Saturday, August 17, 2013

Anne Beate Reinertsen, PhD - Welcome to My Brain

Wow. This paper has, perhaps, the most convoluted and self-reflexive abstract I think I have ever seen. And yet I suspect that is the point - the author is using her own brain function as the research design for a qualitative study of the subject ("recursive, intrinsic, self-reflexive as de-and/or resubjective always evolving living research designs").

The author employs the Möbius Strip as an image for her ideas.

File:Möbius strip.jpg
A Möbius strip made with a piece of paper and tape. If an ant were to crawl along the length of this strip, it would return to its starting point having traversed the entire length of the strip (on both sides of the original paper) without ever crossing an edge.

Interesting . . . "auto- brain- biography - ethnomethodology attempt."

Full Citation:
Reinersten, AB. (2013, Jul 12). Welcome to My Brain. Qualitative Inquiry, XX(X); 1-12. doi: 10.1177/1077800413489534

This is about developing recursive, intrinsic, self-reflexive as de-and/or resubjective always evolving living research designs. It is about learning and memory cognition and experiment poetic/creative pedagogical science establishing a view of students ultimately me as subjects of will (not) gaining from disorder and noise: Antifragile and antifragility and pedagogy as movements in/through place/space. Further, it is about postconceptual hyperbolic word creation thus a view of using language for thinking not primarily for communication. It is brain research with a twist and becoming, ultimately valuation of knowledges processes: Becoming with data again and again and self-writing theory. I use knitting the Möbius strip and other art/math hyperbolic knitted and crocheted objects to illustrate nonbinary . . . perhaps. Generally; this is about asking how-questions more than what-questions.
The article is available to read or download at Scribd, but here is a taste of the first couple of pages:

Introduction and the Möbius Strip
“So freedom of thought exists when I can have all possible thoughts; but the thoughts become property only by not being able to become masters. In the time of freedom of thought, thoughts (ideas) rule; but, if I attain to property in thought, they stand as my creatures. 
 If the hierarchy had not so penetrated men to the innermost as to take from them all courage to pursue free thoughts, that is, thoughts perhaps displeasing to God, one would have to consider freedom of thought just as empty a word as, say, a freedom of digestion.  
According to the professionals’ opinion, the thought is given to me; according to the freethinkers’, I seek the thought. There the truth is already found and extant, only I must—receive it from its Giver by grace; here the truth is to be sought and is my goal, lying in the future, toward which I have to run.” (Stirner, 2012: Kindle locations 5514-5519).
Welcome to my brain. It is plastic, mentally creative, and physically adaptable just like yours if we want to. It is a chaotic noisy place wanting to produce results. I will not let one area dominate however. Also, there are places I do not want to go. Cortex- Hippocampus- learning and memory Cognition, emotional, sensory, bodily, social centers . . . —in the brain . . . So first; start with a long rectangle (ABCD) made of paper. Then give the rectangle a half twist. Third; join the ends so that A is matched with D and B is matched with C. Now you have created a continuous one-sided surface from this rectangular strip only by rotating one end 180° and attaching it to the other end. The brain is/has architecture (The Cortex) and neurons form networks forming larger networks processing information. Networks that for example allow us to recognize and code space, develop tools and navigate thus decide, make matter, and plan ahead. These are processes of orientation in/through space. Navigating and thinking about navigating simultaneously. Movements and moving and words as thinking tools: Complex processes of building complex representations of compass distances—learning and memory—measurements. And important: Thinking/planning also without direct sensory impulses: Thus having the ability to generate new ideas and ideas about the future too . . . in the brain. To live such complexity I turn to “knitting around” Möbius Band Scarves (Zimmerman, 1989) as you will see below. Very easy but not; I had to rehearse. Thus calming but not, product oriented nice and warm—comfortable—if I finish but also while doing.
As you now know, this nonorientable surface is called a Möbius Strip or Möbius Band, named after August F. Möbius, a 19th century German mathematician and astronomer, who was a pioneer in the field of topology. Möbius, along with his contemporaries, Riemann, Lobachevsky, and Bolyai, created a non-Euclidean revolution in geometry. Möbius strips have found a number of applications that exploit a remarkable property they possess: one-sidedness. Joining A to C and B to D (no half twist) would produce a simple belt-shaped loop with two sides and two edges—impossible to travel from one side to the other without crossing an edge. But, as a result of the half twist, the Möbius Strip has only one side and one edge, and I am the no-one-sided teacher/researcher/professor in education: a nonorientable surface with a boundary—architecture—Cortex—and you. Thus I/you/we must/can make choices and make knowledges matter. And sometimes I am forced or I force myself to go places. Qualia: the subjective experience of things, a property of something . . . its feel or appearance perhaps rather than the thing itself . . .: This is about finding the out there in the in here. 
Here is what another teacher/researcher/professor, and this time in brain research at Center for Biology of Memory, Trondheim, Norway (CBM):, says about what he does, knows and thinks: “The Hippocampus is a part of the brain we know is relevant for learning and memory. There are brain structures there that are involved. The brain research area has exploded the recent years but still we are in the beginning of discovering general rules about how the brain processes information. Experimental evidence based science does not—must not/cannot—move too fast. We do not know that much and other so quickly. At least if we speak about evidence. Grounded scientific research is a privilege” (Interview, October 28th, 2011). 
At CBM they started to study memory but ended up in studying sense of place/space: “Now we know that this sense is closely linked to memory. It is almost like a human GPS with grid cells in the part of the brain called the Entorhinal Cortex. Grid cells collaborate with other specialized nerve cells with complementary roles in the sense of place/space and direction. Together they build a map in the brain. And the brain uses this map to orient itself in both familiar and unfamiliar environments. Signals create a coordination system in which positions can be registered. They register our movements and are closely linked to our memory. The grid cells do not reflect signals that come in from the outside from any of our senses. The grid patterns are made by the brain itself. Therefore we can use the grid cells as a way of understanding how activity patterns emerge in the brain. The grid is opening up new possibilities to study how the brain stores information” (Moser & Moser, in Jacobsen, 2012). 
“It is very difficult and risky to deduct anything directly between brain research and pedagogy, but one thing that we might say is that if you want to learn something different and other, it might be sensible to shift between places: Learning different things in different places that is” (Interview, October 28th, 2011). 
Ethnomethodology is an approach to sociological inquiry as the study of the everyday methods that people use for the production of social order (Garfinkel, 1967). It is also called bottom-up microsociology and a member’s methods inquiring into common sense knowledge, self organizing systems, and situated natural language. The aim is to document methods and practices through which society’s members make sense of the world. It is in itself however not a method. It does not have a set of formal research methods or procedures. 
Knitting is a repetitive visual spatial task. These tasks also include e.g. running and folding origami and can put our brain into the state of Theta (Retrieved Dec.7th. 2012). States of Theta can increase creativity, lower stress/anxiety and increase objectivity in difficult situations. Theta is also that state between falling asleep and waking up when we seem to have all of our best ideas. Because the brain is focusing on (literally) the task at hand, it isn’t as judgmental and has lower standards/barriers. Theta is nonjudgmental, more observant . . . objective? No but I try. And as you will see below, I try to hold my brain in my hands.
I and My Research . . . Brain . . . Questions
“Some things benefit from shocks; they thrive and grow when exposed to volatility, randomness, disorder, and stressors and love adventure, risk, and uncertainty. Yet in spite of the ubiquity of the phenomenon, there is no word for the exact opposite of fragile. Let us call it antifragile. Antifragility is beyond resilience or robustness. The resilient resist shocks and stays the same; the antifragile gets better” (Taleb, 2012, p. 3). 
This article is therefore about developing recursive intrinsic self-reflexive as de- and/or resubjective always evolving living research designs. Inquiry perhaps full stop—me: An auto-brain—biography and/or a brain theorizing itself; me theorizing my brain. It is thus about theorizing bodily here brain and transcorporeal materialities, in ways that neither push us back into any traps of biological determinism or cultural essentialism, nor make us leave bodily matter and biologies behind. It is an attempt of seeing the real as/through/in its material-discursive coconstitutive complexity and produce research from within an ontology and epistemology where ‘matter and meaning are mutually articulated’ (Barad 2007, p. 152). It is about learning and memory cognition and experiment poetic and/or creative pedagogical science; learning ultimately pedagogy as movements in/through space. 
It is brain research with a twist and becoming, ultimately valuation of knowledges process; a personal antifragile will born from knowledge. I use knitting and other, as you will see, to illustrate or rather live nonbinary. First, I will write more about research designing, second, about knitting Möbius bands. Third, I will philosophize a bit with Socrates, Meno and Plato: “Meno’s Paradox,” or “The Paradox of Inquiry” (Meno 80d-e) and Max Stirner (1806-1856) over learning and memory, one-sidedness, antifragility research, pedagogy, and will only to end in wonder. Eventually, this is a philosophical brain journey in which the question “how do you know” is more difficult but vital to ask than the “what do you know” question we traditionally have asked both ourselves and our students through years. 
I treat theory, transcribed interview notes, pieces of art, creating knitting Möbius band scarves and myself as data (text). Data shapes and negotiate. Data are shaped and negotiated. There are data dilemmas—paradoxes. I am at hearing of the data; text and textuality. Thus I am (my own) data but as a “montage” in which “several different images are superimposed onto one another” (Denzin and Lincoln, 2003, p. 6). Several different texts: My brain. My knowledge of my ordinary affairs, of my own organized enterprises, as part of the same setting that makes it orderable. 
It is broad and multifaceted and with open-ended references to any kind of sense-making procedure, a domain of uncharted dimensions my auto- brain- biography - ethnomethodology attempt. 
I turn knitting, art into data and tool to see other and beget thinking; activate brain cells—circuits—inquiring minds; experiment—poetic—creative—pedagogical science—and language . . . making, de/re/constructing the world? I told you this was chaotic and noisy and my own moving sensations of sound touch taste and smell. And further, my amalgamations of images in order to make a very unique image of my own, and mine. Seeking to describe the common sense methods through which I produce myself as teacher/researcher. A member’s methods; my methods.

The Endocannabinoid System as a Possible Target for Treating Post-Traumatic Stress Disorder

Around 15-35% of those who experience serious trauma are likely to develop post-traumatic stress disorder (PTSD), and among those who have experienced abuse, neglect, or other adversity in childhood, the number tends toward the high end. Of those who develop PTSD , more than a third will fail to recover even after many years of therapy and medications (Darves-Bornoz et al., 2008). These people demonstrate considerable impairments in their overall quality of life, including physical health and psycho-social functioning (Schelling et al., 1998).

Obviously, the current treatment approaches (SSRI antidepressants, cognitive-behavioral therapy, and exposure therapy) are not working for a significant number of people.

One of the innovations in recent years has been the use of beta-blockers (high blood pressure medication) to reduce anxiety, hypervigilance, flashbacks, and nightmares. The one I see most often is Prazosin, which seems to work, in part, by reducing adrenaline levels, thereby decreasing anxiety.
Prazosin is an alpha-adrenergic blocker originally used to treat hypertension. "The reason we think it works in the setting of nightmares is that prazosin crosses the blood–brain barrier, so it gets into the brain and kind of dampens the norepinephrine effects, which we think contribute to nightmares," Dr. King said.
In my experience, the side-effects of this medication are far less intrusive and long-lasting than those of the SSRI and SNRI medications. The benefits, even if it is only improved sleep can be considerable for those who are good responders.

In this new article from Frontiers in Behavioral Neuroscience, the authors propose that a potential target for treating the anxiety and hypervigilance symptoms, as well as many of the other symptoms (avoidance, arousal, and re-experiencing), is the endocannabinoid system. A quick Google Scholar search turned up a lot of research in this area, including these articles:

  • Fraser, GA. (2009). The Use of a Synthetic Cannabinoid in the Management of Treatment-Resistant Nightmares in Posttraumatic Stress Disorder (PTSD). CNS Neuroscience & Therapeutics, 15; 84–88. doi: 10.1111/j.1755-5949.2008.00071.x
  • Hill, MN and Gorzalka, BB. (2009). The Endocannabinoid System and the Treatment of Mood and Anxiety Disorders. CNS & Neurological Disorders - Drug Targets, 8, 451-458.  

My issue with this Frontiers article is that the authors don't even mention possible treatments for PTSD that do not involve a pill. While I have many clients who need medication, at least in the short term, in order to get benefit from therapy, I have many who do not need medications, or who have enough affect regulation to manage the difficult symptoms when they come up.

No matter how many cool drugs are developed, we should always try to treat people without drugs first and foremost. Even with the medications that seem to have few side effects, such as the concepts proposed below, there are ALWAYS side effects.

The endocannabinoid system regulates memory, appetite, energy balance/metabolism, stress response, immune functions, pain perception, body temperature, and even neurogenesis. There is no way we can manipulate this system for one outcome and not impact its functions in other areas of the body.

Full Citation: 
Trezza V and Campolongo P. (2013, Aug 9). The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD). Frontiers in Behavioral Neuroscience, 7:100. doi: 10.3389/fnbeh.2013.00100

The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD)

Viviana Trezza [1] and Patrizia Campolongo [2]
1. Department of Sciences, Section of Biomedical Sciences and Technologies, University “Roma Tre,” Rome, Italy
2. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
Post-traumatic stress disorder (PTSD) is a psychiatric disorder of significant prevalence and morbidity, whose pathogenesis relies on paradoxical changes of emotional memory processing. An ideal treatment would be a drug able to block the pathological over-consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. While the latter benefit from antidepressant medications, no drug is available to control the cognitive symptomatology. Endocannabinoids regulate affective states and participate in memory consolidation, retrieval, and extinction. Clinical findings showing a relationship between Cannabis use and PTSD, as well as changes in endocannabinoid activity in PTSD patients, further suggest the existence of a link between endocannabinoids and maladaptive brain changes after trauma exposure. Along these lines, we suggest that endocannabinoid degradation inhibitors may be an ideal therapeutic approach to simultaneously treat the emotional and cognitive features of PTSD, avoiding the unwanted psychotropic effects of compounds directly binding cannabinoid receptors.

* * * * *

Post-traumatic stress disorder (PTSD) is a psychiatric disorder of significant prevalence and morbidity (Layton and Krikorian, 2002). In the overall population, more than two thirds of persons may experience a serious traumatic event at some point in lifetime (Javidi and Yadollahie, 2012). Although not everyone develops PTSD after experiencing a traumatic event, the lifetime prevalence of PTSD is high, being estimated as 8.2% in Europe and in the United States, up to 9.2% in Canada (Kessler et al., 1995; Darves-Bornoz et al., 2008; Van Ameringen et al., 2008). More than a third of PTSD patients fail to recover even after many years of treatment (Darves-Bornoz et al., 2008), showing a significant impairments in many aspects of health-related quality of life, including psychosocial functioning (Schelling et al., 1998).

Feeling afraid is a natural response to threats and triggers many physiological changes to prepare the body to defend against the danger or to avoid it. In PTSD, this reaction is changed or damaged. Even if anxiety is a common symptom of PTSD patients, the pathogenesis of the disorder relies on paradoxical changes of memory processing (Cohen et al., 2006;Parsons and Ressler, 2013). From a physiological point of view, memories characterized by a strong emotional salience tend to be well consolidated, they are often retrieved in our brain and therefore tend not to be extinct; from an evolutionary perspective, this is of crucial importance for survival. However, in PTSD patients, all or part of this processes may become maladaptive. Three symptom categories characterize the disorder: (1) persistent re-experience of the traumatic event; (2) persistent symptoms of increased arousal; and (3) persistent avoidance of stimuli associated with the trauma, which may include amnesia for important aspects of the traumatic event (Brewin, 2001). These symptoms reflect excessive retrieval of traumatic memories that are again consolidated, thus cementing the traumatic memory trace, and retaining its vividness and power to evoke distress for decades or even a lifetime (de Quervain et al., 2009). It appears from this symptomatology that three phases of memory processing may become maladaptive and of crucial importance in the development and maintenance of PTSD: consolidation, retrieval, and extinction.

PTSD is heterogeneous in its nature, and often associated with other psychiatric comorbidities; for these reasons, treating PTSD is rather difficult, and the disorder may persist over the patient's lifetime (Albucher and Liberzon, 2002). The therapeutic options to treat the anxiety symptoms of PTSD currently include serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOi), anticonvulsants, atypical antipsychotics and benzodiazepines (Albucher and Liberzon, 2002). Although SSRIs emerge as the preferred first line treatment to treat the anxiety symptoms of PTSD (Dow and Kline, 1997Ipser et al., 2006), a large proportion of patients fails to respond to these medications (Ipser et al., 2006). Furthermore, no suitable treatment is currently available to treat the maladaptive cognitive features of PTSD and/or to prevent its development. This limitation is due to the scarce knowledge of PTSD neurobiology that hampers the identification of new pharmacological targets to treat this disorder. As Albucher and Liberzon (2002) pointed out, the diversity of the symptoms such as flashbacks, nightmares, hyperarousal, avoidance, numbing, anxiety, anger, impulsivity, or aggression suggests the involvement of multiple neurotransmitter systems (Goodman et al., 2012; Packard and Goodman, 2012).

An ideal pharmacological treatment for PTSD would be a drug able to block the pathological over consolidation and continuous retrieval of the traumatic event, while enhancing its extinction and reducing the anxiety symptoms. Although no such drug is currently available, recent clinical (Fraser, 2009; Hauer et al., 2013; Neumeister et al., 2013) and preclinical (Lutz, 2007; Akirav, 2011; Berardi et al., 2012; Ganon-Elazar and Akirav, 2012) studies point to the endocannabinoid system as a possible ideal therapeutic target to treat both the emotional and cognitive dysfunctions characterizing PTSD (Neumeister, 2013).

The central endocannabinoid system is a neuroactive lipid signaling system in the brain which shows functional activity since early stages of brain development; by controlling neurotransmitter release, it plays a relevant role in brain function during both pre- and post-natal life (Fernandez-Ruiz et al., 2000; Harkany et al., 2007; Trezza et al., 2008; Campolongo et al., 2009b, 2011). The endocannabinoid system consists of cannabinoid receptors (CB1 and CB2), their endogenous lipid ligands (endocannabinoids) and the enzymatic machinery for endocannabinoid synthesis and degradation (Piomelli, 2003; Di Marzo et al., 2005). Due to the wide expression of cannabinoid receptors throughout limbic regions of the brain, endocannabinoids control both emotional behavior and cognitive processes (Riedel and Davies, 2005; Campolongo et al., 2007, 2009a; Hill and Gorzalka, 2009; Atsak et al., 2012; Campolongo et al., 2012). Thus, while preclinical studies assessing the consequences of cannabinoid receptor blockade or activation on emotional responses have yielded sometimes controversial results, consensus exists that endocannabinoids have an essential role in maintaining emotional homeostasis (Haller et al., 2002,2004; Hill and Gorzalka, 2009; Moreira and Wotjak, 2010; Parolaro et al., 2010; Ruehle et al., 2012). Similarly, evidence exists that administration of cannabinoid drugs in animals influences memory consolidation, retrieval and extinction (Marsicano et al., 2002; Niyuhire et al., 2007; Marsicano and Lafenetre, 2009; Atsak et al., 2012; Campolongo et al., 2013). In particular, systemic administration of cannabinoid agonists impairs memory retrieval (Niyuhire et al., 2007) while facilitating memory extinction (Lutz, 2007). Direct evidence has been provided that endocannabinoids modulate emotional memory processing acting in the basolateral complex of the amygdala (BLA), in the hippocampus (de Oliveira Alvares et al., 2005, 2008; Campolongo et al., 2009a; Atsak et al., 2012) and in the prefrontal cortex (Egerton et al., 2006), key brain regions involved in memory consolidation, retrieval and extinction of emotionally arousing experiences (McGaugh, 2004; Quirk and Mueller, 2008;Roozendaal et al., 2008; Herry et al., 2010), and dysfunctional in PTSD patients (Bremner et al., 2008; Hughes and Shin, 2011).

Interestingly, emerging empirical work has indicated a link between traumatic event exposure and cannabis use. Data from the National Comorbidity Study demonstrated that adults suffering from PTSD were three times more likely to have cannabis dependence as compared with those without PTSD (Kessler et al., 1995). Studies involving military veterans have demonstrated an even higher rate of cannabis abuse among military veterans with PTSD (Stewart et al., 1998; Bonn-Miller et al., 2011). A positive association between PTSD and cannabis use among teenagers has also been reported (Cornelius et al., 2010). These results could be partially explained by recent data demonstrating that PTSD patients present important changes of plasma endocannabinoid levels and elevation in amygdala-hippocampal-cortico-striatal CB1 receptor availability (Hauer et al., 2013; Neumeister, 2013; Neumeister et al., 2013). The comorbidity between cannabis abuse and PTSD is always described in literature as a negative aspect, with the increase in substance abuse after a disaster as a cause for public long-term health consequences.

However, another side of the coin needs to be considered. It is possible that PTSD patients use cannabis as a self-medication. In support of this hypothesis, one study among Vietnam veterans indicated that cannabis use was helpful in managing PTSD symptoms, with particular respect to the hyperarousal state (Bremner et al., 1996). It has been shown that there is a correlation between post-traumatic stress symptom severity and motivation to use marijuana in order to cope with emotional distress (Bonn-Miller et al., 2007). Although the majority of the currently available clinical studies highlights the beneficial effects of cannabis use in PTSD patients, the positive association between cannabis use and relief from PTSD symptoms is not an universal finding. Thus, it has also been documented that, in certain conditions, cannabis abuse may facilitate PTSD development (Cougle et al., 2011). This may be due to the fact that direct activation of cannabinoid receptors by the active ingredient of cannabis, Delta-9-tetrahydrocannabinol, leads to a rapid down-regulation of the endocannabinoid signaling system (Hirvonen et al., 2012), resulting in tolerance. The complex scenario that emerges from the clinical setting makes it difficult to draw final conclusions about the relationship between cannabis use and PTSD.

Preclinical studies allow to control for the confounding variables that characterize the clinical observations, and therefore can provide essential information to elucidate the link between endocannabinoids and emotional memory processing, from physiological to pathological conditions. Thus, as highlighted above, it has been demonstrated that cannabinoid compounds strongly facilitate memory extinction in animals (Marsicano et al., 2002; Lutz, 2007), while impairing memory retrieval (Niyuhire et al., 2007; Atsak et al., 2012). It is thus tempting to speculate that cannabinoid compounds can attenuate the excessive retrieval of the traumatic event experienced by PTSD patients, while facilitating its extinction. Memory consolidation for emotionally salient events is also affected by cannabinoid drugs, although the results of the preclinical studies performed so far are controversial. Thus, it has been shown that post-training administration of cannabinoid receptor direct or indirect agonists facilitates memory consolidation in the inhibitory avoidance task (Campolongo et al., 2009a; Hauer et al., 2011).

These findings suggest that activation of cannabinoid receptors shortly after experiencing a stressful event could facilitate the development of maladaptive memories of this event. This, in turn, may provide preclinical rationale to the finding that the use of drugs indirectly enhancing endocannabinoid activity, such as propofol, or the use/abuse of cannabis, shortly after the experience of an aversive event, may facilitate PTSD development in humans and has to be avoided in the aftermath of an aversive experience (Cougle et al., 2011; Hemmings and Mackie, 2011;Usuki et al., 2012). However, cannabinoid agonists administered to rats shortly after exposure to a series of intense stressful events have been reported to prevent the impairment in avoidance extinction induced by the traumatic experience (Ganon-Elazar and Akirav, 2009, 2012, 2013). These findings leave open the possibility that cannabinoid drugs may be good candidates for secondary prevention of PTSD, that is, may be a good therapeutic option immediately after trauma exposure (Zohar et al., 2011).

It clearly appears from this scenario that, if from one side the data about the effects of cannabinoid drugs on memory retrieval and extinction are quite consistent and suggest that these compounds may facilitate PTSD recovery, on the other side the role of cannabinoids in memory consolidation is still debated. More research is therefore warranted to determine the extent to which differences in doses, routes of administration, timing of exposure and behavioral tasks used may be responsible for the opposite effects of cannabinoid agonists on memory consolidation reported so far. Conversely, encouraging clinical data exist on the use of cannabinoid compounds after the onset of the pathology (weeks or months after the experience of a traumatic event, when the memory consolidation of the traumatic event is completed) (Passie et al., 2012).

A recent clinical trial to evaluate the effects of nabilone, a cannabinoid receptor agonist, on treatment-resistant nightmares in PTSD patients demonstrated that the majority of patients (72%) receiving nabilone experienced either cessation of nightmares or a significant reduction in nightmare intensity (Fraser, 2009). Subjective improvement in sleep time, the quality of sleep, and the reduction of daytime flashbacks were also noted by some patients (Fraser, 2009). This is the first report of the use of nabilone for the management of treatment-resistant nightmares in PTSD. Although this evidence is encouraging, further studies on larger cohorts and with a more accurate identification of possible side effects of chronic use of direct cannabinoid agonists are warranted. The use of drugs that directly bind and activate brain cannabinoid receptors is indeed limited by their abuse potential (Tanda and Goldberg, 2003; Economidou et al., 2007;Ashton, 2012).

Two alternative pharmacological approaches exist to target cannabinoid receptors in the brain, without inducing abuse liability (Gobbi et al., 2005; Bortolato et al., 2006; Justinova et al., 2008). First, it has recently been reported that the non-psychotomimetic constituent of cannabis cannabidiol facilitates disruption of contextual fear memories (Stern et al., 2012) in rats while inducing anti-anxiogenic-like effects in rats and humans (Bitencourt et al., 2008; Bergamaschi et al., 2011). Alternatively, several preclinical studies have identified endocannabinoid deactivation inhibitors as a novel therapeutic approach for the treatment of neuropsychiatric disorders. In particular, indirect cannabinoid agonists have been proposed as anxiolitic and antidepressant agents (Kathuria et al., 2003; Bortolato et al., 2006; Piomelli et al., 2006; Vinod and Hungund, 2006) and have been reported to facilitate extinction of fear memory in rodents (Bitencourt et al., 2008; Pamplona et al., 2008). Thus, these compounds may prove effective to ameliorate the anxiety symptoms of PTSD and, at the same time, an increase in the endocannabinoid tone may be useful to treat the cognitive features (Varvel et al., 2007) of the pathology. These dual effects make these drugs gold candidates in the treatment and prevention of PTSD. Much attention, however, has to be dedicated to the time framing of pharmacological treatment, with an attempt to avoid the first early phases of memory consolidation.

It clearly appears that a deeper insight into the role of endocannabinoid neurotransmission in emotional memory processing, both in physiological and pathological conditions, will shed light in the neurobiological basis of PTSD; this, in turn, will open new frontiers for alternative and more efficacious therapeutic approaches for a complete resolution of the pathology.

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.

Friday, August 16, 2013

Epigenetics - How Early Life Environment Shapes Future Stress Response

In this new study from Frontiers in Molecular Psychiatry, the researchers looked at the epigenetics of early life environment and how that impacts future ability to manage stress. Essentially, the researchers asked, "if chronic early-life predictable and nurturing maternal care can reduce excitatory synaptic input onto stress-sensitive neurons in the hypothalamus, and hence “desensitize” future stress responses, then might abusive, erratic, or neglectful maternal behavior provoke the opposite?"

Their question is based on newer information suggesting that there is a "critical window" in development following birth during which neuronal gene expression may be reprogrammed through epigenetic mechanisms. These changes seem to persist for the lifetime of the individual.

Fascinating stuff - and very relevant to attachment theory, resilience, and in explaining why some people are more prone to developing PTSD.

Full Citation: 
Karsten CA and Baram TZ. (2013, Aug 15). How does a neuron “know” to modulate its epigenetic machinery in response to early-life environment/experience? Frontiers in Molecular Psychiatry, 4:89. doi: 10.3389/fpsyt.2013.00089

How does a neuron “know” to modulate its epigenetic machinery in response to early-life environment/experience?

Carley A. Karsten [1,2] and Tallie Z. Baram [1,2]
1. Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, CA, USA
2. Department of Pediatrics, University of California-Irvine, Irvine, CA, USA

Exciting information is emerging about epigenetic mechanisms and their role in long-lasting changes of neuronal gene expression. Whereas these mechanisms are active throughout life, recent findings point to a critical window of early postnatal development during which neuronal gene expression may be persistently “re-programed” via epigenetic modifications. However, it remains unclear how the epigenetic machinery is modulated. Here we focus on an important example of early-life programing: the effect of sensory input from the mother on expression patterns of key stress-related genes in the developing brain. We focus on the lasting effects of this early-life experience on corticotropin-releasing hormone (CRH) gene expression in the hypothalamus, and describe recent work that integrates organism-wide signals with cellular signals that in turn impact epigenetic regulation. We describe the operational brain networks that convey sensory input to CRH-expressing cells, and highlight the resulting “re-wiring” of synaptic connectivity to these neurons. We then move from intercellular to intracellular mechanisms, speculating about the induction, and maintenance of lifelong CRH repression provoked by early-life experience. Elucidating such pathways is critical for understanding the enduring links between experience and gene expression. In the context of responses to stress, such mechanisms should contribute to vulnerability or resilience to post-traumatic stress disorder (PTSD) and other stress-related disorders.


Neuronal gene expression is amenable to re-programing by environment and experience (13). The neuroendocrine stress axis is influenced by environment and experience during early postnatal development, and these changes endure. For example, maternal-derived sensory input is critical for setting the tone of the hypothalamus-pituitary-adrenal (HPA) axis for life via changes in the expression of glucocorticoid receptor (GR) in the hippocampus and of hypothalamic corticotropin-releasing hormone (CRH). High levels, or predictable bouts, of maternal-derived sensory stimulation result in an attenuated stress response and resilience to stress (4, 5). In contrast, early-life stress causes adults to exhibit augmented stress responses and cognitive impairments, associated with changes in expression of CRH and GR (68). Recently, it has been proposed that it is the patterns of maternal care that contribute crucially to the perception of stress early in life, and to the subsequent modulation of brain function. Thus, chaotic, fragmented sensory inputs from the mother influence neuronal networks involved in stress for the life of the animal in a direction opposite to that of predictable and consistent patterns (9). Thus, an important common basis may exist for both the beneficial and the adverse consequences of early-life experiences: the pattern of sensory input onto the developing brain might constitute an important parameter that influences the function of stress-sensitive neurons throughout life.

It is suspected that the endurance of the effects of sensory input during this critical period derives from activation of epigenetic mechanisms leading to changes in gene expression that are maintained throughout the lifetime. Here we review the neuroanatomical and molecular pathways bridging sensory input on a whole-brain scale with gene expression programing after distinct early-life experiences. We discuss the implications of these processes to post-traumatic stress disorder (PTSD).

Epigenetics and Early-Life Experience

The nature of epigenetic mechanisms is amply discussed throughout this collection of papers, and will not be described in detail here. Epigenetics offers an enticing explanation for how relatively brief sensory experiences may lead to long-lasting changes in neuronal function. Indeed, changes in components of chromatin, including DNA methylation or histone modifications have been examined after early-life experience, and found in several key genes involved in regulation of the HPA axis [GR, (10); CRH, (11); arginine vasopressin, (12)]. Here we focus on the lasting repression of CRH in hypothalamic neurons that results from positive maternal care early in life (13). This finding has been confirmed by numerous subsequent studies (4, 5). We focus on the CRH gene both as an important regulator of the stress response (14) and as a likely contributor to the phenotype engendered by nurturing early-life maternal signals, because modulation of CRH function through blocking of CRH receptor type 1 recapitulated the effects of augmented maternal care in non-nurtured pups (15). A second reason for a focus on the CRH gene is its use as a “marker” gene: the reliable detection of CRH repression after augmented maternal care suggests that understanding the mechanism that represses CRH expression enduringly might provide a key to understanding general processes that influence expression programs involving numerous other genes as well. Finally, in the context of the current review, a significant body of literature has implicated aberrant expression and central (CSF) release of CRH in the pathophysiology of PTSD (1619).

How Does a CRH-Expressing Neuron Know to Modulate CRH Gene Expression?

Corticotropin-releasing hormone gene expression is regulated by transcription factors, and these in turn are activated by signals that reach the nucleus from the membrane, and often involve calcium signaling (20). Synaptic input onto the CRH-expressing neuron includes a number of neurotransmitters, of which glutamate constitutes a major excitatory input (21). Indeed, glutamatergic signaling in the PVN is necessary for the initiation of the endocrine stress response, and glutamate receptor agonists delivered to the PVN drive CRH release (22, 23). Recent research has revealed that early-life augmented care leads to a transient reduction in the number and function of glutamatergic synapses to CRH neurons in the PVN (11). Using several methods (immunohistochemistry, electron microscopy, and electrophysiology), Korosi et al. discovered that (1) the number of glutamatergic terminals abutting CRH-positive neurons was reduced, (2) the number of asymmetric, putative excitatory terminal boutons onto CRH neurons was reduced, and (3) the frequency of spontaneous excitatory postsynaptic currents to PVN neurons was dramatically reduced (Figure 1). The same measures were taken in the thalamus and yielded no changes. Similarly, there were no changes in markers of inhibitory transmission. Together these data strongly support the notion that augmented maternal care reduces excitatory drive to the CRH-expressing neuron in the PVN.
Figure 1. Augmented early-life experience reduces the number and function of excitatory synapses in the paraventricular nucleus of the hypothalamus (PVN). (A) Total number of synapses was reduced by 50%, attributable to a 70% reduction of asymmetric (excitatory) synapses onto CRH-expressing neurons in the PVN. (B) Levels of the vesicular transporter vGlut2, a marker of glutamate-containing synaptic vesicles, were reduced by approximately 40% in rats with augmented early-life experience relative to controls. (C) Miniature excitatory postsynaptic currents (mEPSC) frequency was reduced by 60% in putative CRH neurons. Adapted from Ref. (11) with permission from the Journal of Neuroscience.
Whereas the correlation between reduction in excitation and reduction of CRH expression is suggestive, it does not answer the question of causality: is reduced glutamatergic input to a CRH cell required and sufficient to repress CRH? To address this question, in vitro methods have been initiated, with the use of organotypic hypothalamic slice cultures to isolate the PVN. In this system, application of glutamate receptor antagonists (blocking both AMPA- and NMDA-type receptors) can effectively eliminate ionotropic glutamatergic transmission. Pilot data suggests that this manipulation may suffice to repress CRH mRNA levels compared to vehicle-treated controls (24). These initial findings are consistent with the notion that augmented maternal care reduces excitatory drive to the PVN, which in turn leads to reduced CRH mRNA production.

How Does the Sensory Signal from Maternal Care Reach the PVN and Serve to Reduce Excitatory Synapse Number and Function?

Maternal input to her progeny consists of a variety of stimuli, among which sensory stimuli and especially touch (licking, grooming) appear to be the most important (2527). Levine’s group demonstrated that augmented HPA responses to stress caused by 24 h maternal deprivation could be prevented by stroking the pups, highlighting the importance of tactile stimulation to normal development of HPA activity (28). Using brain-mapping methods, the pathways through which these signals reach the PVN have been identified (29).

Glutamate-specific retrograde tracing revealed that excitatory afferents terminating in the PVN originate in the paraventricular thalamus (PVT), lateral septum, bed nucleus of the stria terminalis (BNST), and amygdala (30). The BNST integrates and relays signals from the limbic forebrain and amygdala and provides both inhibitory and excitatory drive to the PVN. Specifically, posterior sub-regions inhibit stress-induced CRH expression in the PVN, whereas anterior regions facilitate it (31). The central nucleus of the amygdala (CeA), important for integration of autonomic inputs, facilitates CRH release from the PVN (Figure 2), likely via the BNST (32,33).
Figure 2. Proposed circuitry involved in conveying maternal-derived sensory input to CRH-expressing neurons in the PVN. The PVN receives excitatory and inhibitory projections, including projections from the amygdala, paraventricular thalamic nucleus (PVT), and bed nucleus of the stria terminalis (BNST). These regions are also interconnected by excitatory projections (solid black lines). (A) The amygdala and BNST are both activated after a single day of handling-evoked augmented maternal care, and in turn stimulate the PVN (29). (B) The PVT is not activated after a single day of augmented maternally derived sensory input, but is recruited by recurrent daily barrages. This is thought to activate regions of the BNST that inhibit CRH-expressing neurons in the PVN (31). It is not fully known how this series of events promotes reduced numbers of excitatory synapses on CRH-expressing neurons.
Importantly, both the CeA and BNST are activated by maternal care. Handling rat pups evokes a burst of nurturing behavior (licking and grooming) by the dam upon the pups’ return to the home cage. A single instance of handling results in c-fos activation in both BNST and CeA (29), yet did not influence CRH expression. In contrast, recurrent handling for a week, which led to repression of CRH expression, was associated with c-fos activation also within the PVT (29). This suggests that the contribution of the PVT to the overall circuit that conveys maternal signals to the CRH cells in the PVN is important to reduce the expression of the gene. The PVT has been shown to play an important role in stress memory and adaptation (34, 35). The PVT sends afferents to the PVN, and possesses bidirectional connections with the CeA and BNST (36). Considering that the majority of PVT output to the structures described above are excitatory, how might PVT activation result in repression of the PVN? Here, we speculate that activation of the PVT might excite BNST regions that are known to inhibit CRH expression in the PVN (Figure 2).

Initiation vs. Maintenance of Epigenetic Repression of CRH by Early-Life Experience

When considering the changes in gene expression that occur after augmented maternal care, it is important to note two key differences in timing. Repression of CRH begins around postnatal day 9 and persists through adulthood, while changes in glutamatergic signaling to the PVN were noted only at P9 and were back to control levels by P45 (11). This suggests that following the initiation signal mediated by reduction of glutamatergic signaling, there may be additional factors that are involved in maintaining the repression of gene expression that persists long past the initiating signal. Such factors are likely to be epigenetic in nature.

A likely suspect is the neuronal repressor neuron restrictive silencer factor (NRSF). NRSF is a transcription factor that silences gene expression via epigenetic modifications. The CRH intron contains a functional NRSF binding sequence (37), suggesting that the programing of the crh gene during early postnatal life may be due to NRSF activity. In fact, NRSF levels in the PVN are dramatically upregulated following augmented maternal care, starting at P9 and persisting into adulthood (11). This pattern is an inverse correlate of CRH expression levels following augmented maternal care, supporting the idea that NRSF may be involved in mediating CRH repression.

Implications for PTSD

Post-traumatic stress disorder is often associated with a history of early-life trauma (19, 3840), and more specifically with chronic stressful situations such as abuse and long-lasting war rather than an acute event (4147). PTSD is characterized by a persistently dysregulated stress response (19, 48, 49), and it is reasonable to assume that chronic early-life stressful events influences an individual’s stress response to promote PTSD. There are several processes that might account for altered stress responses in PTSD. It has been posited that the hypothalamic-pituitary-adrenal axis is permanently sensitized by chronic early-life abuse, and this creates a vulnerability to subsequent trauma, resulting in PTSD. However, the mechanism of such sensitization is unclear. Here we provide a novel and plausible solution: if chronic early-life predictable and nurturing maternal care can reduce excitatory synaptic input onto stress-sensitive neurons in the hypothalamus, and hence “desensitize” future stress responses, then might abusive, erratic, or neglectful maternal behavior provoke the opposite? Augmentation of excitatory input to hypothalamic CRH cells may well serve to sensitize CRH release to future stresses. Whereas this notion is speculative at this point, it is highly amenable to direct testing in animal models. A second possible basis of the abnormal stress response in PTSD that follows early-life chronic stress/abuse may include aberrant regulation of the expression of relevant genes, such as CRH. Here we provide insight into how early-life experience – nurturing or adverse – can result in persistently altered regulation of CRH expression. The lifelong changes in CRH release and expression that result from chronic early-life experiences may provide the neurobiological basis for resilience or vulnerability to subsequent stress, and hence to the development of PTSD.

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.

The excellent editorial assistance of Mrs. Barbara Cartwright is appreciated. Authors’ research has been supported by NIH grants NS28912; MH73136 NS 45260 (CM Gall, PI). 

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