introspections tell us they are, but in how we actually behave over the long run. Perhaps paradoxically, the book argues that our introspections, no matter how positive we are about them, tell us absolutely nothing about our minds. The name of the present version of this approach to the mind is "teleological behaviorism."

The approaches of teleological behaviorism will be useful in the science of individual behavior for developing methods of self-control and in the science of social behavior for developing social cooperation. Without in any way denigrating the many contributions of neuroscience to human welfare, The Escape of the Mind argues that neuroscience, like introspection, is not a royal road to the understanding of the mind. Where then should we look to explain a present act that is clearly caused by the mind? Teleological behaviorism says to look not in the spatial recesses of the nervous system (not to the mechanism underlying the act) but in the temporal recesses of past and future overt behavior (to the pattern of which the act is a part). 

But scientific usefulness is not the only reason for adopting teleological behaviorism. The final two chapters on IBM's computer, Watson (how it deviates from humanity and how it would have to be altered to make it human), and on shaping a coherent self, provide a framework for a secular morality based on teleological behaviorism.

Robert J. Wicks – Perspective: The Calm Within the Storm

For generations, classic wisdom literature has taught that a healthy perspective can replenish our thirst for a meaningful and rewarding life. From its inception clinical psychology has followed suit, revealing that how we see ourselves and the world is more important than what we see or have-in essence, that a healthy perspective is tantamount to possessing the psychological "pearl of great price."

Robert J. Wicks, world-renowned psychologist and author of Bounce: Living the Resilient Life, has written a powerful guide for discovering and regaining a balanced and healthy perspective. Combining classic wisdom with cutting-edge research in cognitive behavioral therapy and positive psychology, his new book, Perspective, offers concrete steps for overcoming doubt and resistance to openness, so that beneficial life changes become possible. Drawing on the psychology of mindfulness, gratitude, and happiness, Dr. Wicks also reveals how a healthy perspective makes us more aware of the beneficial things already present in our lives.

Perspective teaches us to see ourselves more completely and will inspire us to become the calm within the storm, better able to enjoy our experiences, maintain balance in our professional and personal lives, and reach out to others without being pulled down in the process.

Barbara Ehrenreich – Living with a Wild God: A Nonbeliever's Search for the Truth about Everything

From the New York Times bestselling author of Nickel and Dimed comes a brave, frank, and exquisitely written memoir that will change the way you see the world.

Barbara Ehrenreich is one of the most important thinkers of our time. Educated as a scientist, she is an author, journalist, activist, and advocate for social justice. In LIVING WITH A WILD GOD, she recounts her quest-beginning in childhood-to find "the Truth" about the universe and everything else: What's really going on? Why are we here? In middle age, she rediscovered the journal she had kept during her tumultuous adolescence, which records an event so strange, so cataclysmic, that she had never, in all the intervening years, written or spoken about it to anyone. It was the kind of event that people call a "mystical experience"-and, to a steadfast atheist and rationalist, nothing less than shattering.

In LIVING WITH A WILD GOD, Ehrenreich reconstructs her childhood mission, bringing an older woman's wry and erudite perspective to a young girl's impassioned obsession with the questions that, at one point or another, torment us all. The result is both deeply personal and cosmically sweeping-a searing memoir and a profound reflection on science, religion, and the human condition. With her signature combination of intellectual rigor and uninhibited imagination, Ehrenreich offers a true literary achievement-a work that has the power not only to entertain but amaze.

Nicholas Epley – Mindwise: How We Understand What Others Think, Believe, Feel, and Want

You are a mind reader, born with an extraordinary ability to understand what others think, feel, believe, want, and know. It’s a sixth sense you use every day, in every personal and professional relationship you have. At its best, this ability allows you to achieve the most important goal in almost any life: connecting, deeply and intimately and honestly, to other human beings. At its worst, it is a source of misunderstanding and unnecessary conflict, leading to damaged relationships and broken dreams.

How good are you at knowing the minds of others? How well can you guess what others think of you, know who really likes you, or tell when someone is lying? How well do you really understand the minds of those closest to you, from your spouse to your kids to your best friends? Do you really know what your coworkers, employees, competitors, or clients want?

In this illuminating exploration of one of the great mysteries of the human mind, University of Chicago psychologist Nicholas Epley introduces us to what scientists have learned about our ability to understand the most complicated puzzle on the planet—other people—and the surprising mistakes we so routinely make. Why are we sometimes blind to the minds of others, treating them like objects or animals? Why do we sometimes talk to our cars, or the stars, as if there is a mind that can hear us? Why do we so routinely believe that others think, feel, and want what we do when, in fact, they do not? And why do we believe we understand our spouses, family, and friends so much better than we actually do? Mindwise will not turn other people into open books, but it will give you the wisdom to revolutionize how you think about them—and yourself.

The following books are much less mainstream than any of those listed above. All of these books are edited and include a variety of authors presenting their own views on the topics. Most, if not all, are from Springer, and consequently are stupid expensive (which is when it's nice to get review copies).

Brain, Mind and Consciousness in the History of Neuroscience – C.U.M. Smith • Harry Whitaker, Editors

This volume of essays examines the problem of mind, looking at how the problem has appeared to neuroscientists (in the widest sense) from classical antiquity through to contemporary times. Beginning with a look at ventricular neuropsychology in antiquity, this book goes on to look at Spinozan ideas on the links between mind and body, Thomas Willis and the foundation of Neurology, Hooke’s mechanical model of the mind and Joseph Priestley’s approach to the mind-body problem.

The volume offers a chapter on the 19th century Ottoman perspective on western thinking. Further chapters trace the work of nineteenth century scholars including George Henry Lewes, Herbert Spencer and Emil du Bois-Reymond. The book covers significant work from the twentieth century, including an examination of Alfred North Whitehead and the history of consciousness, and particular attention is given to the development of quantum consciousness. Chapters on slavery and the self and the development of an understanding of Dualism bring this examination up to date on the latest 21st century work in the field.

At the heart of this book is the matter of how we define the problem of consciousness itself: has there been any progress in our understanding of the working of mind and brain? This work at the interface between science and the humanities will appeal to experts from across many fields who wish to develop their understanding of the problem of consciousness, including scholars of Neuroscience, Behavioural Science and the History of Science.

Ecopsychology, Phenomenology, and the Environment: The Experience of Nature – Douglas A. Vakoch, Fernando Castrillón, Editors

This book seeks to confront an apparent contradiction: that while we are constantly attending to environmental issues, we seem to be woefully out of touch with nature. The goal of Ecopsychology, Phenomenology and the Environment is to foster an enhanced awareness of nature that can lead us to new ways of relating to the environment, ultimately yielding more sustainable patterns of living. This volume is different from other books in the rapidly growing field of ecopsychology in its emphasis on phenomenological approaches, building on the work of phenomenological psychologists such as Maurice Merleau-Ponty. This focus on phenomenological methodologies for articulating our direct experience of nature serves as a critical complement to the usual methodologies of environmental and conservation psychologists, who have emphasized quantitative research. Moreover, Ecopsychology, Phenomenology and the Environment is distinctive insofar as chapters by phenomenologically-sophisticated ecopsychologists are complemented by chapters written by phenomenological researchers of environmental issues with backgrounds in philosophy and geology, providing a breadth and depth of perspective not found in other works written exclusively by psychologists.

The Wiley-Blackwell Handbook of Psychoneuroimmunology – Alexander W. Kusnecov and Hymie Anisman, Editors

The term psychoneuroimmunology was originally coined to acknowledge the existence of functional interactions between the brain, the immune system and the endocrine system. As our understanding deepens of the interplay between the brain and the way bodies function, the field continues to grow in importance. This comprehensive handbook is an authoritative source of information on the history, methodology and development of research into psychoneuroimmunology. 

The interdisciplinary nature of the contributions reflects the fact that the subject is a multifaceted field of research integrating the traditionally separate subjects of biological and behavioral science. Psychoneuroimmunology attains a realistic appreciation of the interplay between different biological systems as they collectively maintain health and combat environmental challenges to health. Background material is balanced by a detailed assessment of emerging topics in psychoneuroimmunological research that focuses on the clinical and practical implications of findings from empirical studies on both humans and animals. While specialist readers will appreciate the coverage of progress made in psychoneuroimmunology, newcomers will gain much from its informed and accessible introduction to the field, as well as its exploration of a variety of methodological approaches.

New Frontiers in Social Neuroscience (Research and Perspectives in Neurosciences) – Jean Decety and Yves Christen, Editors

Traditionally, neuroscience has considered the nervous system as an isolated entity and largely ignored influences of the social environments in which humans and many animal species live. In fact, we now recognize the considerable impact of social structures on the operations of the brain and body. These social factors operate on the individual through a continuous interplay of neural, neuroendocrine, metabolic and immune factors on brain and body, in which the brain is the central regulatory organ, and also a malleable target of these factors. Social neuroscience investigates the biological mechanisms that underlie social processes and behavior, widely considered one of the major problem areas for the neurosciences in the 21st century, and applies concepts and methods of biology to develop theories of social processes and behavior in the social and behavioral sciences. Social neuroscience capitalizes on biological concepts and methods to inform and refine theories of social behavior, and it uses social and behavioral constructs and data to advance theories of neural organization and function. This volume brings together scholars who work with animal and human models of social behavior to discuss the challenges and opportunities in this interdisciplinary academic field.

Handbook of Executive Functioning – Sam Goldstein and Jack A. Naglieri, Editors

Planning. Attention. Memory. Self-regulation. These and other core cognitive and behavioral operations of daily life comprise what we know as executive functioning (EF). But despite all we know, the concept has engendered multiple, often conflicting definitions and its components are sometimes loosely defined and poorly understood.

The Handbook of Executive Functioning cuts through the confusion, analyzing both the whole and its parts in comprehensive, practical detail for scholar and clinician alike. Background chapters examine influential models of EF, tour the brain geography of the executive system and pose salient developmental questions. A section on practical implications relates early deficits in executive functioning to ADD and other disorders in children and considers autism and later-life dementias from an EF standpoint. Further chapters weigh the merits of widely used instruments for assessing executive functioning and review interventions for its enhancement, with special emphasis on children and adolescents.

Featured in the Handbook:

• The development of hot and cool executive function in childhood and adolescence.
• A review of the use of executive function tasks in externalizing and internalizing disorders.
• Executive functioning as a mediator of age-related cognitive decline in adults.
• Treatment integrity in interventions that target executive function.
• Supporting and strengthening working memory in the classroom to enhance executive functioning.

The Handbook of Executive Functioning is an essential resource for researchers, scientist-practitioners and graduate students in clinical child, school and educational psychology; child and adolescent psychiatry; neurobiology; developmental psychology; rehabilitation medicine/therapy and social work.

Brain Theory: Essays in Critical Neurophilosophy – Charles T. Wolfe, Editor

From its beginnings until the present day, neuroscience has always had a special relationship to philosophy. And philosophy has long puzzled over the relation between mind and brain (and by extension, the relation of cerebral processes to freedom, morals, and justice, but also to perception and art). This volume presents some of the state-of-the-art reflections on philosophical efforts to 'make sense' of neuroscience, as regards issues including neuroaesthetics, neuroethics and neurolaw, but also more critical, evaluative perspectives on topics such as the social neuroscience of race, neurofeminism, embodiment and collaboration, memory and pain, and more directly empirical topics such as neuroconstructivism and embodied robotics. Brain theory as presented here is neither mere commentary on the state of the sciences, nor armchair philosophical reflection on traditional topics. It is more pluralistic than current philosophy of neuroscience (or neurophenomenology), yet more directly engaged with empirical, indeed experimental matters than socio-cultural discussions of 'brainhood' or representations of the brain.

Late Modernity: Trajectories towards Morphogenic Society (Social Morphogenesis) – Margaret S. Archer, Editor

 

This volume examines the reasons for intensified social change after 1980; a peaceful process of a magnitude that is historically unprecedented. It examines the kinds of novelty that have come about through morphogenesis and the elements of stability that remain because of morphostasis. It is argued that this pattern cannot be explained simply by ‘acceleration’. Instead, we must specify the generative mechanism(s) involved that underlie and unify ordinary people’s experiences of different disjunctions in their lives. The book discusses the umbrella concept of ‘social morphogenesis’ and the possibility of transition to a ‘Morphogenic Society’. It examines possible ‘generative mechanisms’ accounting for the effects of ‘social morphogenesis’ in transforming previous and much more stable practices. Finally, it seeks to answer the question of what is required in order to justify the claim that Morphogenic society can supersede modernity.