SSRIs Add to the Existing Surplus of Serotonin in the Raphe Nucleus and Reduces Serotonin in Hippocampus, Where it Is Needed Most

This appears to be the first good research showing why SSRIs do not work for most people in treating depression and anxiety. It appears that early life stress increases serotonin levels in the brain to the point that a negative feedback loop develops, reducing the brain's sensitivity to the serotonin. The resulting depression and/or anxiety that develops is exacerbated by SSRIs, which just add to the existing surplus of serotonin in the raphe nucleus and reduces serotonin in hippocampus, where it is needed most.

Early life stress may cause excess serotonin release resulting in a serotonin deficit

Data suggest a reason why SSRI medications may fail in many patients
 
Studies indicate that the majority of people with mood and anxiety disorders who receive the most commonly prescribed class of antidepressant medications, Selective Serotonin Reuptake Inhibitors or SSRI's, are not helped by these medications. SSRIs are designed to increase serotonin, a neurotransmitter in the brain that is key to maintenance of mood. 

Researchers led by Jeremy D. Coplan, MD, professor of psychiatry at SUNY Downstate Medical Center, have published data suggesting an explanation for the longstanding puzzle as to why low serotonin could not be detected in depression without suicidal intent, even though many antidepressant treatments work by increasing serotonin in areas key for mood regulation, such as the hippocampus. The pre-clinical research was published in a recent edition of Frontiers in Behavioral Neuroscience.
 
Dr. Coplan explains, "We have shown that serotonin is too high near the serotonin brain cells, reducing firing of the serotonin nerve cells through a well-documented negative feedback mechanism in the raphe nucleus. The result is that the hippocampus and other critical brain structures needed for mood maintenance do not get enough serotonin. We can see this because the hippocampus is shrunken and the white matter loses integrity. By the time serotonin metabolites are measured in a lumbar spinal tap, the usual way serotonin levels have been measured, the high serotonin has mixed with the low serotonin and you have no difference from people who are healthy." 

He continues, "We have hypothesized in an earlier paper that this is a plausible reason why SSRIs may not work in a majority of people, because SSRIs will tend to make the high serotonin even higher in the raphe nucleus. The serotonin neuron may not be able to adapt and restore its firing, inducing a presumed serotonin deficit in terminal fields, evidenced by shrinkage of the hippocampus." 

He adds, "We cannot say categorically, in our pre-clinical model, that high serotonin in the raphe nucleus leads to low serotonin in the hippocampus, but studies by J. John Mann, MD, a co-author on the paper, and Victoria Arango, PhD, both of Columbia University Medical Center, have shown that people who committed suicide exhibited high serotonin in the raphe nucleus and low serotonin in another area of the brain critical for mood maintenance, the prefrontal cortex. Additional studies should be performed, especially since better understanding of the serotonin system will significantly improve future treatment options." 

In the earlier paper, also in Frontiers in Behavioral Neuroscience, Dr. Coplan proposed augmentation therapies in treatment-resistant patients, including stacking one medication upon another in the most difficult cases: "This is what physicians do for hypertension, diabetes, and congestive heart failure," said Dr. Coplan. "But in psychiatry, we sometimes act as if our medications are so effective that we are exempt from how the rest of medicine deals with difficult-to-treat cases." 

Other approaches to bypass the high midbrain serotonin impasse, according to Dr. Coplan, are shutting glutamate input into the raphe nucleus, a portion of the brain that controls the release of serotonin, and utilizing drugs that block noradrenergic input into the dorsal raphe. 

Dr. Coplan notes that a recent large-scale study showed only a minority of patients do well on SSRIs, and of those, many lose response in a year or two. "There is an epidemic of inadequately treated depression and psychiatrists are not well trained to deal with this challenge," he observed. "What they often do is change from one antidepressant to another when there is a lack of response. Eventually the patient becomes non-compliant and the patient, rather than the treatment, is blamed for the non-efficacy." 

"These two papers provide possible insights as to why our treatments are ineffective and what we should be doing to treat patients effectively," Dr. Coplan said. "Many academic researchers currently do not practice clinically, so they are out of touch with real-life patients and their struggles. In the meantime, suicide rates have not budged in decades." 

Here are the abstracts from the original articles, both of which are open access.

Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders

Jeremy D. Coplan^1*, Sasha L. Fulton², Wade Reiner³, Andrea Jackowski⁴, Venkatesh Panthangi¹, Tarique D. Perera², Jack M. Gorman⁵, Yung-yu Huang⁶, Cheuk Y. Tang⁷, Patrick R. Hof⁸, Arie Kaffman⁹, Andrew J. Dwork⁶, Sanjay J. Mathew^10,11, Joan Kaufman¹² and J. John Mann⁶

• ¹Nonhuman Primate Laboratory, Department of Psychiatry and Behavioral Sciences, Downstate Medical Center, State University of New York, Brooklyn, NY, USA
• ²Geriatric Psychiatry, New York State Psychiatric Institute, New York, NY, USA
• ³College of Medicine, State University of New York Downstate Medical Center, Brooklyn, NY, USA
• ⁴Departamento de Psiquiatria & Neuroradiologia, Universidade Federal de São Paulo, São Paulo, Brazil
• ⁵Franklin Behavioral Health Consultants, Bronx, NY, USA
• ⁶Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA
• ⁷Departments of Psychiatry, Neuroscience, and Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• ⁸Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
• ⁹Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
• ¹⁰Mental Health Care Line, Michael E. Debakey VA Medical Center, Houston, TX, USA
• ¹¹Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA
• ¹²Child Study Center, Yale University School of Medicine, New Haven, CT, USA

Background: Early life stress (ELS) is cited as a risk for mood and anxiety disorders, potentially through altered serotonin neurotransmission. We examined the effects of ELS, utilizing the variable foraging demand (VFD) macaque model, on adolescent monoamine metabolites. We sought to replicate an increase in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) observed in two previous VFD cohorts. We hypothesized that elevated cisternal 5-HIAA was associated with reduced neurotrophic effects, conceivably due to excessive negative feedback at somatodendritic 5-HT_1A autoreceptors. A putatively decreased serotonin neurotransmission would be reflected by reductions in hippocampal volume and white matter (WM) fractional anisotropy (FA).

Methods: When infants were 2–6 months of age, bonnet macaque mothers were exposed to VFD. We employed cisternal CSF taps to measure monoamine metabolites in VFD (N = 22) and non-VFD (N = 14) offspring (mean age = 2.61 years). Metabolites were correlated with hippocampal volume obtained by MRI and WM FA by diffusion tensor imaging in young adulthood in 17 males [10 VFD (mean age = 4.57 years)].

Results: VFD subjects exhibited increased CSF 5-HIAA compared to non-VFD controls. An inverse correlation between right hippocampal volume and 5-HIAA was noted in VFD- but not controls. CSF HVA and MHPG correlated inversely with hippocampal volume only in VFD. CSF 5-HIAA correlated inversely with FA of the WM tracts of the anterior limb of the internal capsule (ALIC) only in VFD.

Conclusions: Elevated cisternal 5-HIAA in VFD may reflect increased dorsal raphe serotonin, potentially inducing excessive autoreceptor activation, inducing a putative serotonin deficit in terminal fields. Resultant reductions in neurotrophic activity are reflected by smaller right hippocampal volume. Convergent evidence of reduced neurotrophic activity in association with high CSF 5-HIAA in VFD was reflected by reduced FA of the ALIC.

Full Citation: 

Coplan JD, Fulton SL, Reiner W, Jackowski A, Panthangi V, Perera TD, Gorman JM, Huang Y, Tang CY, Hof PR, Kaffman A, Dwork AJ, Mathew SJ, Kaufman J and Mann JJ (2014, Dec 24). Elevated cerebrospinal fluid 5-hydroxyindoleacetic acid in macaques following early life stress and inverse association with hippocampal volume: preliminary implications for serotonin-related function in mood and anxiety disorders. Front. Behav. Neurosci. 8:440. doi: 10.3389/fnbeh.2014.00440

* * * * *

A neurobiological hypothesis of treatment-resistant depression – mechanisms for selective serotonin reuptake inhibitor non-efficacy

Jeremy D. Coplan¹*, Srinath Gopinath¹, Chadi G. Abdallah^2,3 and Benjamin R. Berry⁴

• ¹Division of Neuropsychopharmacology, Department of Psychiatry and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, NY, USA
• ²Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
• ³Clinical Neuroscience Division, National Center for PTSD, West Haven, CT, USA
• ⁴State University of New York Downstate College of Medicine, Brooklyn, NY, USA

First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are <50%. The authors examine the putative biological substrates underlying “treatment resistant depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin system becomes impervious to the desired enhancement of serotonin neurotransmission by SSRIs. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple serotonin deficit state but rather an excess of midbrain peri-raphe serotonin and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in serotonin-mediated neuroplasticity. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part by “flooding” 5-HT_1A autoreceptors by serotonin itself. Certain factors putatively exacerbate this scenario – presence of the short arm of the serotonin transporter gene, early-life adversity and comorbid bipolar disorder – each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing serotonin neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic, and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on serotonin neurons. Future studies are recommended to test this biologically based approach for treatment of TRD.

Full Citation: 

Coplan JD, Gopinath S, Abdallah CG and Berry BR. (2014, May 20). A neurobiological hypothesis of treatment-resistant depression – mechanisms for selective serotonin reuptake inhibitor non-efficacy. Front. Behav. Neurosci. 8:189. doi: 10.3389/fnbeh.2014.00189

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.

The following article is an introduction to the Research Topic on Frontiers in Psychology: Cognitive Science: Towards an embodied science of intersubjectivity: Widening the scope of social understanding research.

This is an interesting article and a very cool research area.

Full Citation: 
Di Paolo, EA, and De Jaegher, H. (2015, Mar 2). Toward an embodied science of intersubjectivity: Widening the scope of social understanding research. Frontiers in Psychology: Cognitive Science. 6:234. doi: 10.3389/fpsyg.2015.00234

Toward an embodied science of intersubjectivity: Widening the scope of social understanding research

Ezequiel A. Di Paolo^* and Hanne De Jaegher

• Logic and Philosophy of Science, IAS-Research Centre, University of the Basque Country, Donostia/San Sebastián, Spain

The study of human social phenomena in their proper scope demands the integrated effort of many disciplinary traditions. This fact is widely acknowledged but rarely acted upon. It is in practice often difficult to cross disciplinary boundaries, to communicate across different vocabularies, research goals, theories and methods. The aim of this Research Topic has been to make some progress in stepping across these borders.

Not attempting this crossing in a subject as multi-faceted as intersubjectivity inevitably binds us to remain within self-enclosed conceptions. By this we mean a bundle of self-reinforcing perspectives, hypotheses, experimental methods, debates, communities and institutions. Traditional ways of thinking about social cognition frame the questions that are deemed worth researching. These all revolve around the issue of how we figure out other minds, assuming that other people's intentional states are hidden, private and internal. The proposed answers rely only on how the perceived indirect manifestations of other people's mental states are processed by individual cognitive mechanisms (Van Overwalle, 2009).

We would like to raise, instead, the question of what an embodied science of intersubjectivity would look like if we were to start from different premises than those that delimit classical approaches to social cognition. For doing this, we thought the time was ripe for bringing together work that crosses disciplinary boundaries and informs us about different conceptions of how people understand each other and act and make meaning together.

The move is timely. The internalist assumptions in social cognition research are beginning to shift. We have more and better tools to explore the role of interactive phenomena and interpersonal histories in conjunction with individual processes (Dumas et al., 2010; Di Paolo and De Jaegher, 2012; Konvalinka and Roepstorff, 2012; Schilbach et al., 2013). This interactive expansion of the conceptual and methodological toolkit for investigating social cognition, we now propose, can be followed by an expansion into wider and deeply-related research questions, beyond (but including) that of social cognition narrowly construed.

Our social lives are populated by different kinds of cognitive and affective phenomena apart from figuring out other minds. They include acting and perceiving together, verbal and non-verbal engagement, experiences of (dis-)connection, relations in a group, joint meaning-making, intimacy, trust, secrecy, conflict, negotiation, asymmetric relations, material mediation of social interaction, collective action, contextual engagement with socio-cultural norms, etc. These phenomena are often characterized by a strong participation by the cognitive agent, in contrast with the spectatorial stance of social cognition (Reddy and Morris, 2004; De Jaegher and Di Paolo, 2007). We use the broader notion of embodied intersubjectivity to refer to this wider set of questions.

Forty-two contributions to this Research Topic explore several of these themes. They combine ideas and methods from psychology, neuroscience, philosophy of mind, phenomenology, psychiatry and psychotherapy, social science, and language studies. The number of contributions confirms our suspicions that there is a genuine interest in embodied intersubjectivity.

All of the contributions in some way or other move beyond traditional cognitivist perspectives. Here we can simply highlight some of the most interesting ways in which this happens. As already mentioned, there is a recent trend to investigate the dynamics of actual interactive encounters between people. Several empirical studies in this Research Topic continue further along this line. They look at interactive encounters using methods such as thermal imaging, interactive virtual environments, or 1/f noise analysis, or combine existing methods with novel theoretical starting points.

Other work looks at aspects of embodied social understanding which are pertinent even in the absence of ongoing interaction. These include the richness of body kinematics, affect regulation, and life-story analysis. A few contributions focus on how embodied and interactive perspectives impact on developmental research. They study real-life interactions between infants and their care-givers in various contexts (infant pick-up, book sharing, pointing, cooperation, and expressiveness during play in chimpanzees). Aspects of psychopathology are explored also from an embodied intersubjective angle, inspiring research on intra- and inter-personal emotion regulation, social affordances, personal biography, and therapeutic play, and their effects on somatic symptom disorders, autism, and schizophrenia.

Broadening the scope of relevant questions for embodied intersubjectivity inevitably means including research on language. Many of the contributions make headway on this matter, questioning the notion of the common ground, the role of conformity in social understanding, the processes involved in the activity of reading texts, and the links between conversational coordination and meaning-making. Others investigate the participatory nature of understanding narratives, and the role of organizational, temporal, and inter-affective aspects in language. Similar advances can be made in the area of connecting the cognitive and the social sciences. This is a very fruitful but still largely unexplored territory. A discussion is offered along Marxist lines concerning the interaction between categories of understanding and modes of social exchange and production. And the lessons of embodied/enactive approaches to intersubjectivity are summoned to contribute to understanding the phenomenological and social effects of solitary confinement.

Finally, some contributions elaborate theoretical and methodological implications and concepts, and in this way contribute to shaping the core of an embodied science of intersubjectivity. Methodological issues include whether dynamical systems concepts can bridge the multiple scales involved in social understanding, from the biological and neural to the personal, interactive and societal, how second person perspectives in cognitive science can help psychopathology research, and whether techniques used in theater can refine intuitions and theoretical concepts about interactive experience. Theoretical advances include radically embodied accounts of intersubjectivity that bring together conceptions from enactivism and ecological psychology, the notion of intersubjective time, and a socially embodied notion of the human self. Other discussions offer links between interpersonal interaction and phenomenal experience, between social normativity and conceptual abilities, or unearth the importance of opacity, i.e., the secret, silent or hidden aspects of personal experience, for understanding each other.

It is noteworthy, and especially satisfying, that many novel themes and questions emerged, several of them in some way related to personal meaning. To name a few: joy, secrecy, solitude, influence of capitalist mode of production on cognition, book sharing in infancy, the search for comprehensiveness and integrity in interacting, literature, and enactivism, ethics of care, shame in relation to interaction, and the interactive building blocks of culture and institutions.

Once again, we notice that the contributions to this Research Topic demonstrate the richness of enquiry and research work that is opened by the combination of novel methods and the bringing together of fields that traditionally work in isolation from each other. It also shows that criticisms of classical approaches as being sometimes too narrow are not just idle but point to genuinely new perspectives on concrete and everyday intersubjectivity that are opened to investigation.

Conflict of Interest Statement

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

Acknowledgments

This work is supported by the Marie-Curie Initial Training Network, “TESIS: Towards an Embodied Science of InterSubjectivity” (FP7-PEOPLE-2010-ITN, 264828).

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Here are some of the articles posted in this Research Topic so far. If you follow the link, you'll be on page one of four (43 articles going back to the beginning of 2014).

Enactive account of pretend play and its application to therapy

Zuzanna Rucinska and Ellen Reijmers

Perspective: This paper informs therapeutic practices that use play, by providing a non-standard philosophical account of pretence: the Enactive Account of Pretend Play. The EAPP holds that pretend play activity need not invoke mental representational mechanisms; ...

Published on 02 March 2015
Front. Psychol. doi: 10.3389/fpsyg.2015.00175

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Embodied intersubjective engagement in mother–infant tactile communication: a cross-cultural study of Japanese and Scottish mother–infant behaviors during infant pick-up

Koichi Negayama, Jonathan T. Delafield-Butt, Keiko Momose, Konomi Ishijima, Noriko Kawahara, Erin J. Lux, Andrew Murphy and Konstantinos Kaliarntas

Original Research: This study examines the early development of cultural differences in a simple, embodied and intersubjective engagement between mothers putting down, picking up, and carrying their infants between Japan and Scotland. Eleven Japanese and 10 Scottish ...

Published on 27 February 2015
Front. Psychol. doi: 10.3389/fpsyg.2015.00066 

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Assessing embodied interpersonal emotion regulation in somatic symptom disorders: a case study

Zeynep Okur Güney, Heribert Sattel, Daniela Cardone and Arcangelo Merla

Original Research: The aim of the present study was to examine the intra- and interpersonal emotion regulation of patients with somatic symptom disorders (SSD) during interactions with significant others (i.e. romantic partners). We presented two case couples for ... 

Published on 10 February 2015
Front. Psychol. doi: 10.3389/fpsyg.2015.00068

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Navigating beyond “here & now” affordances—on sensorimotor maturation and “false belief” performance

Maria Brincker

Perspective: How and when do we learn to understand other people’s perspectives and possibly divergent beliefs? This question has elicited much theoretical and empirical research. A puzzling finding has been that toddlers perform well on so-called implicit false ... 

Published on 15 December 2014
Front. Psychol. doi: 10.3389/fpsyg.2014.01433

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Jointly structuring triadic spaces of meaning and action: book sharing from 3 months on

Nicole Rossmanith, Alan Costall, Andreas F. Reichelt, Beatriz López and Vasudevi Reddy

Original Research: This study explores the emergence of triadic interactions through the example of book sharing. As part of a naturalistic study, 10 infants were visited in their homes from 3-12 months. We report that (1) book sharing as a form of ... 

Published on 10 December 2014
Front. Psychol. doi: 10.3389/fpsyg.2014.01390

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Keep meaning in conversational coordination

Elena C. Cuffari

Perspective: Coordination is a widely employed term across recent quantitative and qualitative approaches to intersubjectivity, particularly approaches that give embodiment and enaction central explanatory roles. With a focus on linguistic and bodily coordination ... 

Published on 03 December 2014
Front. Psychol. doi: 10.3389/fpsyg.2014.01397

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Toward an expansion of an enactive ethics with the help of care ethics

Petr Urban

Opinion
Published on 27 November 2014
Front. Psychol. doi: 10.3389/fpsyg.2014.01354

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Enacting a social ecology: radically embodied intersubjectivity

Marek McGann

Hypothesis & Theory: Embodied approaches to cognitive science frequently describe the mind as “world-involving”, indicating complementary and interdependent relationships between an agent and its environment. The precise nature of the environment is frequently left ... 

Published on 18 November 2014
Front. Psychol. doi: 10.3389/fpsyg.2014.01321

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Quantifying long-range correlations and 1/f patterns in a minimal experiment of social interaction

Manuel G. Bedia, Miguel Aguilera, Tomás Gómez, David G. Larrode and Francisco Seron

Original ResearchIn recent years, researchers in social cognition have found the `perceptual crossing paradigm' to be both a theoretical and practical advance towards meeting particular challenges. This paradigm has been used to analyze the type of interactive ... 

Published on 12 November 2014
Front. Psychol. doi: 10.3389/fpsyg.2014.01281

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Why call bodily sense making “languaging”?

Giovanna Colombetti

General Commentary
Published on 07 November 2014
Front. Psychol. doi: 10.3389/fpsyg.2014.01286

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Pooling the ground: understanding and coordination in collective sense making

Joanna Rączaszek-Leonardi, Agnieszka Dębska and Adam Sochanowicz

Hypothesis & Theory: Common ground is most often understood as the sum of mutually known beliefs, knowledge and suppositions among the participants in a conversation. It explains why participants do not mention things that should be obvious to both. In some accounts of ...

Published on 07 November 2014
Front. Psychol. doi: 10.3389/fpsyg.2014.01233