Born for Joy   
Evolution of the Human Genome, Childhood Vulnerabilities, and life-long Depressive Syndromes
N.B. As will be noted, the clinical neuropsychiatric patient care described here depends on a different diagnostic approach and different terminology than that of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders.  Since the DSM-IIIR, diagnoses have relied on diagnostic criteria chosen as “easily identifiable behavioral signs or symptoms . . . requiring a minimal amount of inference on the part of the observer" (p xxiii). Medical training guided creation of the semi-structured diagnostic tool I've used to understand the neurobiology underlying my patients' disabling symptoms. Having spent considerable effort trying to understand what a patient was subjectively feeling (their symptoms), I found the DSM's diagnostic criteria and, consequently, its diagnostic terminology unhelpful.

Peer Review:
The data presented here was reviewed by the senior editors at both Nature and Science.
Life-long Depression : Childhood Experience  and our Genetic Template 

OVERVIEW
        While the data reported here have important clinical value, the work also has social relevance. I hope the following outline of the paper will be helpful.

THE BACKGROUND: Sets the stage for understanding the research data as challenging current presumptions about human
            history.                  

THE RESEARCH is presented in such a way as to emphasize its findings in the context of our knowledge of evolution and,  
                     specifically, our knowledge of the evolution of the human genome.      
    Subjects and Methodology: presents a brief overview of the research in the context of my clinical practice of
               neuropsychiatric medicine.  Demographic data on the subjects (patients) and methods of collecting data are
               reported separately.
                 The 1992 Epidemiology study correlates 3 adult neuropsychiatric syndromes with specific childhood experiences
                 The 2000 Treatment Outcome study documents effective treatments for the same 3 syndromes
    Results: To make the most sense of the research data it is presented in concert with our current knowledge of the
               evolution of the human genome.  The data presentation is divided in 3 sections correlating with the 3
               neuropsychiatric syndromes.
          The human genome - serotonin
                         Clinical data on pervasive dysphoria (a life-long sense of being "cut-off" from life) is presented in the
                            context of our knowledge about serotonin and serotonin-medicated neurocircuitry)        
          The human genome -- animal response to threat
                         Clinical data on autonomic hyper-reactivity (unpredictable and uncontrollable explosive episodes) is
                            presented in the context of the evolution of the autonomic nervous system.
          The human genome -- human childhood
                         Clinical data on profound alienation (distrust of Life) is presented in the context of the evolution of the
                            human cerebral cortex through upright stature, complex language, and our uniquely long human
                            childhood
     Discussion: How patients' symptoms and treatment outcome data provide an understanding of then neurobiological     
              mechanisms by which childhood experience produce the adult neuropsychiatric syndromes addressed here.
     Conclusion: How data presented here allows a new and richer perspective on human history, and new approaches for
             healing.        


BACKGROUND            
            At some point, modern Homo sapiens split off from an ancestral group and founded our own species.
            They were us from the beginning, are us now, and shall be us until we blow ourselves up or genetically
            engineer ourselves out of current existence.  Homo sapiens … is an entity, not a tendency.  Once we      
            arose as a species –and 100,000 to 250,000 years ago in Africa is our best current assessment of time
            and place – we were probably pretty much ourselves in terms of mental organization.

                                                                                                 Stephen J Gould
                                                                                                 Honorable Men and Women
                                                                                                 Natural History Magazine  (March, 1988:16-20)  

To rephrase Gould, the genetic template responsible for human mental organization has been stable since we emerged as a species. Human social organization, however, experienced a dramatic shift 10,000 years ago.
 
One interpretation of human history is that,  “Early human societies lived in small bands of hunter-gatherers, their existence dominated by incessant warfare. Only gradually did humans evolve to become less aggressive . . . In the Near East, around 15,000 years ago, people at last accomplished a decisive social transition, the founding of the first settled communities” (Wade). There, in the “Cradle of Civilization,” humankind began a “social evolution” that would allow full expression of our genetic birthright. The Pulitzer Prize-winning Guns, Germs and Steel (Diamond), also, addresses the social differences between primitive peoples and peoples of modern Europe. The book proposes to answer a question posed to the author by a prominent New Guinean -- “Why is it that you white people developed so much cargo ["stuff"] and brought it to New Guinea, but we black people had little cargo of our own?” In arguing that those people who would become modern cargo-laden Europeans have, essentially, just happened to be at the right place at the right time, Gould fails to address the violence underlying human conquest.
     
A competing hypothesis is supported by the neurobiological research presented here. Specifically, that around 10,000 years ago nomadic peoples (long cut off from knowledge of the developmental needs of children) began a violent march of conquest propelled by profound alienation and greed.  
       
Both DNA and linguistic evidence (Ruhlen) support Gould (above) in understanding Homo sapiens to have emerged as a species 200,000 years ago -- with a single, stable genetic template billions of years in design. Data presented here demonstrate the full expression of our genetically stable mental organization to produce peoples highly in tune with their internal and external environments, calm in the face of danger, cooperative, generous, and fun. These human qualities, however, depend on social conditions highly protective of children’s neurodevelopmental vulnerability.  Our species could not have evolved under conditions of incessant warfare. Nor would hunter-gathering groups, nor early settled agricultural communities survive under such conditions.
       
Supporting this second hypothesis is World Health Organization data reporting unipolar depression to account for almost 25% of the economic and social burden of disease placed upon countries with established market economies – more than all cancers combined.  Funded by the World Bank, the World Health Organization (WHO) Global Burden of Disease Study (1996) determined that unipolar major depression alone accounts for 6.1% of the societal burden of disease in countries in the economically developed world -- second only to ischemic heart disease.  Alcohol use, road traffic accidents, self-inflicted injuries, cirrhosis of the liver, and drug use (all strongly associated with depression) rank within the top 25 burdensome conditions (5th, 4th, 9th, 18th, and 22nd respectively).  Taken together, they account for 23.6% of the Disability-Adjusted Life Years (DALYs) – the measure used by the WHO for assessing health outcomes. In comparison to the epidemic burden placed by unipolar depression on countries with established market economies, depression and related conditions account for only 5.4% of the societal burden of disease placed on countries of the developing world – peoples as yet not fully integrated into our modern civilization. Reworking the data and comparing rich and poor nations, a 2008 WHO update found unipolar depression to have the highest societal burden any disease world-wide. Looking at gender differences, they found women to have a 50% higher prevalence of depressive symptoms, and men to be 7 times more likely to suffer alcohol and drug use disorders.
   
What is unipolar depression? 
       
The WHO distinctly differentiates unipolar major depression from bipolar, manic depression -- the latter being a genetic disorder affecting the molecular structure of the sodium potassium pump of the neurocellular membrane and specifically treated by lithium.  Unipolar depression can be either acute or chronic. Acute unipolar depression is the consequence of mental (neuro-metabolic) exhaustion -- very much the same neurobiological process that results in mammalian hibernation. Also called melancholia, this mental exhaustion causes disordered sleep patterns (early morning awakening), lack of appetite, lack of sexual interest, and an inability to experience any pleasure so severe that patients are prone to suicide. Melancholia is effectively treated by medications specifically effecting noradrenergic neurotransmission.
       
The vast majority of patients with unipolar depression have suffered symptoms of crippling anxiety and despair since childhood – symptoms severe enough to complicate or prevent intimate family relationships and work. Sexuality, deeply imbedded in our genetic template, is among the most primitive animal behaviors; yet the Journal of the American Medical Association reports 43% of American women and 31% of American men to suffer disturbed sexual responsiveness -- a consequence of chronic depression.  
       
Data presented here will demonstrate the symptoms of chronic depression to be the consequence of normal neurobiological sensitivity to childhood experience -- that sensitivity encoded in the stable human genome. The data provide a window onto 200,000 years of human motivation and behavior and allow the reasoned argument that societal practices detrimental to childhood neurodevelopment are a new cultural phenomenon.

THE RESEARCH  

Subjects:  The Patients

       
Practicing neuropsychiatric medicine for 18 years, enjoying listening to their "stories" (in medical parlance, their histories), I worked with thousands of patients.  The goal was to give them the best clinical care I was capable of.  Here I present clinical data of a small but highly representative sample of those patients. In 1992, with 10 years of clinical practice, I realized I'd gradually become aware of a pattern linking childhood experience with neuropsychiatric illness. To test that hypothesis, I reviewed diagnostic records of patients seen prior to formulation of the study. Data from 190 evaluations were tabulated and statistically analyzed.  In 2000, having completed a 2 month stint working at a residential treatment facility for troubled adolescents, I realized I had the data to do a reliable treatment-outcome study of fluoxetine and clonidine. I had evaluated 35 of the 38 kids in the program, treating as many as I could. No patient's name has ever been associated with the data.

The
1992 Epidemiology Study        
   
Data included in the epidemiology study are of patients evaluated during the same chronological period in 2 separate treatment settings: an in- and out-patient substance abuse program and a community mental health clinic. Except for gender differences (about 2/3s of the substance abuse patients were men, and 2/3s of the clinic patients women), demographic data on the 2 patient groups are essentially the same.  Of 202 evaluations, data from 12 were excluded because patient symptoms precluded their giving a reliable history: 3 were diagnosed with psychotic melancholia; 3 were sociopathic; 3 had organic brain syndrome secondary to recent intoxication; 2 refused evaluation, and one was diagnosed with DSM Factitious Disorder. Because evaluation notes from both settings were easily retrievable and in chronological order, data tabulated are of "all-comers" -- with no record added or left out of analysis.
       
Of the 190 patient records tabulated, 129 (67.9%) were those of patients who reported chronic depressive symptoms since childhood or early adolescence. One (0.5%) had had no psychiatric symptoms until experiencing life-threatening terror in adulthood. DSM Diagnoses of the remaining 60 patients (31.6%) included adjustment disorder, primary addiction, non-psychotic melancholia, organic affective disorder, obsessive-compulsive disorder, manic-depressive disorder, schizophrenia, paranoid disorder, mental retardation, and no psychiatric disorder. (Subject diagnoses)

The 2000 Treatment Outcome Study --
Using fluoextine and clonidine
       
       
By 2000, I had extensive clinical experience with fluoxetine and clonidine. I knew their pharmacologic properties to be very different than reported in the recent scientific literature and different than reported in the industry-written Physician's Desk Reference (PDR). Having diagnosed and treated 35 of the 38 adolescents in treatment at a residential facility, I realized that, while the sample was small, the findings were so strong as to represent important clinical data nowhere else available. 
       
Individual children’s behaviors had met DSM criteria for: Asperger’s syndrome, attention-deficit/hyperactivity disorder (ADHD), autism, bipolar disorder, borderline personality disorder, conduct disorder, oppositional-defiant disorder, and schizophrenia.  All were deemed too behaviorally disturbed to be safe anywhere but at a facility with 24-hour observation. Children were seen and treated on the basis of urgency. Diagnosis and treatment plans of most were based on the interview, staff observations, and records of prior treatments.  For those too explosively reactive to tolerate an interview, I relied on behavioral patterns reported by staff members and observation.  Approval for any trial of medication was obtained (after diagnostic reasoning and treatment protocols had been explained in detail) from parents and/or from the Department of Human Services (custodians for many of the children). Children receiving medication were evaluated as often as necessary – often on a daily, sometimes on an hourly, basis. Case conferences with each child’s treatment team were frequent.

DATA AND RESULTS PRESENTED IN THE CONTEXT OF HUMAN EVOLUTION
THE HUMAN GENOME -- SEROTONIN 
    
         
The earth formed 4.5 billion years ago and, within the next billion years, very primitive life forms emerged. The first one-celled animals (eukaryotes) appeared 1.85 billion years ago. The genetic template for the molecule serotonin, found in paramecia, has been an integrated "piece" of animal DNA for 1.85 billion years.  Since the evolution of triploblasty (e.g., flatworms) more than 550 million years ago, serotonin has also functioned as a neurotransmitter -- chemically linking nerve cells which, together, comprise the animal serotonin neuronal system.  To quote Azmitia, serotonin-mediated neuronal systems integrate "external sensory and motor systems as well as internal endocrine, glial and vascular signals with the various cellular elements comprising neural tissue.” In other words, serotonin-mediated neuronal circuitry allows multicellular animals to function in their environments with the coordinated grace of the single-cell paramecium.
CLINICAL DATA -- PERVASIVE DYSPHORIA      
    
Symptoms
:  Patients with pervasive dysphoria have difficulty putting words to their understanding that "something" is terribly "wrong" with them.  While painful to even think about, they recognize experiencing “alone-ness” can precipitate a terrifying sense of "free-fall" into black emptiness and often appreciate that only talking with another person can quiet that terror. Patients report thinking all the time -- "mindless chatter" that's often ruminatively self-critical and keeps them from falling asleep. They are typically responsible people, and often highly educated; but, at the same time, uptight and unable to have relaxed fun. Obsessive behaviors (gambling, reading, exercising, crafting) are common, and many are alcohol dependent (the typical story being: "I distinctly remember that first drink. I felt normal. I just keep looking for that feeling.")
        The words "pervasive dysphoria" describe an emotional perception. The disorder has physical symptoms easier to assess. Patients can and do work themselves beyond exhaustion. Most, if older, have pain symdromes; some have autoimmune disorders. Many patients have eating disorders and don't feel normal satiety. Men suffer premature ejaculation; women suffer vaginal insensitivity.          
    
1992: Epidemiology Study
. Patients' stories tended to be of 2, sometimes overlapping, scenarios.  Some had been terribly frightened as young children -- suffering terrifying physical or sexual trauma. Others, quite differently, had been responsible, respected children with high expectation of future success in life. It took some time, looking for a common denominator, to find that both groups had been overly preoccupied by worry -- so preoccupied they didn't play.
       
A chi square analysis of the data correlating 'symptoms of pervasive dysphoria' with 'reporting a "worried" childhood devoid of free play' produced a highly significant value of 171.15 (p=0.000. . .). This analysis of the data says, in essence, that the chance that lack of free play is not associated with pervasive dysphoria is infinitesimally small. We can statistically assume that a childhood preoccupied by worry and devoid of free play causes pervasive dysphoria.
    
2000: Using fluoxetine to treat pervasive dysphoria: neurophysiologic observations    (Figure I)
       
Of the 35 children evaluated, 29 were clinically diagnosed with pervasive dysphoria. Of these 29, 19 had had previous treatment with a serotonin reuptake inhibitor (SSRI) or were given a test dose of fluoxetine. None suffered toxicity -- indicating 100% neurobiological confirmation of the clinical diagnosis. Eight children had their medication doses titrated to therapeutic levels with resolution of symptoms. At doses lower than therapeutic no child was noted to have any significant change (Figure II)., Many children reported a dramatic change when reaching their therapeutic dose; one calling it “a miracle.” Two children's doses were lowered, with immediate recurrence of troubling symptoms which resolved as soon as the therapeutic dose was resumed. These children (terrorized at a young age and with autonomic hyper-reactivity) generally required a therapeutic dose of 100mg fluoxetine; none experienced side effects. All the boys became concerned when one found he could no longer masturbate to ejaculation. Learning fluoxetine allowed normal sexual response without premature ejaculation, all but one boy chose to continue the medicine.

THE HUMAN GENOME -- ANIMAL RESPONSE TO THREAT 
        
As animal life evolved, from fish, through reptiles, to mammals, primates, and humans, our brain evolved with newer brain structures incorporating (and essentially “on top of”) existing neuronal systems.  Porges, author of the Polyvagal Theory, presents compelling data to suggest that our animal response to threat (the autonomic nervous system) passed through three evolutionary stages prior to the emergence of Homo sapiens. The parasympathetic nervous system, found in our piscine ancestors responds to threat by acutely depressing metabolic activity. When triggered, the parasympathetic response stops cardiac output: fish "play dead." Deeply imbedded in the human central nervous system (and human DNA), this parasympathetic neuronal response is 400 million years old.       
       
With the evolutionary move to land, the sympathetic nervous system, evolved as the animal first line of defense. Coordinated by adrenalin, the reptilian sympathetic nervous system (the fight-or-flight response) massively increases metabolic output. Adrenalin increases both the heart rate and contractility (pumping power) at the same time preferentially directing blood flow to large muscle groups of fight/flight. Relaxing arterioles to powerful muscles of fighting and/or escape, adrenalin constricts arterioles to the skin, digestion, and the brain. Highly effective, but metabolically exhausting, the sympathetic fight-or-flight response has been integrated in our human DNA for 315 million years.
       
Mammalian species emerged 220 million years ago with unique metabolic demands requiring adaptation of the autonomic nervous system. Homeostasis, a stable internal temperature, and inter-uterine fetal development are all evolutionarily associated with parasympathetic emotional expression and vocalization. Only when screaming, screeching, and aggressive posturing fail does adrenalin trigger the metabolically exhausting sympathetic fight-or-flight response.

CLINICAL DATA -- AUTONOMIC HYPER-REACTIVITY  
   
Symptoms
: Some patients with autonomic hyper-reactivity (typically men) only remember "seeing red" and nothing else until learning about their violent reaction. Others, typically women, report feeling their heart stop and/or difficulty breathing followed by terrifying heart pounding, shaking, sweating, nausea and/or stomach cramping, and the sense they're going to die.  Some patients (typically adolescents) cut or burn themselves, or "punch a wall."
    
1992: Epidemiology Study
. In listening to patients' stories, it seemed they had all had terrifying experiences prior to developing symptoms.  With more clinical experience, I came to see fear -- or experiencing something that would terrorize "anyone" was not the issue. Rather, it seemed, the patient had to have been so afraid they knew they were going to die.
      
 A chi square analysis of the data correlating 'symptoms of autonomic hyper-reactivity' with 'experiencing a terror so great they "knew" they would die' produced a highly significant value of 163.69 (p=0.000. . .). This analysis of the data says, in essence, that the chance that experiencing a terror so great one know's one will die is not associated with autonomic hyper-reactivity is infinitesimally small. We can statistically assume autonomic hyper-reactivity to be caused by the experience of life-threatening terror.
      
Many patients with autonomic hyper-reactivity since childhood also suffered pervasive dysphoria and had not freely played as children.  It seemed reasonable to correlate childhood terror with the inability to play. A chi square analysis correlating the 'experience of life-threatening terror in childhood with the absence of free play' was performed.  The value, 30.99 (p=000. . .) allows the statistical assertion that without treatment, the experience of life-threatening fear will prevent childhood play.    
   
2000: Using clonidine to treat autonomic hyper-reactivity: neurophysiologic observations
(Figure I)
         
Of the 35 children evaluated, 30 were clinically diagnosed to suffer autonomic hyper-reactivity. Of these 30, 19 had had previous treatment with, or were given a test dose, of clonidine. None suffered toxicity -- indicating 100% neurobiological confirmation of the clinical diagnosis.
         
The frequency with which children terrorized at a young age suffered both autonomic hyper-reactivity and pervasive dysphoria corroborates the epidemiology data reported above. Eleven children had their medication doses titrated to therapeutic levels with full resolution of symptoms (Case Study). At doses lower than therapeutic no child was noted to have any significant change (Figure II). Despite frequent, sometimes daily, episodes of autonomic hyper-reactivity prior to taking a therapeutic dose of clonidine, no child had an explosive outburst when the dose received was therapeutic. When 2 children had their dose reduced, their symptoms immediately reappeared -- disappearing again once the therapeutic dose was resumed.

THE HUMAN GENOME -- TEACHING OUR CHILDREN TO SERVE A COMMON GOOD 
       
Homo sapiens cognitive evolution adds a fourth stage to Porges’ model of the animal brain evolution. The chimpanzees/ bonobo/human line diverged from the other  ape species 8 million years ago. Our human ancestor, Australopithicus afearensis emerged 3 million years ago walking upright but with the cranial size and neurodevelopment of chimpanzees. Upright stature allowed the changes in facial musculature and laryngeal anatomy necessary for the explosion of human language -- with a concomitant increase in the size of the cerebral cortex. Homo erectus (our closest pre-human ancestral species) emerged 1.8 million years ago.
       
Recent discovery of a nearly complete female pelvis demonstrates that, with Homo erectus, childhood cranial size at birth reached that of Homo sapiens.  In contrast, the adult Homo erectus brain reaches approximately the size of a human 3-year-old. What this shows is important: By limiting the size of the female pelvic aperature, our upright stature determined the extent of cerebral evolution that could be occur in utero. All further evolution of our human brain occurred "outside" influenced and influencing our "evolving" human culture.
       
In her 2008 essay published in Science, Gibbons asserts that our childhood defines our Homo sapiens "human-ness." Our childhood defines us as a species. Humans are the only species with 2 generations of caretakers. By age 4, the human brain triples in size; by sexual maturity, it has quadrupled. When Homo sapiens emerged as a species 200,000 years ago evolutionary forces had had one and a half million years to influence human childhood neurodevelopment. In those one and a half million years, adults -- protecting children from life-threatening terror, nurturing carefree play, and teaching the skills of human-ness --  shaped and molded the evolving human cortex.
       
Our pre-human hominid ancestors use reasoned patience -- in reconciliation after conflict. Humans are the only species evolved to face life-threatening danger with calm, reasoned, assurance.

CLINICAL DATA -- PROFOUND ALIENATION       
    
Patient symptoms
: Patients suffering profound alienation seek neuropsychiatric help when they can't get what they want. Asked their "major problem," it's someone else. With careful, non-judgmental exploration, they report that the disabling "anger" and "anxiety" they've felt their "whole lives" only happens when they don't get what they want.
    
1992 Epidemiology Study
: Diagnostic exploration revealed that no adult had helped them learn basic human skills allowing frustration tolerance and patience. Patients suffering profound alienation -- whether, as children, abandoned to the streets or abandoned in wealth and extravagance -- all seemed to report a childhood devoid of nurturing adult guidance.
   
A chi square analysis of the data correlating 'symptoms of profound alienation' with 'absence of attentive adult guidance' produced a highly significant value of 176.52 (p=0.000. . .). This analysis of the data says, in essence, that the chance that symptoms of profound alienation are not associated with lack of attentive adult guidanceis infinitesimally small. The data allows us to statistically assume that the absence of attentive adult guidance in childhood causes adult symptoms of profound alienation.
  
2000: Treating profound alienation
        
Of the 4 children whose evaluations ruled out autonomic hyper-reactivity and pervasive dysphoria (Figure I), one had never been prescribed an SSRI or clonidine. His diagnosis was unclear to me and, in retrospect, test-doses of fluoxetine and clonidine should have been diagnostically prescribed. The three other boys had had previous trials of both an SSRI and clonidine. All 3 had had been unable to tolerate both medications. One, newly admitted, was still under observation.  A second had a history of setting fires, threatening suicide, and harming himself when frustrated by not getting what he immediately wanted. While previous medication interventions had been unhelpful and caused side-effects, his behaviors and self-confidence were improving with cognitive behavioral therapy. The third boy, handsome and superficially mature, had been raised by an over-indulgent father. Cowardly and cunning, he preyed on the more vulnerable boys and carefully took advantage of "holding" situations to cruelly hurt staff members. He had no remorse or shame and was also the most dangerous child at the facility.
       
DISCUSSION
        
Patient symptoms and treatment outcomes allow us to understand the mechanisms by which damaging childhood experiences produce the crippling syndromes described above.

Pervasive Dysphoria
: Although patients have difficulty putting words to their symptoms, those symptoms clearly reflect the serotonin-neuron- communication dysfunction (SNCD) that underlies pervasive dysphoria. Patients with pervasive dysphoria feel "cut off" from the incomprehensible Life forces guiding the behaviors of eurkaryotes and all their descendents. Silence,  comforting and holding our attention to those forces, is experienced by people with pervasive dysphoria as a black free-fall of empty despair; busy-ness, talk, and obsessive "mind chatter" provide sanctuary. Physical symptoms demonstrate that serotonin-mediated neuronal circuitry guiding animal sexuality, eating, and rest is equally broken.
     
Understanding the pharmacologic mechanism by which one medication, fluoxetine, treats the disorder clarifies why play is so important to animal neurodevelopment. Fluoxetine is the selective serotonin re-uptake inhibitor (SSRI). Normal serotonin neurotransmission occurs as follows: 1) Electric current flowing through neuron #1 (the pre-synaptnic neuron) on reaching the synapse causes release of serotonin from the vesicles into the synapse. 2) the serotonin molecule reacts chemically with receptors on neuron #2 (the post-synaptic neuron) causing electric current to be generated. 3) the serotonin molecule then reacts with the re-uptake receptor back on neuron #1 (the pre-synaptic neuron) and is reincorporated in the vesicles for reuse.  If this is unclear, maybe linking to this picture (neurotransmission) will help.
   
Fluoxetine, quite simply, sits in the serotonin re-uptake receptor. By blocking re-uptake, fluoxetine increases serotonin concentration in the synapse. This increase in concentration drives the reaction at the post-synaptic receptor. Fluoxetine corrects pervasive dysphoria by reconnecting the serotonin-mediated neuronal circuitry. This chemistry underlies the importance of childhood play. Through play, human children (like all animal young) maintain neuronal connection between the developing body/brain with our primary animal instincts (i.e., our feelings, our unexplainable connection to "Life"). Children too worried to play look for direction rather than listening to and trusting their instincts. Eventually, the circuit is broken; in chemical terms, the post-synaptic receptor no longer reacts to serotonin released into the synapse.  Increasing the serotonin concentration drives that chemical reaction.  A therapeutic dose of fluoxetine connects the circuitry without side effects. As would be expected, too high a dose causes an uncomfortable "racy" feeling. Pharmacologic data support this interpretation. 

Autonomic hyper-reactivity: Knowledge of Porges' Polyvagal theory and patient symptoms, in themselves, suggest the pathophysiology of autonomic hyper-reactivity.  When terror overwhelms an animal's ability to fight or run, the (fish) parasympathetic nervous system kicks in and stops heart pumping.  While this works for ectothermic (cold-blooded) fish who can survive long periods of metabolic shut-down, it doesn't work for humans. The instant chemoreceptors throughout the body recognize acidosis (build up of tissue carbon dioxide) the sympathetic nervous system responds with outpouring of adrenalin.
   
Data on clonidine support this interpretation.  Clonidine is known to be "an alpha-adrenergic agonist (a-2 agonist) that functions as an antagonist reacting with cells of the brains locus ceruleus." Locus ceruleus cells lie deep in the human brain -- at the level piscine parasympathetic neurons. The therapeutic dose of clonidine depends, not only on liver metabolism (see pharmacologic observations) but on the severity and duration of the terrifying experiences, indicating mnemonic receptor formation occurs with exposure to terror. We can easily surmise that clonidine treats the cascading symptoms of autonomic hyper-reactivity by reacting with and blocking these locus ceruleus receptors from being triggered by events reminiscent of that earlier terror.

Profound alienation: Understanding our humanness within an evolutionary context, our uniquely human ability to face threat with calm, reasoned, assurance emphasizes the importance of careful adult attention to childhood developmental needs.  The suffering of people unable to trust Life deserves compassion. At the same time, with their highly evolved human cortex solely in the service immediate personal gratification, profound alienation has been the source of incalculable human suffering and degradation of our earth.

CONCLUSION
       
Without knowing exactly when our species emerged on earth (150,000 to 250,000 years ago), we do know we emerged with a genetic template worked and re-worked over billions of years. Data presented here is of patients all with that same stable genetic template, all born with the capacity for life-long joyful connection with Life.
       
Ancient myths and stories tell of selfish, profoundly alienated persons, threatening to early human communities and sent "away."  Smart, cute, and funny, or sick and over-protected children do slip though the cracks of watchful parental care. Human culture has difficulty dealing with people who, smilingly, simply won't play by the rules -- people for whom "winning" and "getting what they want now" is all that matters.  Banishment has been one solution.
       
While the earliest conquests of earth-based communities are only recorded in archaeology, linguistic data suggests a nomadic source.  Archaeological and linguistic evidence for the origins of the Sumerians of Mesopotamia and the Peoples of the Alteic Mountains ("Mountains of Gold) cannot be found. The terror unleashed by later conquests is well-documented. Depending on who's "side" they were on, that terror has been interpreted as advancing human "civilization" or as destruction of rich cultures living in harmony with nature. 
        

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