TABLE OF CONTENTS

Key question: What causes schizophrenia?

 

This article is a synthesis of ideas and personal speculation of a patient; not a doctor. The conclusion is that cerebral hypoxia [decreased oxygen supply to the brain]  is the developmental majority of schizophrenia, just as sunburn is such for melanoma: everybody gets sunshine, not everyone gets sunburned and not everyone who gets sunburned gets malanoma.  Smoking for example, does not necessarily mean lung cancer, but the chances of it are increased.  In the case of schizophrenia, hypoxia is the developmental majority: everyone is exposed to global hypoxia in the first trimester of gestation; as at this time the placenta is hypoxic.    It has been said that the state of the d2 receptor may be a sensitive indicator of hypoxia (8016). The site for antipsychotic medicine binding is the d2 receptor.   

The next decade or so will probably focus on the neurodevelopmental model, of which hypoxia is showing an influential role, with promising results (8004).  Already, scientists who study schizophrenia use animal models of the disease which would unintentionally inflict hypoxia when they increase dopamine by amphetamine and observing signature movement disorders.  These studies have sometimes shown the current antipsychotics as sometimes not working.(8012)

 

If you are newly diagnosed with schizophrenia and are looking for robust proof that it is a legitimate disease follow the link here to Dr Seeman's results (published in the most cited science journal Nature).
 

I first became interested in hypoxia when I read that hypoxia can increase dopamine by 1000%.  Then I wondered if hypoxia leaves any signs and struck an article which said poor motor coordination on exacting tasks is a sign of prenatal hypoxia.  So I wondered if schizophrenics displayed such poor motor coordination - and they do.

  
Following on the ideas of minor brain damage, then minor brain dysfunction; four hypoxia-related symptoms of schizophrenia are selected:  poor motor coordination and delayed righting reflex, social dysfunction and lack of insight and presents research indicating that prenatal hypoxia (even in the first trimester - when the placenta is hypoxic) may be influential in schizophrenia.  The article shows how parts of the brain are probably maintained in a state of constant hypoxia, facilitating the schizophrenic process (by making the d2 receptor permanently activated or by the inability of the brain to escape vasoconstriction quickly).  It also proposes that hypoxia is inflicted on the fetus by fetal programming if through the mother; inadequate placenta, if through the father, or immature defenses to hypoxia if sporadic.  For those who suffer delusions it proposes a mechanism for them.  It seems that hypoxia draws together valuable results from animal modeling, biology, genetics and developmental research.

The last section of the article lists many other hypoxia-related symptoms which are found in schizophrenia, showing repairing d2 abnomalities may be only one damage of hypoxia: as an analogy, for example, a computer hit by a flame thrower may need its' screen replaced and work fine, and this may happen with a lot of such damaged computers; but if the flame thrower was active at specific times as the computer was being assembled, it could be amazing if it worked at all.  That way a patient can say he is on the hypoxic  spectrum, or has minor brain damage - even if he/she doesn't have insight they have schizophrenia.   That schizophrenia is a heterogeneous affliction (that is - no two cases are the same) is shown in the variety of brain sections affected in each patient (246).

As the cause of schizophrenia is unknown, various models have been used.  The dopamine hypothesis is largely derived from observing the effect of amphetamine psychosis.  But amphetamines work via a hypoxic process (269) - reducing oxygen to the striatum and reducing cerebral blood flow.  A hypoxic model could be proposed as climbers or residents at high altitude get 'mountain sickness' - at extremes: psychosis.  

 

Poor motor coordination is the focus of the first half of the article.  Ismail et al found that 100% of schizophrenics had at least one neurological soft sign, whereas 45% of controls did (701); the most common sign in patients was poor motor coordination.  This article (below) posits that a layman's explanation for poor motor coordination is hypoxia.  Further, according to another study, we should expect the most severe disruption of motor coordination to be with the schizophrenic patients, lesser disruption with their siblings and even less with the controls (701b).

When I first had psychosis, the doctor treating me said I'd burnt out a neurotransmitter in my brain.  So I asked him what the name of the neurotransmitter was, and he just covered his mouth.  Just as people stuck with a chronic complaint that the medical profession can't help with reach out for alternative therapies; this research is my own reasoning on my own schizophrenia - and so has only amateur credibility.  I'm only giving it a go.  I hope it gives other new patients some information to start with on their own journey.  If you have any questions there is a message board provided by 'Schizophrenia Connection' for this topic and get an answer from an expert.  Please be aware that even genuine scientists of the first caliber have had to withdraw their articles from publication because they were wrong.  At least 1% of the world's population is schizophrenic - and each patient understands his/her condition in their own way and no theory has credibility unless it explains, cures and prevents a disease..

The future now looks like early detection of schizophrenia by examining vasodilator response and early treatment.; even isolation of those factors which enable a fetus to survive placental hypoxia and monitoring and intervening...

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In 1947, Strauss and Lehtinen, proposed the concept of Minimal Brain Dysfunction, involving social dysfunction and lack of coordination. (1b) (2) - two factors which are still relevant to some schizophrenics.  The American Journal of Psychiatry, in 1975, recorded a proposal that schizophrenia was caused by Minimal Brain Dysfunction via hypoxia [lack of oxygen] (1).  If this assertion is true, unfortunately it is the case that, "...The precise cellular and molecular events that underlie brain pathologies under hypoxic conditions are poorly understood..." (3)

In 1967 (a time when Minimal Brain Dysfunction was being examined) a 25 year follow-up study (in which poor motor coordination was a common factor) reported that four of fourteen patients had been institutionalized for psychosis and another four had at one time been - assuming a psychiatric institution is meant. (49) Minimal Brain Damage was also associated with disorganized behaviour (45a) and antisocial behaviour (46). 


Minimal Brain Dysfunction was originally Minimal Brain Damage, but on failing to discover any actual damage it eventually became a 'learning difficulty' and Attention Deficit Hyperactive Disorder (32)).


[Firstly though, hypoxia is a normal developmental factor - especially as the placenta is hypoxic in early gestation (56) and then again in the third trimester as the placenta's reserves are drawn on by the fetus (40) - it seems a threshold of dopamine must be exceeded for it to start creating vasoconstriction which, I think, could be a marker for schizophrenia spectrum disorders.  Noone is at fault in causing schizophrenia by hypoxia.  For example, maternal hypoxia may play a part and yet placental insufficiency may play a part too.  The placenta originates with the embryo.  Yet it may be that the insult is caused in the natural hypoxic period of the first few weeks of the placenta.  Even at term all infants are to some extent more vulnerable to insults such as hypoxia because their defenses against such insults are immature (401) - I see schizophrenia as an accident, perhaps we will never have enough information to prevent it.]

Is schizophrenia real? Consider your own nightmares not repressed.

In this section I was looking for a rule of thumb which a layperson could use to detect past, perhaps chronic, prenatal hypoxia - with the view that I might be able to use it as supportive diagnosis.

It would be useful to know how many people who were subjected to hypoxia in utero became schizophrenic, but there is currently no published study of adult outcomes of adults who were growth restricted in utero (4)(which often accompanies hypoxia - in the case of placental insufficiency for example). In the search for signs of prenatal hypoxia, a measure is needed.

Apgar scores, fetal heart rate patterns, meconium stained amniotic fluid and umbilical artery pH "are indirect markers.    Moreover, neurologic outome seems to correlate poorly ... additional markers are required to distinguish between acute and chronic fetal hypoxia." (208)(introduction).  This seems to say the neurological outcome is the gold standard.  The article concludes saying: "There is no standard diagnosis of fetal hypoxia."  The Apgar factors, for instance, " are dependent on the integrity of brain stem and upper spinal cord structures (1)."  Even in the case of cyanosis, " one should not rely on the absence of cyanosis as reassurance that hypoxemia is not present".  The manifestation of cyanosis being dependent not only on oxygen level but hemoglobin level too. "Conversely, many patients who are chronically hypoxemic (low PaO₂ and/or low SaO₂) are perfectly lucid and without any obvious physical signs of their low oxygen state (at least while at rest)."

It is well known that cerebral hypoxia results in uncoordinated motor behaviour, This uncoordinated behaviour could be a useful sign if it remains as a signature of past hypoxia.


While firstly considering schizophrenia as an example, Golan et al analysed a series of studies on rodent models - although not conclusive and not always repeated - suggests while some hypoxic deficits disappear, others remain:  motor deficits including motor function and coordination remain and are a "hallmark of prenatal hypoxia" (5).  - while there are caveats, I have used this as s a useful 'rule of thumb'.

And the hypoxia need not be perinatal.  More precisely, hypoxia given at a specific gestational day in rats (which was crucial to their development; the human equivalent of which is the fourth or fifth week of gestation ((5)Golan et al's chart)) produced more adult rats unable to learn a new whole body coordination task (321).  In these weeks the human placenta is hypoxic.

It seems uncoordinated movement is a consequence of hypoxic injury in humans as well.  In animal models of cerebral palsy, prenatal hypoxia was induced and the pups in the litter had notable motor difficulties (151) (the article doesn't specifically mention coordination): "Antenatal hypoxia-ischemia at preterm gestation results in hypertonia [abnormal tightness of muscles] and abnormalities in motor control."  If I read the study correctly, pups were subject to placental insufficiency by surgery, then those pups born; some were subjected to 40min hypoxia, with the result that 83% of the survivors had a higher degree of muscle tension.  Another study of graded prenatal hypoxia mentions deficits in motor skill and motor development (328) - a hypoxia spectrum!  Other studies show notable relevant results (1002)

More recently, Golan et al have said that prenatal  hypoxia often lead to "life span" cognitive and motor deficits and say this is implicated in schizophenia (327) along with perinatal hypoxia.  This interpretation challenges that of others who have interpreted the relative stability of motor defects as a sign of genetic libility (329)

There is damage in some schizophrenias.  Permanent symptoms of uncoordinated motor behaviour are shown to affect the cerebellum (7) [a 'little brain' at the base of the brain]- which is responsible for coordination. Damage to the cerebellum is commonly caused by hypoxia (9). Mukaetova-Ladinska et al have said: "Alterations to the cerebellar neuronal network can occur as a result of hypoxia/ischaemia or trauma confined to the frontal cortex and vice versa", while saying in summary: "...alterations of the cerebellar synaptic network occur in schizophrenia....These changes may influence cerebellar-forebrain connections, especially those with the frontal lobes, and give rise to the cognitive dysmetria that is characteristic of the clinical phenotype in schizophrenia".(9b) - but emphasise that motor abnormalities need not result.

 (Just before the publication of cognitive dysmetria another disconnectivity hypothesis was proposed and considered hypoxia (64)).  There is a statement that in some cases hypoxia causes the type of schizophrenia where mental functions overshoot their proper place - dysmetria.


("The association between hypoxia and fetal brain damage is well described and proven. Hypoxia can produce temporary brain dysfunction or permanent brain injury, depending on the duration, intensity of the oxygen deprivation, and the age of the fetus." (6).  Also, although the cerebellum is commonly involved, ataxia can result from injuries to other areas of the brain or body)

Against this, 'animal modelling' derived conclusion is the epidemiological conclusion that no type of motor dysfunction in schizophrenia is associated specifically with hypoxic obstetric complications; and that the robustness of abnormal motor abnormality findings in schizophrenic cohorts indicates a genetic susceptibility (335). The conclusion that genetics are involved seems to be based on findings that the lack of motor coordination is familial; but it could be argued the shared defiicit is due to a shared prenatal environment. In another study, in summary, the authors state: "A great number of studies indicate clearly that schizophrenia patients have a significantly increased history of OCs, representing many different OCs from pregnancy, labor-delivery and the neonatal period. The probable common denominator of these OCs is oxygen deprivation" (336).  As far as a 'genetic liability' to poor motor coordination goes, a study by Lawrie et al concluded 'sensory integration abnormalities', which included motor coordination, "showed no genetic association" (337).

 
One epidemiological study revealed that mothers with hypoxic obstetric complications and mothers without had a correlation of 5.75% and 0.39% with their offspring having schizophrenia..  There is only a 0.04% chance, from these figures, that schizophrenia is not related to hypoxia (17)(17).  The study cited validates the method used in this article, as it too considered the equivalent of neurological soft signs to be an indicator of hypoxia (although I am not sure if the article says these factors were genetically mediated; it seems unlikely as the criteria were derived from  hypoxic ischemic encephalopathy - and in any case what it would more accurately mean is that it was familial).

Mary Cannon in her own conlusion stated: " we need to do more detailed study of the interaction between timing of hypoxia and biological and motoric effects. Perhaps animal studies are the way to go. But I have some doubts about how much we can extrapolate from rats and guinea pigs  to humans!" (pers comm 23-10-09)

 

Some vasodilators have been shown to have reduced response in schizophrenia and this has been posed as a diagnostic criteria.

 

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In this section I looked for previous research describing schizophrenia as containing the rule of thumb for prenatal hypoxia.

It is vaguely, but nevertheless well known that people with schizophrenia can be clumsy and uncoordinated.  However, academic research has well established there are deficits in motor coordination with schizophrenia.

One study reports: "Epidemiological [studies of the health of a community] studies which have examined the childhood characteristics of individuals who later manifest schizophrenia, have shown that they have problems in motor development particularly in coordination..." (11) Another study in 1999 reviewing childhood performance at sport of 400 schizophrenics concluded: "Poor coordination skills in childhood, as measured by school performance in sports and hand crafts, predicted schizophrenia in adulthood in this sample. This effect was strongest in the youngest age group, between 7 and 9 years of age...". The report cites other studies in agreement (12) (such as an earlier British cohort) Indicating by inference hypoxic insult is characteristic of schizophrenics.

In 1972-73 an unselected birth cohort of 1037 children was collected in Dunedin New Zealand. In 2002 a study was reported which said that obstetric complications involving hypoxia were relevant to those who went on to develop the broad category of schizophreniform disorders [virtually schizophrenia but lasting less than six months]. It also noted that: "The schizophreniform group also performed worse than controls...on standard tests of motor skills at age 3,5 and 9 years, but not at age 7 years." (13, p452). There were other problems for these schizophreniform patients and the deficiencies were not related to obstetric complications. "In conclusion, this study demonstrates that schizophreniform disorder is associated with childhood developmental deficits across a range of domains. Motor, language, and cognitive developmental deficits emerge early and are persistent and specific to schizophreniform disorder."(13)) (The exclusion of age 7 in this report is important as a previous study mentioned drew its conclusions for motor coordination from that age and found little difference.) The study of schizophreniform patients compared them to a group of depressive/anxious and a group of manic patients. The depressive/anxious patients performed the same as controls on motor variables while the manic patients performed better.
A longitudinal report on pre-schizophrenics reported hypoxia (as indicated by hypoxic-associated obstetric complications) resulted in less motor coordination and more unusual movements (16).  One unusual movement is 'high guard' where the arms are extended to the side and elbows bent, sometimes out to the front.

Yet at least in the case of childhood schizophrenia, similar but more abnormal and severe motor disorders are seen. (61).

A 2008 article in Nature Neuroscience says: " ...defects in human brain function observed after hypoxic insults may be caused by a whole spectrum of distinct developmental defects..."(18)  If such a spectrum exists then diagnoses are related.

A 2005 article warns that of the five or so percent who have motor abnormal neurological soft signs as children [symptoms like missing touching one's nose], it is not known what percentage have undiagnosed neurological disorder (14). (15) . There is no well-publicized opinion about a boundary in the severity of motor coordination. Motor coordination, it seems to me, is usually clinically measured by a set of tests which seem to use similar skills as basketball, or playing the piano.

It seems the common factor with schizophrenic coordination deficit is its severity.


If hypoxia was the cause of these motor defects; this leaves hypoxia as one option in the neurodevelopmental model (and "some forms of schizophrenia may be preventable" (21) (other authors also say schizophrenia may be preventable (70)); however, does this account for fetal programming?)

However, in a very small sample in a survey I conducted, only 50% of schizophrenia patients said they were below average at sport at school.  The Dunedin study mentioned before reported z scores of 0.3 difference for motor coordination of schizophreniform below controls.  According to the report 0.5 is a moderate score - so the schizophreniform group was noticable but not markedly - "not when freely roving in a plain area," as Golan et al found.
 
However, Nancy Andreasen et al have said: "Schizophrenia may be conceptualized as a disease that is characterized by poor coordination, or dysmetria, in all domains of functioning, including both motor and cognitive" (247).

The Minimal Brain Dysfunction theory initially hypothesized lack of coordination was usually involved due to damage to cells including the "Purkinje" cells in the cerebellum possibly caused by blood flow hypoxia. (1).

In a smaller study motor coordination deficits correlated well with the schizophrenic patients (p87) (316).  In this study it was always (or at least well correlated as) more than controls and always more than unaffected siblings (who themselves had coordination scores) the article suggesting there must be a shared genetic or environmental heriatage. 

 

"With a hemoglobin content of less than 9 g/dL, the patient would likely succumb from hypoxemia before cyanosis became evident."

Those with poor coordination have no increased or decreased chance of Antisocial Personality Disorder (8015).

This article uses the phenocopy model - that schizophrenia is caused by hypoxia without the influence of genes; but others use the gene-environment "covariation" or "interaction" models.  Inconclusiveness remains because it is not certain if lack of coordination is a genetic factor or environmental.  It is reliable that lack of motor coordination is a independent factor of schizophrenia (see Mary Cannon (420) below and Tyronne Cannon (421)(early fetal complications recorded were:(abnormalities of fetal heart rate or rhythm, umbilical cord knotted or wrapped tightly around neck, third trimester bleeding, placental hemorrhaging or infarcts, polyhydramnios, meconium in amniotic fluid, breech presentation) (fetal heartbeat can't be heard by stethoscope till week 20.)

 - if the minor brain dysfunction conjecture is correct and it is the Purkinje cells which are damaged(422) in the cerebellum as the 'computer' is being 'assembled'; this would happen before week 8 according to Golan et al - before these obstetric complications could be measured; the Archives of General Psychiatry article does not search for hypoxia at this early stage either; this would account for the independence of motor coordination scores and obstetric complications). In a subsequent study it was concluded: "The analyses did not support an interaction between genetic risk and coordination or a model whereby coordination deficits are mediated by genetic risk".  The study nevertheless pointed towards a genetic influence on schizophrenia; but sought other reasons for the lack of motor coordination (431).  One factor of coordination used was normal in 50% of schizophrenics; over 60% of those with other pathologies and about 70% of controls.

Indication the striatum is involved in work (DSM*):

From the journal 'Frontiers in Science.  Frontiers in Integrative Neuroscience' two circuits using the striatum are important in: 1. Learning new tasks by repitition and as the task is learned this circuit becomes less important and 2. automatic performance.  The D2 receptor is also involved. (6000)

Importance of Sociability.  In this section, as the neurodevelopmental theory describes a life's trajectory before schizophrenia; I wondered whether asocial behaviour was normal for schizophrenics.

Research on animal models for mental illness have noted a difference in response to social cues (even from their pups (73)) in animals subject to perinatal hypoxia and pups with hypoxia are more inquisitive about social interaction but solicit play less (72). The timing of perinatal hypoxia is the equivalent developmental stage of the third trimester in humans.   Declining social function is one of the diagnostic criteria for schizophrenia.  A study of monozygotic twins discordant for schizophrenia noted different psychosocial development could have been caused by hypoxia (31).  Interpreting social cues is a function of the premotor cortex mirror neurons and the prefrontal cortex (which gives the interpretation).  An internal picture guides the interpretation (240).

 

Recently one study proposed future schizophrenia could be predicted by a range of social factors - this finding was considered radical.  If I have read the right study (The British Journal of Psychiatry ISOHANNI et al. 187 (48): s4) they actually conclude there is no powerful risk factor in the general population; but do present a 'high risk group'.  This only goes to showthat each hypoxia connected sign has an association with schizophrenia; statistically implying hypoxia - but only as a sign not a cause.

Within the psychoses, sociability is a strong predictor of schizophrenia: "in this study premorbid motor impairments and obstetric complications fail to distinguish between schizophrenia and other early-onset psychoses. In other words, impaired ‘sociability’ (similar to concepts of schizoid personality and ‘schizotypy’ (asociability)) may provide the clearest distinction between the developmental phenotype of schizophrenia and precursors of other psychoses" (77).  Yet, repeated study of the Northern Finland Cohort reveals another non-significant trend in sociability deficits over time. (186).  (One study on the same cohort confirmed a highly significant factor - disagreeable attitude (186) - irritability?).  From the Northern Finland Cohort preschizophrenic students aged 14 were three times ore likely than normal to be graded not normal in class (187).  Asociability though is not malice.

An Israeli study  achieved high predictive scores using socialization.  The criteria measured were: intelligence, social functioning, organizational ability, interest in physical activity, and individual autonomy.  Socialization on its own was  a reasonably accurate predictor of schizophrenia (76).

"Many studies have suggested that children who go on to develop schizophrenia may be different from their peers and display some developmental deviations, such as mild social, motor and cognitive dysfunctions" ((20), p58). Also, "...developmental problems (a pragmatic equivalent of soft signs), weakness in speech or language and difficulties in peer relationships, as the strongest childhood precursors of adult schizophrenia. Indeeed easily more relevant than a family history of psychosis, or demographic characteristics" (24).
; 
It is well known that activation  of the immune system causes social withdrawl, but one study goes further and says acute hypoxia may trigger this immune response (9000).  The immune system response is inversely related to symptom score (9001);  and Leptin is part of the body's defence against hypoxia (9002)

In this section I looked at the current dominant paradigm for schizophrenia - cognitive dysmetria- to see if it could be explained by hypoxia - progressing further into the spectrum of problems that hypoxia creates. (Dysmetria means disproportional action to the stimulus - as if you went to cut a sandwich and cut through the plate too.  Cognitive dysmetria was proposed by Nancy Andreasen of Iowa University.  However, even this theory has its' critics).  The concept says the normal developmental circuits in the brain lose 'synchrony' or coordination.(247).  Surprisingly it was found that the speed of learning to walk - or Infant Motor Delay - depended on the same circuits as cognitive dysmetria and may be somewhat predictive.

Golan ((6) p341) says several studies have found that the righting reflex is delayed in mice subject to prenatal hypoxia. Other authors have noted the same: "The righting reflex was significantly affected in the hypoxia groups"(8).

The Motor Development circuits are those involved in 'Cognitive Dysmetria' (see below).


Learning to walk is a measure involving motor behaviour which seems specific to schizophrenia. A predictive cohort of over 12,000 children says: "Altered motor development in schizophrenia is, therefore, fairly robust across many different study designs" (22) - and a main feature was learning to stand and walk. The results show motor development - especially learning to stand and walk - to be predictive of psychotic disorders but not other pathologies. The predictive power of this variable was confirmed in another prospective study, however its' discriminatory power among other pathologies was not examined (23) (Although a later study on the same cohort said there was a certain specificity to psychosis (51)). Another study also examined the time it took for infants to stand and walk. The measurement was taken by asking mothers as their child reached age three. Later some of the children of the whole sample were found to have mania, depression, anxiety or schizophreniform disorders. The study noted that schizophreniform patients leant to walk significantly later than controls (13) and did not make similar comments regarding the other pathologies.  Another study of the Northern Finland cohort found there was an odds ratio of 0.7 for delayed righting reflex and antisocial violent behaviour (8014); and 1.2 for non-violent criminals, so statistically significant - these subjects (with delayed righting reflex) were more likely than usual to have non-violent criminal records and less likely than normal to have violent ones.  If you can average these two odds ratios the result is nearly normal ~ 0.95

Another prospective study found controls learned to walk on an average of 13.5 months, while schizophrenics learned 1.2 months later on average (still within 1 standard deviation of the controls value) (51) - revealing the possibility of some difference in brain regions responsible for gross motor skills: the striatum. In the same study, "Investigations of this cohort into childhood factors predicting affective and neurotic symptoms at age 36, identified social factors, not educational or neurodevelopmental, features which suggests some degree of specifity for our findings in this study, at least to psychosis" (p1401); but they say in the same paragraph "...no child destined to have schizophrenia could be singled out as a late walker ..."

In the Dunedin study reported before, once again learning to walk was significantly delayed (p78).
Delayed motor milestones are possibly caused by delayed brain development (62); there being correlations between rate of brain development and later grey matter densities (62) because the same brain circuits involved in Infant motor development are involved in adult executive function (62).

The idea of Cognitive Dysmetria could reflect the DSM allowance for diagnosing schizophrenia at the clinician's discretion because of the intensity of the symptoms.

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Yet the result of the first study (or any other) can hardly be described as predictive when 1541 children learned to walk in over twelve months and only 27 of those became schizophrenic ((22) table 2 p5). There is an oddity however - a disconnection - perhaps a difficulty understanding self and others -  which singles out the schizophrenics. (62)


Technical information on Brain Volume showing schizophrenic profile after a range of ages learning to walk.

It is a disconnection or 'discontinuity' of areas concerned with infant motor development which is schizophrenic.

A study reported in the highly cited journal Proceedings of the National Association of Sciences of the USA found infant motor delay and a disconnection was predictive of cognitive dysmetria in schizophrenics.

The PNAS report had three strange graphs.  On all three graphs examined (62) of different brain areas, the schizophrenics had almost the same brain volume for any Infant Motor Development (IMD) agegroup - a steady line accross the graph of motor development times.  Normal people had a sloping line according to increasing or decreasing IMD.  Please view the graphs.  It is almost like the cause of the IMD had disconnected the various region involved in IMD in schizophrenia, and the article implied these regions are those of cognitive dysmetria.  The journal says they were disconnected from the premotor cortex.  In non schizophrenics: "... relatively precocious motor development was significantly associated with better executive function in adulthood and vice versa"; while in schizophrenia the correlation between executive function and infant motor delay was not significant(62).

The report said cognitive dysmetria was particularly suitable here. It also says: "Assuming that axonal [nerve line] connectivity is a key neurodevelopmental mechanism ... with schizophrenia ... [there is] a developmental failure to establish axonal connectivity to or from premotor cortex." (p15654) (Grey matter volume to and from the premotor cortex is confused by lack of axonal connection.)


This disconnection or "developmental dysmetria" determines the clinical and social course of the illness (164).  This summary said the trajectory of normal as opposed to schizophrenic lives, from birth to death, was "distinctly different".  Yet the same report described the subtle pre-illness trajectory as 'difficult to tease apart' .  When referring to this very abnormality reported in PNAS, one earlier report said:  "It may be that this “developmental dysmetria” relates to the clinical and social outcomes and severity of illness as well, but this hypothesis needs future studies." (255).  Ridler et al said developmental dysmetria was shown in mild social, motor and cognitive dysfuntions.

The PNAS report says the disconnection is with the premotor cortex as well as parietal cortex.  This area of the brain, including the parietal cortex, (which was also affected (62) p15653) contains mirror neurons which are used to understand the actions of others and yourself.  One report says these neurons have a role to play in empathy, and personality disorders (256).  The report says projection (where you attibute your own feelings to the outside world) - a function of paranoia - is via the mirror neurons; it also might be that, if the neurons are to understand the action of oneself, their isolation might be the reason for the lack of insight in schizophrenia.   The mirror neurons may or may not explain insight.  They are a discrete mechanism which has been used to explain Theory of Mind - a way of understanding others; and involving insight - acknowledged to be relevent to schizophrenics (267).  The neurons in the parietal lobe monitor the external environment (270)  Hypoxic mother rats are more often found outside the nest grooming themselves (73)- and seem to lose maternal instinct (requiring the mirror neurons or empathy) for self-oriented activiities - preoccupation involves a lack of insight and is a kind of self grooming: "This could be interpreted as a 'mothering factor' ...opposing self-directed maintenance activities..." (p574).  The DSM describes schizotypal people as: "...A pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships"; this animal model indeed shows a preference for solitary activities.

No study has included antisocial personality or any other personality in the study design to look for correlation with infant motor delay. or premotor cortex abnormality

Abnormal use of the mirror system in schizophrenics results in social problems  ((75)).  So lack of insight goes hand-in-hand with poor social skills.  Lack of insight is a socialization statement.

Ridler et al's article says there is a 'long-term' discontinuity; ie from Infant Motor Delay to adult schizophrenia.

 Schizophrenic disconnection cause and future cure.


Hypoxia overstimulates VAB [guideposts  for nerve axons in the schizophrenic brain].  Nature Neuroscience reports: "These new results also suggest that this undesired VAB-1 activity functions in the guidepost cells and the tissues that growing axons traverse, which is quite reminiscent of the astrocytic expression of Eph receptors in the injured mammalian spinal cord. In theory, selective removal of this repulsive activity might help restore axonal connection in nervous system injuries caused by hypoxic insults" (37)) - it is hypoxia (or HIF-1-alpha) which makes VAB-1 overactive (39). This leaves us in no doubt about the cause of the disconnection.  The author of Cognitive Dysmetria pointed to development as a cause in saying the cause will be found in future years with a combination of genomic and developmental studies (37).  The need to remove such 'repulsive activity' shows current antipsychotics are not able to fully restore the schizophrenic brain.  HIF-1-alpha is caused by hypoxia and causes overactive VAB.  Normoxia degrades the HIF-1-alpha - so it is important to avoid vasoconstriction and allow for oxygen perfusion - the medication helps do this.


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In this section I found a report by a well respected scientist who incorporated motor coordination [the rule of thumb for hypoxia] and the [hypoxia related prerequisites for cognitive dysmetria] Infant Motor Delay increasing the credibility of this article.  I added the 'Interpersonal Competence' ratings following data in another study.

Chance of Good Interpersonal Competence Most likely Poor Interpersonal Competence

Image used with author's knowledge and permission and permission of Oulu University. Copyright Olou University Press Interpersonal competence measures an adaptation (From Table 5, factor III (264)). For further interactions between Neurologic Soft Signs and typical portrait of schizophrenia please go to the end of this page and click on the link.

This graph of adolescent motor skill reveals that a later date of learning to stand, and development of schizophrenia is reflected in adolescent motor skill. The graph shows that lower adolescent motor skill on average indicates a longer time to learn to walk, and both combined make the profile of a schizophrenic. Measurements of motor skills were taken from school teacher's rating of athletic ability, so presumably a patient's knowledge of his average or below average performace is valid. Repeating this graph resulted in the same trends proving it is reliable as a supportive diagnosis. This would be because the difference in the five percent or so who have developmental coordination problems is that the caudate nucleus (which is part of the basal ganglia) is protected from mild hypoxia, which would however affect the coordination region of the brain. The caudate along with the putanem contain most of the brain's d2 receptors which are the antipsychotic receptors. "If perfusion is markedly reduced" all of the brain is affected, but the areas with highest metabolism ... suffer most" (42). One such area is the 'deep grey nuclei - which includes the caudate nucleus [containing most of the d2 receptors and responsible for motor movement]. So the lack of coordination spans hypoxia of the cerebellum from which the caudate nucleus may be protected from. Then the striatum [the larger area containing the caudate nucleus] is included in cognitive dysmetria, a syndrome in schizophrenia.  The addition of poor sporting ability selects those developmental delays caused by hypoxia.  If hypoxia is even worse, it will affect the thalamus which is responsible for hallucinations, but is more resistant to hypoxia.

Added to this graph is the finding that those with high 'neurological deviation' (which included coordination) had 100% poor interpersonal competence skills, while only 48% of low ND subjects have such a poor score (264).

Graham Murray's graph is reproduced in table form (see Table 1 reference).  The table says that if there is no variance of motor coordination with righting reflex, the subject is almost certainly normal, whereas if the subject has elevated coordination at early age of waliking or notably uncoordinated at delayed righting reflex there is a fair chance the subject is schizophrenic  (but there is a one per cent chance the variables are unrelated)..

 

However Golan says results of motor coordination are not evident while the subject is freely roving in a plain field.  Infact a French study showed 100% of schizophrenics (nearly); while a much smaller percent of controls had elevated Neurological Soft Signs - mainly consisting of three factors, the main one being motor coordination (8010).

The persistence of developmental markers in childhood and adolescence and risk for schizophrenic psychoses in adult life. A 34-year follow-up of the Northern Finland 1966 birth cohort Original Research Article
Schizophrenia Research, Volume 71, Issues 2-3, 1 December 2004, Pages 213-225
Matti Isohanni, Graham K. Murray, Jari Jokelainen, Tim Croudace, Peter B. Jones

 

 

Deficits in motor coordination are one of the most robust findings of schizophrenia research http://schizophreniabulletin.oxfordjournals.org/content/early/2009/04/17/schbul.sbp011/F2.large.jpg

 

Motor coordination is special in about all studies of schizophrenia (8013)

 
 
The text says:  " Moreover, the funnel plot (figure 1) showed a higher concentration of studies on the right side of the mean, suggesting a bias against publishing small studies with no effect. Therefore, the CMA recomputed the effect size using the method of Duval and Tweedie40 described previously. The number of “missing” studies and adjusted effect size and adjusted Q statistic are shown in table 2. The adjusted standard difference in means is lower than uncorrected results for NSS total and for every subscale comparison. Nevertheless, the fail-safe number of studies required to overturn the mean effect size was 341, which is sufficiently large to make the existence of large numbers of unpublished negligible findings unlikely"

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*It has to be pointed out that those with schizophrenia and showing no abnormal motor score (which I used as a measure of prenatal hypoxia); draw attention to the observations made in practice of several doctors: "The cerebellum is obviously not vulnerable to prenatal global hypoxic-ischaemic insults. This conclusion is derived from clinical observations: in a number of twin–twin disruption sequences due to the death of one twin, the surviving monozygotic co-twin tends to have extensive bilateral  supratentorial brain damage while the cerebellum is preserved.  We have seen singleton infants with bilateral prenatal cerebral hemisphere infarctions of unknown aetiology in whom the cerebellum was also intact."  (315) So the absence of poor motor skill is not the absence of prenatal hypoxia. 

 

American Journal of Medical Genetics 127A:133–138 (2004) Natural History of Twin Disruption Sequence Andreas Zankl,1* Daniela Brooks,1 Eugen Boltshauser,2 Remo Largo,3 and Albert Schinzel11* Daniela Brooks,1 Eugen Boltshauser,2 Remo Largo,3 and Albert Schinzel1 - this study shows that poor fine motor skill is the rule with surviving twins, even though occasionally that skill wasn't affected

The claim is made that such information can only be used as 'supportive' and not 'difinitive' in diagnosis - which indicates it can be used retrospectively, but not without the formal diagnosis.

No reliable measure of sociability was included in the cohort study; and the results would no-doubt have been more precise if they had.  However the 1958 UK cohort,was said to include this measure and relate it to schizophrenia: "At the age of 7 children who developed schizophrenia were rated by their teachers as manifesting more social maladjustment than controls (overall score 4.3 (SD 2.4) v 3.1 (2.0); P <0.01)." (162).

 

Graham Murry, in the above paper (41) shows executive function to be related to coordination (fig2 (41)) - as the executive dysfunction happened via disconnection of the premotor cortex, perhaps this has ramifications for sociability (as the premotor cortex was crutial in the cognitive dysmetria section 4).

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Statistics show  that both parents are much more likely to both not be affected (2317 cases in one study, compared with 4 both parents affected, 33 father alone affected, and 64 mother alone affected in a survey of nearly 2 million people) (319).  The study notes that in the case where both parents were schizophrenic, the were increased odds of the child being schizophrenic, but  there was no 'interaction' between the status of the two: so it was possible that the child was schizophrenic if the mother or father was schizophrenic in this specific case didn't depend on both parents being schizophrenic.

Hereditry functions which could increase chances of parents having schizophrenic children:

One report described nutritional deficiencies in the Grandmother could  pass similar symptoms caused by fetal insufficiency (which sometimes is accompanied by hypoxia), through the Mother to the Grandchildren (257).  This has been confirmed by several studies - up to 12 generations (258).

Adaptation to low oxygen levels is passed on to progeny, even in normoxic environment.  Children of Tibetan parents; at low altitude; display this behaviour, so persistently so, authors have speculated it could be a genetic trait (263).

Hemoglobin levels have been reported to be lower in schizophrenics (301)  (301b).  With the normal range for schizophrenics being slightly lower than normal (303)

 Including a reference to the programming of the mesolimbic circuit one article said fetal programming occurred in the presence of synthetic glucocorticoids; suggesting sGS could permanently program or modify the dopamine system (308).  Another article said hypoxia influenced glucocorticoids.(309) - hence the permanence of hypoxia in schizophrenics with raised dopamine? The effect was transgenerational.


In hereditary schizophrenia, where is the hypoxia? - Maternal lower hemoglobin transport or Paternal influence on the placenta.

Maternal hemoglobin lower concentration during pregnancy is indicated as a risk of schizophrenia.  One study, to measure iron levels, found: " A mean maternal hemoglobin concentration of 10.0 g/dL or less was associated with a nearly 4-fold statistically significant increased rate of SSDs [schizophrenia spectrum disorders] (adjusted rate ratio, 3.73; 95% confidence interval, 1.41-9.81; P = .008) [the p vakue means there is a 0.8% chance the two factors are unrelated] compared with a mean maternal hemoglobin concentration of 12.0 g/dL or higher, adjusting for maternal education and ethnicity." (156).  However, there are many causes of psychosis (157). 

"It is a well replicated finding that mothers of schizophrenic probands are more likely to be affected than fathers...groups have been exploring the influence of the microenvironment in utero provided by mothers affected by schizophrenia to their offspring" (262)

 

But paternal influencehttp://harvardmagazine.com/2006/09/prenatal-competition.html may not depend on the mate's womb to involve hypoxia: " Because genetic imprinting by paternal genes contributes to the development and maintenance of the placenta, placental insufficiency and hypoxia could be a proximal cause of schizophrenia from mutations or epigenetic events arising in paternal genes." (408)  Hypoxia can reduce sperm viability (409). Damage to sperm can then be passed on to offspring and their sperm - up to four generations.

Hypoxia could be the intergenerational 'designer' of consequences from mother and father as: Hemoglobin levels have been reported to be lower in schizophrenics (301)  (301b).  With the normal range for schizophrenics being slightly lower than normal (303)

 

Sporadic cases.
Bearing in mind from the above study 96% of patients had no parent schizophrenic; the cause can be put down to the complicated process of hypoxia-defense which matures with the maturity of the fetus' brain, and is still immature at term.

In this section I tried to understand the connection between Philip Seeman's d2high receptors and Nancy Andreasen's 'cognitive dysmetria'.  These circuits are very important because they are reflected in the measures of Neurologic Soft Signs of which only the motor coordination factor is predictive of diagnosis according to one article (see next page).

Recalling a previous finding: A longitudinal report on pre-schizophrenics reported hypoxia (as indicated by hypoxic-associated obstetric complications) resulted in less motor coordination and more unusual movements (16).

Nancy Andreasen explained cognitive dysmetria as a way of keeping schizophrenia as one diagnosable entity; rather than discrete misfunctions (247).  [The second option is more appealing to a hypoxia spectrum].

Two circuits are of interest (169).  For coordination, the fronto-cerebellar circuit - which is also implicated in mood disorders and schizophrenia (implying a continuum); and for movements, the fronto-striatal-thalamic pathway - specific to schizophrenia.

I mention this second pathway because tests on it descriminate schizophrenia from mood disorders and also because, Philip Seeman reported on the striatum in Nature in 1993 (168) one of the most reproduced and robust findings of schizophrenia research.  That is, that there were more d4-like receptors in the schizophrenic striatum.  Later he said these were probably excess d2-monomers.  The d2 receptor (located mainly in the striatum) is responsible for psychosis.  The thalamus is responsible for hallucinations.  The main objections to this increase proposed that dopamine chemical dysfunction was present.

In the next section I mention how the caudate nucleus of the striatum becomes involved after more extreme hypoxia - this explanation also shows how hypoxia is linked to dysfunction in this circuit.

 

Some of Dr Seeman et al's pathways to psychosis could be explained by hypoxia (157).  For example gene knockouts by chromosomal fragility.

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(A)

If hypoxia is worse, the caudate nucleus may become involved. One 2002 study, without saying why, detected smaller caudate nucleus volume in schizotypal patients (schizotypal [nearly schizophrenic] people were chosen to avoid neuroleptic drugs) (45)(150).  It is appealing to say that the state of the caudate nucleus is probably maintained by the fact that dopamine in high doses can have a 'pressor' or vasoconstrictive affect.

Dopamine itself can increase 1000% in striatal samples under hypoxia reversably provided (in part) the reuptake is not blocked (213).

One 1998 study mentioned the possibility of vasoconstriction in schizophrenia and couldn't believe it was true - even though vasoconstriction correlated with symptom severity and that chronic schizophrenics had a reduction in perfusion: "It may be argued that the increased CBFV [cerebral blood flow velocity] seen in acute schizophrenics is due to vasoconstriction. However, vasoconstriction would considerably decrease brain perfusion, which in turn would result in lowered oxygenation and glucose supply; under such conditions, however, sustained activity is hardly possible."(88).  [Yet as mentioned above, amphetamines work on a hypoxic principle - and the user is conscious]..  The same article says: " Most studies deal mainly with chronic schizophrenia, and the essential finding is hypoperfusion.".  As far as I can work out SPECT and PET don't measure vascular diameter, just transport of radioactive element - there is no remote sensing technique for vessel diameter.  Since its' first use the doppler method has been acknowledged to measure vasoconstriction: "Vasoconstriction therefore induces an increased LDPI signal."  (7012)

  The main reason the article gave for dismissing vasoconstriction is that there was no pathmorphological measurements of it in schizophrenics; and it said: "...high spatial resolution of imaging procedures such as PET and SPECT may result in further understanding of the pathophysiological processes of mental illness and thus may contribute toward more effective therapy."  Two following facts - reduced perfusion, and mitochondrial HIF transcripts - convince me there is such a state.

A PET study of vascular engorgement and neuroleptics on the caudate nucleus found the more potent D2 antagonist, the more blood flow there was to the region and the more metabolism (which I assume is oxygen metabolism too) there was(120).  This test was done on schizophrenics.  The left basal ganglia was the only area in the brain to show a significant change of p<0.01 off and on medication.  The testing agent was HMPAO which is for perfusion.  This calls to mind the objection in the second paragraph which was that there would be a decrease in brain perfusion.  A statistical difference of 0.01 indicates on average there was good, but not perfect solution. 

The relationship between perfusion and vasoconstriction is stated: "... dopaminergic terminals form synapses in close proximity to the cerebral vasculature and dopamine agonists have been shown to cause vasoconstriction133 and a global reduction in cerebral perfusion."(226)

The body has natural defences against continuous hypoxia; but whether this applies to the brain has not been thoroughly researched.  Reduced vessel size begins or increases hypoxia: "...that constricts resistant vessels.  This reduced flow causes tissue hypoxia.  The more hypoxia a tissue receives the longer it remains hypoxic..." but metabolites build up and eventually override the vasoconstriction (137).  Does such a mechanism exist in the brains of humans? One study said its' results were "...not consistent with such a ‘vasomotor escape’ phenomenon" (136) [this article is the most recent to comment on human vasomotor escape], whereas it seems to be present in rabbits (145) and is present in other structures in humans (244).  Yet another study had to conclude that such an 'escape' could no longer be assumed for humans with sympathetic stimulation (245).  In any case, what degree of hypoxia is necessary to induce the escape phenomenon is not clear; dopamine constriction and any need for escape is an unresearched topic; and the question is only academic as reduced perfusion and (see (B)) HIF transcripts provide hard evidence).

Further autopsy proof of vasoconstriction will be impossible to find if the vessels have just vasoconstricted and haven't deformed and there is no calcification, according to one authority (Pers Comm. 11-05-09); as after death the vessels go back to their normal size.

To explain the difference in volume, causes have been speculated to be vascular or neurological (45); a smaller striatum could be due to reduced glucose metabolism (117), which may be to spare the brain from psychosis; and hypoxia and glucose metabolism are related (118); metabolism being reduced in hypoxia (119).  Considering  dopamine receptors as abnormally active and vasoconstrictive unites the two schools of thought - vascular and neurological.

(B)

Finally, if hypoxia were to continue into adult life we would expect to see more transcripts of Hypoxia Inducible Factor, as it is present during hypoxia and degrades during normoxia.  The prefrontal cortex is hypothesised to play a crutial role in schizophrenia in that it only comes online in sexual maturity - when the disease becomes manifest (236). 

"Two hypoxia-inducible factors (HIF-3 and HIF-1) were significantly increased at the transcript level in the schizophrenia prefrontal cortex." (25)  Further, "We have not identified a single unifying cause of the illness that could fully explain the disorder; however, the majority of our results support a state of intermittent or chronic low-grade hypoxic stress or, perhaps, local ischemia within the schizophrenia prefrontal cortex (possibly due to abnormal cerebral blood flow)." and "To ensure that the antioxidant activities and the metabolic dysfunctions that we observed were not a drug effect, this study included seven drug-naïve and four minimally antipsychotic-treated schizophrenia patients (2500–6000 lifetime fluphenazine units). The drug-naïve patients showed similar metabolic and antioxidant disturbances when compared to the antipsychotic-treated group (Figure 1c) and no correlation was found of the mentioned differentially expressed genes with fluphenazine equivalent drug exposure (see supplementary notes)."

Another study repeated the same results (not mentioning HIF but downregulation of the respiratory genes).  However, because only two unmedicated patients were included they could not exclude the influence of antipsychotics (237), which the above study was able to do.


And the disease began in neurodevelopment: "Oxidative stress that can lead to DNA damage, protein inactivation, altered gene expression and apoptotic events, robably starts in SCZ during neurodevelopment. The close connection of these mechanisms to neuronal plasticity suggests that an oxidative component may be relevant to disease pathogenesis" (233).

(C) Vasoconstriction is part of Reversible Cerebral Vasoconstrictive Syndrome and CNS Vasculitis.  RCVS is short term and has focal vasoconstriction (299), is a new diagnosis and does not lead to psychosis.  CNS Vasculitis is long-term and does lead to psychosis.  RCVS involves the Circle of Willis, which, if narrowed in part, has enough redundancy to avoid ischemia - tissue hypoxia.

(D) Russian studies of schizophrenia show alterations to immune function, before treatment with neuroleptics, after it; but after HBOT treatment the immune system is normalised.  Hypoxia alters the immune system.

However, although this is convincing to me it may not be true, as in a personal communication with a leading scientist, he said however that there is no hypoxia in the schizophrenic brain (but, he later said he wasn't qualified to comment on the information just presented), and that brain volumes increase when anyone is placed on antipsychotics (01-05-09).  A scientist in the same area said they think there is something wrong with the way the striatum functions, rather than perfusion. However,  Causes have been speculated to be vascular or neurological (45).


(E) A type of chorea (chorea is sometimes caused by hypoxia) - dyskynesia - is associated with neuroleptic naive schizophrenics and their relatives.  (8011).  Dyskynesia associated with hypoxia is normal in Cerebral Palsy.

Military personell are advised that a sign of acute mountain sickness is incoherence. 

 

A new article has found that fetal hypoxia is responsible for various types of 'stereotypic' or distinct pathologies.  The hypoxia causes a signalling pathway to be disrupted and various frequencies of brain wave (which are meant, partially, to harmonise the brain) to be disrupted.  It is called 'Stereotyped fetal brain disorganization is induced by hypoxia...'

 

 

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In 2003 Psychiatry and Clinical Neurosciences (231) published a story of monozygotic twins who were born discordant for schizophrenia.  During the prenatal period the mother had proteinuria - a symptom usually in late preganancy and accompanying placental hypoxia (232).  The affected twin had a much lower birth weight and enlarged ventricles.  As a child she was noticably less social and even though the pair learned to walk in a normal time, the affected one learned somewhat later than the other.  At school the affected twin soon gave up sport for a reading club, while the unaffected one continued.  Scans showed damage to the cortex of the affected twin and she had poor medication response.

One study has shown that proteins with additional fragments show increased permanent stable and cooperative folding (8020)- increasing as the fragment increased; and Dr Seeman found additional fragments in schizophrenic d2 receptors. 

 

According to the web,  fluoxetine and  diazepam are effective against hypoxia; whereas saffron, while it is debated if it blocks dopamine reuptake, gave one user: "my dose of 250mg gave me the feeling of about 30mg of MDMA" and olanzipine works better in delerium cases without hypoxia.   Infact on trying saffron (when I was taking fluoxetine (which has 1000 times affinity for the sigma site than saffron and fluoxetine is an agonist) I first found myself refreshed; but six hours later on the second try I found myself irritable.  I think the d2 receptor has been programmed to create hypoxia and supplementary cures like saffron cause the receptor to battle against it.  So I tried it again a week or so later and after a week's twice daily drink have had no bad results.  I have read that too much saffron can be lethal and that saffron can act as an abortifant too.

One summary said the general impression of a number of studies was that fetal hypoxia was associated with poor medication response and prognosis, independent of age (170)   This is consistent with the methamphetamine model of schizophrenia [as mentioned before, amphetamines work by a hypoxic mechanism].  One report says methamphetamine provides the perfect model of schizophrenia 1.  It says meth kills serotonin and dopamine cells and that this damage is irreversible as the cells don't grow back. [for references see p2].  However, frank psychotic relapses can hopefully be prevented.

 

One book used the phenomenon of 'cognitive distance' from symptoms, where sick people show less distance(302) other authors have said: "Antipsychotics do not eradicate symptoms, but create a state of “detachment” from them" (305)

Enhancing the hemoglobin's potential to deliver oxygen by EPO has helped schizophrenics regain cognitive capacities (although when delivered at that stage have not altered the pathology).  Nevertheless, the technique has been called 'proof of principle' by Ehrenreich.

Remember if human brain blood vessels have no vasomotor escape reaction (as mentioned before) it is nothing to do with your way of life that causes the vasoconstriction - or an additional fragment - on the d2 receptor and it is not your fault.  Your lifestyle can exagerate symptoms though. 

If vasoconstriction is a cause of schizophrenia; avoiding excessive vasoconstrictors should help.  I have found this in my case; even though I still drink now and then; particularly as an aid to socialization - the only thing to remember is that once endogenous dopamine is built up, it will later be released.  So in my case I try to keep vasoconstricors to a balanced level.  The best cure for schizophrenia is to get to it early with antipsychotic drugs.  If you have permanent damage to serotonin axons (as evidenced by psychological discomfort (see next page)) or dopamine axons (as evidenced by negative symptoms, why not enjoy moderate drinks of coffee etc. Even though SSRIs restore some density to the serotonin axons, they don't restore its' length, so the damage is permanent.

In cases of Reversible Cerebral Vasoconstrictive Syndrome patients are advised not to consume vasoconstrictive substances (273) and there is improvement - but it won't get rid of other causes such as inflamation by the immune system or dopamine in schizophrenia.

Have fun when you can.  Laughter increases vasodilation, seriousness or stress increases vasoconstriction.

With even strict abstinance of coffee and alcohol relapses will still occur, but in experiments these drinks are abstained from perhaps because they increase the same metabolites which cause relapses.  Adenisine A2a and D2 dopamine receptors have a see-saw relationship.  Treated schizophrenics show no deficiencies in peripheral adenisine at least.  Caffeine antagonises the A2a receptor, thus promoting the D2 (psychosis) receptor. For the possibility of new antipsychotics based on this reaction, see (229).

In the test tube, sodium converts d2high (the psychotic state of the receptor) to d2low (275), they point out that in the petri dish brain samples with d2high, are converted to d2low by NaCl. Even with the benefits of this new method, Dr Seeman recommended future experiments to be done in hypotonic medium to halt the conversion to d2low.  While stable schizophrenics show no difference in the sodium content of their CSF (276), subjects who are in need of hospitalisation benefit significantly from the addition of sodium valpoarate until they become stable (after a month) (277) and chronic schizophrenics often have hyponatremia (278)
Several of the body's natural salts increase sodium naturally(279).  As one, AVP (Arginine Vasopressin) is inhibited by caffeine (280) .  Dr Simola et al have shown an increase of 126% in d2high sites in caffeine sensitised rats - this seems to be for a high amount of caffeine (15mg/kg) (311).

The same leading scientist, said (Pers Comm April or May 2009) if you like the taste of coffee you should have some.

Even moderate amounts of alcohol affect the brains of schizophrenics: "Despite lower alcohol exposure than in pure alcohol dependence, the comorbidity of schizophrenia with AUD compounds or accounts for brain volume abnormalities of schizophrenia in cortical prefrontal (Mathalon et al.2003), cerebellar (Sullivan et al. 2000), pontine and thalamic (Sullivan et al. 2003) sites." (154).  I can personally testify that increased alcohol use sometimes corresponds with worsening symptoms.  During about the first five years of my schizophrenia I would drink five or six beers to calm down before I went home.  However, I thought the short-term benefits were there - temporarily my symptoms reduced, but these were the worst years of schizophrenia.  However, Dr Seeman et al (310) have shown that d2high sights are elevated 360% at least 8 days after ethanol and return to normal after two weeks.

Substance use - as estimated by cannibas use - worsened psychotic scores.  But even those who abstained had a symptom score of 60 before treatment and 38 after (a normal score though is 24 if measured on all criteria) (188).  The difference between those who abstained and those who continued to use was fractional, indicating the medication was the main reason for improvement (see table 4 in the reference - click on the PDF).  Yet, in my experience, the small difference is that between psychosis as a nagging doubt and as a conviction.  The BPRS scores show the difference is between mildly and moderately ill (291).  But these lifestyle factors are unlikely to cause all the symptoms of schizophrenia as we can gather intuitively from the fact that the Mormon church does not drink alcohol or coffee but still has schizophrenics.

One study noted the eventual failure or tolerance of antipsychotics in many cases: "One possible explanation for the progressive loss in the ability of antipsychotics to suppress amphetamine-induced locomotion is an increase in dopamine availability over time, which would surmount the antidopaminergic effects of the antipsychotic. However, in vivo microdialysis measurements revealed that amphetamine-induced increases in extracellular dopamine were unchanged during haloperidol treatment."..."However, microdialysis measurements are a function of release and uptake and the lack of change in dopamine overflow in our study could be reflecting increased release and increased uptake or, alternatively, decreased release and decreased uptake..."  So while this statement is not the conclusion to the article, I take it to mean that we wouldn't want to consistently do anything which increased dopamine release.(159).  This is a conclusion Dr Seeman approves of (Pers. Comm 21-02-09).

If alcohol has a proven effect on brain regions, perhaps it accompanies other lifestyle choices with a similar effect. Just as alcohol and caffeine are, nicotine is also a vasoconstricor as is lack of condition.  Physically fit people have better cerebral blood flow, cerebovascular reserve, mean arterial pressure and cerbovascular conductance (225).  Some of the antipsychotic manufacturers have sites on the importance of maintaining a healthy lifestyle - but the medication is still essential, you could say we only have the breathing space the medication allows.
Good sleep is essential, especially REM.  During REM sleep perfusion is increased to grey matter.

As a patient there were times when delusions were so intense I couldn't help myself. But now (after 10 years) I think there are things I can do for myself; for example:
"Typically 15% of schizophrenics have a good outcome...For those with a good outcome positive and negative symptoms gradually dissipate after the first or few or few psychotic episodes, possibly never to return. This is more likely (but not guaranteed) to occur with:" ...Developing and sustaining a healthy lifestyle (eg avoidance of alcohol and illicit substances, obtaining a job to help self esteem, regular exercise, healthy diet) with a goal of independent living."(153)  These factors could be a symptom though of whether the antipsychotic is binding and blocking the d2 receptors enough However, one of the criteria for a good outcome was strict adherance to treatment - a good outcome may not be treatment free: infact my treatment was going very well until I missed my medication for a few days because I was out of work, and the condition has never been as good since. There is a study recruiting participants, started in 2008, sponsored by NIH which will look at the effect of lifestyle intervention.

Only theoretical solutions have been put forward for the removal of hypoxic disconnection in cognitive dysmetria, so established symptoms will remain though.




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Delusional? themes and hallucinations (*DSM)

This section also reflects my own experience.  I went to all possible lengths to make amends for what, in horror, I remember as past wrongs - all of which were unnecessary; and for a long time I was preoccupied with a dread that my gender was changing - once again this was unnecessary. The area of the brain concerned with suppressing thoughts has less perfusion in schizophrenics - dopamine from hypoxia recalls these thoughts if they are existentially important to the patient.  I found that in some cases the topic of delusion was vasoconstrictive - which would be why explanatory delusions are invoked. Cultural influences have "a decisive factor in shaping delusions"(177)  For example, delusions of guilt and punishment are frequent in a Western, Christian country like Austria, but not in Pakistan - where it is more likely persecution. Cultural factors have a decisive influence in shaping delusions (178).  That dopamine is responsible for delusions is presented in Parkinson's disease patients treated with l-dopa and having delusions - although only selected case studies, several were afraid of the police  (179) similar to amphetamine induced 'bull horrors' (a feeling that would normally be automatically repressed).   "...dopamine has been suggested previously to contribute in a related way to pathological exaggerations of fearful salience, as a motivational component of paranoia in human schizophrenia." (242) A reference on the net says methamphetamine users experience hallucinations if theyhave been using for days.  This article shows, when dopamine is steadily increased, serotonin increases up to a certain point, but then begins to deplete.  This would be the cause of hallucinations; and then because of serotonin excess, guilt and depression predominate in recovering meth users,

Don Quixote, his horse Rocinante and his squire Sancho Panza                                                        after an unsuccessful attack on a windmill. By Gustave Doré.                                                     http://en.wikipedia.org/wiki/Don_Quixote       GNU copyleft.

Topics of delusions.

The relationship of delusional theme to background culture is explicitly stated again: "While religious delusions and delusional guilt are primarily found in societies with a Jewish-Christian tradition, these contents are infrequent in Islamic, Hindu or Buddhist societies...(180).  And again in Roman Catholic (15.5% of schizophrenic patients had delusions of guilt) verses Muslim (3.8%) patients (243).  The abstract said Muslim patients had fewer negative delusional identities.

On another tact, but on delusional themes: repeated research results show delusional themes occur according to the main existential concern of the patient at a given age for their sex (205) (206).  In my own case I found out later that each of my siblings had the same theme; only not to delusional intensity.  This would rate as mild on BPRS.

In determining delusions chemical overreactions set the mood; ie serotonin, noradrenaline and dopamine create a aggressive or hypoactive mood; the mood is modified by the personality encountered - for example noradrenaline, accompanied by an avoidant personality is likely to produce guilt - the personality is described in terms of the dominant culture.  There were reports of violent criminal suicides having shorter serotonin axons too.

"Possibly reflecting a higher level of homophobia in contemporary Western societies, European and North American male schizophrenic patients often express severe doubts about their gender identity...Such preoccupation is rare in non-Western patients with comparable diagnosis (K.M.Lin 1987)" (307).

 

Guilt is vasoconstrictive; and religious images have been measured according to vaso constriction/dilation in zealous followers and the fear produced vasoconstriction: Seery, Mark D (30/09/2005). "The nonconscious influence of religious symbols in motivated performance situations". Personality & social psychology bulletin(0146-1672), 31(9), p.1203.  Morbid jealousy has been invoked in a subject by small doses of amphetamine showing vasoconstriction plays a part - could this also explain alcohol related jealous violence?  A case study is reported of delusion of jealousy in a patient with hypoperfusion (9003).


Retrieving the topic.

My own thoughts are: perhaps the mechanism for this is imperfect voluntary repression of thoughts, or dopamine driven recall of repressed thoughts - repressed because of the importance of the cultural or psychological importance (according to criteria mentioned above)..   There are said to be only seven important themes to humanity, (which one could imagine being consistently monitored and repressed): hypochondira, religion, guilt, love, jealousy, grandeur and persecution (253)..  My delusions are of normal male concerns, which are exagerated.

If, given similar amounts of dopamine, or having similar dopamine sensitivity, schizophrenics have similar delusions, it says something for our similar experiences.

Andrew Sims has said that the top 'Factor mainly concerned in the germination of delusions' is Disorder of brain functioning (282)  Sims quotes Ian Brockington in listing these criteria, and says these and other theories assume delusions are primary, and not secondary to a personality.

In 1991, Brockington included as examples of 'disorders of brain functioning': "...amphetamines, and the influence of endogenous pharmaceutical agents ..." (283)
One such 'endogenous pharmaceutical agent' is dopamine.

Proving the dopamine hypothesis in schizophrenia has had an inconsistent success rate.  One researcher group sought to eliminate the heterogeneity of schizophrenia by studying a similar syndrome unencumbered by other complications.  Higher levels of dopamine are needed to sustain certain delusions as is confirmed by a study on delusional disorder: "...pHVA [homovanillic acid] was employed as a "state marker" of the [delusional] disorder...": Delusions of persecution and delusions of jealousy were able to be differentiated by the amount of acid that was released when the dopamine was digested. (284) 

Anecdotally, the correlation of delusion with dopamine is confirmed by amphetamine use (a dopamine model for some schizophrenias).  Very high and rare recreational use of amphetamine can produce Gender Identity Disorder delusions (which the DSM says are rare in schizophrenia),(285)(286)(287) while low medical doses of amphetamine can produce more common morbid jealousy(288).  Similary, two cases reported using high doses in order to become transvestites (another Gender Identity Disorder); cases of which have been reported in schizophrenia(289).  Jealousy, a common delusion, ranked requiring less dopamine in the HVA experiment and the 'anecdotal' amphetamine cases.

 

Anxiety disorders can also be treated with D2 antagonists in animal models (334) - allowing extinction of conditioned fear In the sense that preoccupation is a conditioned response (because the topic relies on conditioning by society); memory of spontaneous extinction of the response is reliant on the PreFrontal Cortex and Supplementary Motor Area (333); everyone has these regions and probably uses them, but it is an area which has less grey matter in schizophrenics than controls (62)(as reflected by Infant Motor Delay).  If the delay in walking is an analogy for later delusions it predicts a less capable or coordinated response to these delusions. To be an explanatory delusion the memory must match the conditioned literal definition.  So only the memory of the preoccupation remains if the salience is fearful; if the salience is grandiose presumably such grandiose thoughts, usually suppressed by the Supplementary Motor Area (because of conditioning that such thoughts are inappropriate) are drawn out.  The inadequate grey matter leading to the the extinction response explains long-term delusions rather than inappropriate feelings which disappear quickly.  Changes in 'fractional' white and grey matter can be caused by hypoxia.

 

It is not past conscious suppression of a feeling which leads to psychosis as everyone does this: "Parents, culture, religion, and society all approve and reinforce the suppression of emotions--in fact, it is an essential part of our socialization" (as at 08-12-09).  This site asks the question, which everyone could relate to, " Have you ever felt racial or religious prejudice? Did it make you feel guilty or ashamed? Did you try to suppress it?"

Personal examples.

Since I've had schizophrenia I've had trouble on social occasions repressing some feelings (the Supplementary Motor Area being part of the premotor cortex - which was the crucial area mentioned in 4.1).  Sometimes the repression should have been automatic.  As one example I was walking home from work at night in a very safe place in the city and suddenly a terror of people gripped me.  One of the pedestrians noticed and made a noise like a chicken.  Another time a feeling of disgust came over me for everyone - I couldn't even look at people.  I rang my doctor and he said to increase my medication and it disappeared in a couple of days. (Although some of my long-term delusions have had past voluntary repression.)  So schizophrenia is not the result of suppressing homosexuality, but every inappropriate emotion or thought.  The theory of repression is that it is a normal function which is unable to be done by schizophrenics: "Repression ... appears to be ubiquitous...everyone seems required to expend a more or less amount of psychic energy in keeping inevitable persisting and infantile strivings... out of conscious" (Schafer 1954)(184). It has been found that the hypothalamus, which is the oral and sexual pleasure centre in the brain, has vasodilating sympathetic nerves from the motor cortex.   A dysfunctional premotor cortex then shows why schizophrenics are overwhelmed by infantile desires.  

 

 Amphetamine (202) and other drugs have been used to recall repressed thoughts - showing dopamine will do this, bringing about an 'exceptional self-honesty'.  LSD was used originally for that purpose, and one old Nature report described it as a 'potent' dopamine agonist (207). It has been noted that LSD mimics schizophrenia.  Those thoughts I had voluntarily repressed would not disappear with medication, but were resolvoved spontaneously (unexpectedly) by socialization (239) to remain only infrequently intrusive and with diminished intensity.  The article in Science says for most people this happens over time: "...in tandem with systems involved in extinction of conditioned emotional response or in the cognitive reappraisal..." (204) .  So, yet, other preoccupations which contain a truthful memory, but were resolved by extinction over time (equally true memories); are reduced to the recurrent preoccupation.

The theory behind voluntary and involuntary repression.

Scientists at the University College London found automatic, unconsciously triggered actions to be repressed by the Supplementary Motor Area.  Professor Masud Husain was the spokesperson (as at 01-06-09):"Dr Petroc Sumner, Cardiff University, said: “When visual stimuli automatically activate motor planning in the brain, this activation can be very quickly suppressed again, presumably so that we are not forever making actions triggered by what we happen to see. This all happens ‘behind the scenes’ without our conscious knowledge. In the patients, however, we found no suppression [because their SMA was damaged by stroke]. Therefore, we’ve discovered that the supplementary motor areas play an important role in suppressing automatic activations. We believe automatic triggers and how they are suppressed are critical to understanding how we overcome habits, and make choices between alternative actions.”"

 Research (203)(204) shows that (voluntary repression as defined in (203) is a real phonomenon and involves the presupplementary motor cortex (171) an  area being involved in the coordination of thought and action, (part of the premotor cortex - which is implicated in social cognitive dysmetria).  Its' volume is reduced in schizophrenia.  Once again the volume may be due to perfusion.  In the supplementary motor area in schizophrenic patients, perfusion is increased with the substitution of atypical antipsychotics for typical (174).  My preoccupations have been with things that would be repressed by Christians.  I was a Catholic growing up and used to go to church twice a week, later became a Jehovah's Witness.  One study, the results of which have been reported again and again shows Jehovah's Witness are five times as likely as the general population to have a diagnosis of paranoid schizophrenia (182), both denominations are homophobic to some degree - paranoid schizophrenia is sometimes accompanied by questions on sexuality.  The article from the journal Science (204) includes a footnote in which it says that Freud used the term 'repression' for both conscious and uncounscious repression; and the article itself was concerned with conscious repression: "Thus, the current findings provide the first neurobiological model of the voluntary form of repression proposed by Freud."

Singer said that only if science could show a 'qualitative' difference between unconscious and conscious repression could a destinction be warranted (241), and as the above examples show, whether voluntary or automatic, both processes access the preSupplementary Motor Area.  A difference is that the thoughts can remain uncouscious or be conscious.  In the conscious case: it is often said that some aspects of delusions may be true.

The author of one article considered the possibility that dopamine as amphetamine would act in an organizational function for delusions on past significant (salient(dopamine)) behaviour (181) - I suppose this could be why paranoid schizophrenia is an organized system.  The dopamine is shown to disallow proper suppression by the size of the supplementary motor area.  Hypoxia causes more dopamine.  More dopamine is needed to organize different delusions (185).  When the first episode arrives, the schizophrenic has a somewhat culturally normal store of memories which the influx of dopamine makes delusionally intensive with delusional conviction.  The memories or thoughts are originally normal as delusions have a gross distortion.  I have even had memories which I acted on which the other person involved said never happened.

 

As shown previously though schizophrenics have trouble with empathy which whould usually override literalism.

I think hallucinations could work in a similar way; where the filtering mechanism fails the schizophrenic in his waking hours and dream-like symptoms happen; possibly with dream-like organization.  How else do we explain bizzare delusions - involving Martians etc.

It seems prenatal programming can't be overcome.  Philip Seeman said to me the new drug mentioned below will not have an effect on schizophrenia; and you can see this in the only transient results of HBOT and senile psychosis.  Hyperoxemia can cause vasoconstriction though which would explain the negative reasction of some patients.  If TSC blocks the reuptake of dopamine it will only make symptoms worse.  Saffron has even been said to cause delerium.  Ginkgo biloba is being widely discussed as a preventative against Acute Mountain Sickness - which can cause psychosis - and there have been some cautiously optimistic reports with respect to schizophrenia (with your medication).  The medication itself is a combattant against hypoxia (see under 'Is there a chance I can take).  I tried saffron  because I was taking fluoxitine, which has a thousand times more affinity than saffron to the sigma receptor and is an agonist.  Additional fragments form in a protein when it is in the 'high'  position and are a sign that it is about to be degraded (8019).  Dr Seeman showed the D2 receptor shows  an additional fragment in schizophrenia.  This means the high affinity of the receptor is permanent (I think).  This explains why various methods to reduce hypoxia (including saffron) only work temporarily as the receptor reinforces the hypoxia.

 

 

 

Sodium reduces d2high to d2low, but hypoxia inhibits sodium transport (113).  On hypoxia, sodium leaves the plasma and enters the cell in large proportions (114)  I read in Dr Seeman's writing that some antipsychotics may be more effective in reaching the d2 receptor because they can penetrate the lipid substance of the cell, so the body may be trying to combat elevated dopamine.
Speculatively (in a land of boundless optimism) avoiding vasoconstriction could result in salt getting to d2high receptors which are on the membranes - and salt goes into the cell in hypoxia - and converting them to d2low and reactivation of the d1 - d2 receptor link (see section below "Other damage by hypoxia").  If this were true the reptile in us would be sure to be 'abyssed'.  However, there is no study which indicates of guaranteed cure for schizophrenia by exercise or diet.  In one study, seemingly from a general health point of view,  "Regression analysis revealed that schizophrenia by itself or in interaction with demographic variables influences physical activity as well as alcohol, nicotine, and healthy grocery consumption"; "Schizophrenia patients are an appropriate target group for public health interventions. They need information about a healthy diet and motivation to prepare their own meals, to quit smoking, and to exercise." (165).  This and other studies emphasise the prevention of comorbid illnesses.  Howerver, one study says lifestyle choices can affect, for example, chances of relapse (166) (improvement is aimed at by monitoring: sleep, diet, exercise, interesting activities, alcohol, cigarettes and street drugs (p56) - many of these things in large amounts, can give psychosis - ex. lack of sleep, excess alcohol or caffeine and total sensory deprivation).

Doctors define recovered as experiencing no more than mild symptoms (176) - so don't look for perfection.  With cannabis for example, those who abstained after treatment started attained a halving in their BPRS score (188), closer to a normal score.

There is a study being done until the end of 2009 which uses oxygen therapy.  However, will it be able to overcome fetal programming?  Positive, but old results, have come from Russia with the use of Hyperbaric Oxygen Treatment.  A recent review of Russian literature on schizophrenia shows HBOT to be possibly a standard method of treatment, based on different theory of causality, but presumably effective nonetheless (322).  More recent results (2004) come from China, where it was concluded: "HBO is very effective to rehabilitation of chronic schizophrenia." (312)  A recent Russian study showed: "On the thirtieth day of hospital treatment the severity of psychological symptoms was not significant;" after treatment with neuroleptics and HBOT and those treated with oxygen had a much longer interval before relapse (313).

 

In the study by Isakov IV et al (323); HBOT treatment actually made acute schizophrenia worse and was stopped.  A similar worsening of symptoms happened in another small study of the effect of exercise; where one participant had to withdraw -  however it helped others.  However for most other cases where there was psychopharmacology resistance; the oxygen treatment helped some and greatly helped others.  Especially those with a chronic course and hysterical exacerbations.  Interestingly it improved motor coordination and socialization in some subjects.  The only Western report of HBOT being used for psychosis is, "Hyperbaric Oxygen and Senile Psychosis"  in which case: "The effect, although it lasts longer than expected, is only transient (mean twelve hours).  Nevertheless, results show that mental deterioration in senile psychosis can be, at any rate temporarily, improved." (324)

.  There is a new drug which effectively treats hypoxia (326) and is safe in humans and improves oxygen delivery in the brain and  I was hoping it may be useful in schizophrenia - however, Philip Seeman has said it definitely won't (pers comm13-11-09);  Dr Prabakaran  was interested in my suggestion of TSC to see if it could help according to his research on hypoxia (25). (pers comm. 23-11-09), still believing hypoxia had a major role to play in schizophrenia. and kindly complimenting this site.

 

Recently there have been some positive, credible, (yet by no means conclusive) studies into Ginkgo Biloba's affect assisting regular antipsychotics (403)(404).  This supplement has antioxidant and anti-hypoxic properties and there is information on the internet about it.  One report says Acute Mountain Sickness (a form of psychosis at high altitude hypoxia) was prevented in many cases and for those who had it its' severity was diminished (405).  Actually there have been many favourable studies, with reference to AMS and one study which found it to be non significant did so, not because of Ginkgo Biloba's failure, but for some reason the placebo worked too (430).  A number of studies are on the web about Ginkgo's affect on schizophrenia.  A lot seem to be by the same author.  Another one mentions significant improvement in those with refractory schizophrenia on Olanzapine (800).  A similar study using Haloperidol found Ginkgo Biloba extract more effective than placebo on positive and negative symptoms (801); and there was evidence of antioxydent affect.  The are negative studies however.  One is most recent with Clozapine which showed an improvement in negative symptoms but not positive.  However, clozapine is a strong antioxidant in its' own right.

 

Schizophrenia seems at first an arbitrary combination of factors drawn from the same source: hypoxia.

In conclusion, A Jablinsky has said, when referring to genetic polymorphisms and neurobiological deficits: "Such polymorphisms and deficits need not be intrinsically pathological and may represent extreme variants of normal structure and function. Above a certain density threshold, their additive or nonlinear interaction could give rise to the diagnostic symptoms in probands, but subclinical manifestations as endophenotype traits will be detectable in otherwise healthy people, with a higher relative risk in biological relatives of probands." (54)



Thus hypoxia (as indicated by statistical values for poor motor coordination or late developmental milestones) could be the invisible 'developmental majority'(16)(20)of schizophrenia (just as cholesterol is to heart disease, smoking is to lung cancer and sunburn is to melanoma), and has a retrospective diagnostic value. Measuring with prenatal hypoxia takes into account the gestation period, which tests for perinatal hypoxic insults may not detect.  However, one report, after acknowledging preliminary motor deficits said: "No powerful risk factor, premorbid sign, or risk indicator has been identified that is useful for prediction of psychoses in the general population." (55)

 

 It has been objected that schizophrenia cannot be caused by hypoxia as disorders known to be caused that way (cerebral palsy for ex) are not comorbid with it.  However, a better understanding of cerebral palsy reveals that schizophrenia and cerebral palsy cannot be comorbid (or at least not frequently) as the damage done to cerebral palsy d2 receptors renders them unfunctional as revealed by the fact that radioligands do not bind to the striatum d2 receptor because they are so damaged(8016).  It turns out that rather than a continuum, the disorders of hypoxia are more discrete.  Behavioural disorder or psychopathy for example shows an increase in the volume of the caudate nucleus.  Increases in volume and thus blood vessels is a remnant of post natal adapatation to hypoxia where additional blood vessels and microvessels are supplied.  The same is true in psychopathy and the striatum more generally - it is enlarged.  In schizotypal people (as the prevriously mentioned quotation says) the volume is reduced - revealing a different style of adaptation to hypoxia.

 

Perhaps the timing of the insult is important as illustrated by methamphetamine's influence on the striatum.  In those exposed to methamphetamine in the womb the caudate nucleus remains small after birth (8018); whereas for those who take methamphetamine as adults and are then abstinent, the striatum is mostly enlarged (8017).  (Recall amphetamines work via hypoxia).

(Dopamine receptor blockade only treats part of the problem).

On a molecular level hypoxia is shown as well. Prabakaran et al (25) in a search for 'disease signatures says: "Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls". The study rules out the effect of antipsychotics by using non-medicated patients partly, and controls for many other factors including brain pH, The article says microvasculature abnormalities could explain cellular hypoxia (for specific reasons the article names hypoxia as the probable cause of oxidative stress) and energy depletion, but p694 says an increase in oxygen deprivation causes an increase in glucose demands. Glycogen is a brain energy source that can be quickly mobilised in response to abnormally high glucose demand or insufficient glucose supply (such as under hypoxic conditions) p694.

Another sensitive indicator of hypoxia would be memory dysfunction, as hippocampal volumes are reduced in a significant number of schizophrenics (28).

 

Hypoxia provides an explanation of an anomoly.   One study reports that it is curious that those with treatment resistant schizophrenia have lower catecholamines in CSF .  In hypoxia dopamine and adrenaline have different responses in different organs in different species (402)

Studies have found volume differences in the striatum and caudate nucleus (areas of most dense d2 receptors). Causes have been speculated to be vascular or neurological (45). These structural differences provide evidence of a post gestational consequence of Minimal Brain Dysfunction.


Many genes are triggered by hypoxia and have been listed as candidate genes for schizophrenia. While two percent of genes are regulated by hypoxia (p256), 50% of schizophrenic candidate genes, that have been reported at least twice, are triggered by hypoxia (p253)and could be expressed in the vasculature.(27)

Sodium reduces d2high to d2low, but hypoxia inhibits sodium transport (113).  On hypoxia, sodium leaves the plasma and enters the cell in large proportions (114)
The dopamine receptors are on the nerve cell membrane (281)

A symptom of striatal hypoxic damage is lessened ability to learn movement rules for behavioural rewards for material necessities(48) - which would seem to indicate work tasks etc. Infact, thinking may become ego-centric rather than socio-centric (66). Occupational dysfunction is a diagnostic criteria for schizophrenia.

Mallard et al have done experiments suggesting that placental or umbilical insufficiency may be responsible for many diseases including schizophrenia. These experiments even show enlarged lateral ventricles - similar to 50% of schizophrenics. Although the article points out hypoxic complications, the resultant animals were also growth restricted.    "Recently, it was shown that a number of obstetric complications are associated with early onset schizophrenia and it was proposed that fetal hypoxia was a common denominator in most of these cases and, therefore, a risk factor for some types of schizophrenia ( Verdoux et al., 1997)"; they say.
(28)   Hydrocephelus provides an interesting analogy to schizophrenia monozygotic heritability.  One study, not concerning schizophrenics, found hydrocephelus concordance rates of 50% (240), yet the above information suggests it is a developmental or environmental problem.

A translocation in DISC! is present in fifty times schizophrenics and related cases than controls.  Hypoxia may play a part in this.  This article says it plays a part in transcription; but maybe also translocation - as mentioned below hypoxia introduces chromosomal breakage points.  Haploinsufficiency has been speculated as a reason for it (8009) but again, this can be caused by hypoxia.


Astoundingly, a report shows an actually increased density or high density of D2R in the striatum after hypoxia: " It has been shown that the D2R density in the striatum in infants might be upregulated after hypoxia (Tranquart et al 2001)(29)(30)

In one special case of maternal hypoxia - it is known that the risk of schizophrenia is higher where the mother has had influenza virus: "...An infection of this level of severity could also compromise maternal oxygenation, leading to fetal hypoxia, a putative risk factor for schizophrenia..." (304)

A Japanese case study of monozygotic twins with discordant schizophrenia draws attention to their different weights at birth and concludes hypoxia may be the differentiating factor:(31)

Bearing in mind that: "...The precise cellular and molecular events that underlie brain pathologies under hypoxic conditions are poorly understood..."(3); perhaps G proteins hold some sort of key. The gene responsible for general regulation of G proteins, RGS4, has been implicated in schizophrenia (43) and responds to hypoxia.

G alpha proteins can be inhibitory or stimulatory types. (56). So the G alpha protein determines the signal. Interestingly, hypoxia disables the inhibiting G-alpha inhibiting protein, while not affecting the stimulating G-alpha protein (33)(33) The binding of the stimulatory or inhibitory alpha protein to the chain depends on the presence of a binding protein, which is upregulated in hypoxia and abolished with an inhibitor (44)). So in hypoxia we expect the Gprotein to stimulate the G coupled receptor. (Perhaps this is why mountain climbers experience hallucinations, and high altitude Peru has a higher percentage of schizophrenics in mental hospitals). Perhaps also, the prolonged affect of prenatal hypoxia is due to the presence of arrestins at gprotein sites like the dopamine receptor (69).  However, according to a 2008 article in Schizophrenia Research Forum, antipsychotics prevent some arrestins from binding to d2 sites (79).

One study revealed that mothers with hypoxic obstetric complications and mothers without had a correlation of 5.75% and 0.39% with their offspring having schizophrenia..  There is only a 0.04% chance, from these figures, that schizophrenia is not related to hypoxia (17)(17).  The study cited validates the method used in this article, as it too considered the equivalent of neurological soft signs to be an indicator of hypoxia.


Chromosomal breakage points related to hypoxia are of interest to schizophrenia research(35)(35)"Hypoxia has been shown to induce chromosomal fragility"(36).


Faulty axon guidance is reported to influence a number of diseases, including schizophrenia and can be influenced by hypoxia (38)(39)(39) There was a proximity relationship between hypoxic influence and the motor neurons:"We found that overexpression [of vab-1 (Variable Abnormal Morphology receptor)] in midline motor neurons and not in the HSN [Hereditary Sensory Neuropathy] neurons caused HSN axon-pathfinding defects..."(p897). "HIF-1–mediated upregulation of VAB-1 protected embryos from hypoxia-induced lethality, but increased VAB-1 levels elicited aberrant axon pathfinding. Similar genetic pathways may cause aberrant human brain development under hypoxic conditions"(Abstract). Reiterating a relationship between hypoxia and motor function.
As mentioned above, influenced G-protein coupling, through different molecular mechanisms (perhaps including a hypoxic or toxic threshold) alters d2 receptor dissociation constants. Perhaps this increases the sensitivity to dopamine by altering the d2 threshold (34
Most articles use the terms "hypoxic/ischemaic" when referring to prenatal injury. If minor ischemia is an interchangable factor, its possible permanence may be manifest in the lack of motor coordination and deficiency in gross motor skills mentioned previously. Calprotectin is detected in postmortem schizophrenic brains at a higher level than that of other pathologies or controls. It has previously been shown to be elevated in ischemaic lesioned brains. (57). Another study says, of newborns: "Calprotectin is already present in the first passed meconium, with higher levels in preterm and low birthweight neonates, as well as in neonates with some degree of perinatal asphyxia, as indicated by the negative correlation with 5'-Apgar score. These findings are probably secondary to both the immaturity of the intestinal mucosa and its hypoxic-ischaemic damage." (58)

 

Dr Seeman noted that general anesthetic converts d2high to d2low (411); one article noted that until an extreme reduction in oxygen, one anethetic prevents the hypoxic process (410).


Hypoxia also disconnects  the muscarinic receptors (104) which aid cognition

Hypoxia influences glutemate metabolism and receptors.

 

Catatonia; a distinctive feature of some schizophrenias can be caused by steroids; which are vasoconstrictive.  Hypoxia itself has been anecdotally associated with catatonia (6001) via CSF lactate measurements; which have been found to be elevated in schizophrenics - even appreciating concerns of effect of medication (6002)

 

In schizophrenia, D4 mrna is elevated three fold in the frontal cortex.  Hypoxia regulates translation and transcription..

Table of contents

 

Professor Seeman's  results while remaining the same have been reinterpreted as time went on, but they are solid, reliable results. You should know that, by using different experimental methods, Dr Seeman's initial conclusions had to be modified; but that the important thing is that by using this method on schizophrenic vs other populations the same result is always achieved.

 

 

This figure shows an increase in receptors which responded to nemonapride in schizophrenia.

 

Experiments reveal the nature of the schizophrenic brain as attracting methylspiperone, and nemonapride more than controls, but having about the same raclopride affinity.

 

 

Dopamine D2-Like Sites in Schizophrenia, But Not in Alzheimer’s, Huntington’s, or Control Brains;Synapse Vol 25 1997; pp137-146, for [3H]Benzquinoline; copyright 1997 PHILIP SEEMAN, HONG-CHANG GUAN, JOSE NOBREGA, DILSHAD JIWA, RUDOLPH MARKSTEIN, JA-HYUN BALK, ROBERTO PICETTI, EMILIANA BORRELLI, AND HUBERT H.M. VAN TOL Reprinted with permission of John Wiley & Sons, Inc.No rights are granted to use content that appears in the work with credit to another source. The authors say:"Therefore, although long-term neuroleptics may cause a twofold elevation in the density of 3H]SDZ GLC 756 sites, such a neuroleptic effect did not occur in the eight schizophrenia tissues with absent [3H]SDZ GLC 756 sites or in the nonschizophrenic cases where long-term neuroleptics were used" and also say the d2-like sites detected in this diagram could represent the d4-like sites in other replicated experiments and that these are probably d2 monomers GNU  


One point merits attention in connection with this graph.  The chemical used (a benzo[g]quinoline) stimulates an anticancer protein tp53, which is usually released in response to cellular 'insults' such as hypoxia; and I think it would be a shame not to mention that this graph shows some sort of exagarated response (or lack of response) to insults such as hypoxia;( confirming the diathesis-stress theory as well as cognitive dysmetria- which must be hardwired as the reaction occurred postmortem.  The insult of 'benzo[g]quinoline could be the uniting factor in its' multichemical affect.

I don't know if there has been an experiment where controls were given antipsychotics for some time too, before the ligand was applied and measured (although this could be the Huntington's group).

 

References:

(1) R.A. Hanford, Brain Hypoxia, minimal brain dysfunction and schizophrenia, American Journal of Psychiatry 132:2 1975 p192
(1b). Strauss AA, Lehtinen LE: Psychopathology and Education of the Brain Injured Child. New York, Grune & Stratton, 1947
(2). This reference is cited in a 2006 work, in giving a history of minimal brain dysfunction saying: "It was also noted that individuals who experienced perinatal brain hypoxia constituted a population at risk for minimal brain dysfunction, and that children attending psychiatric clinics often presented with illnesses or perinatal complications of a sort known to be associated with neurological brain damage (Handford 1975)."Disorganized Children : A Guide for Parents and Professionals Jessica Kingsley Publishers Ltd. Stein, Samuel M.p1353.
(3). NATURE NEUROSCIENCE VOLUME 11 NUMBER 8 AUGUST 2008 Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans - p899 Roger Pocock & Oliver Hobert p894
(4)(4). J.B.Pitcher, D.J Henderson-Smart and J.S. Robinson (2006) " Prenatal Programming of Human Motor Function" in Early Life Origins of Health and Disease Edited by: E. Marelyn Wintour and Julie Owens I v573 Part 4 Springer US p47
(5)(5).Golan, Hava and Huleihel, Mahmoud (2006). "The effect of prenatal hypoxia on brain development: short- and long-term consequences demonstrated in rodent models," Developmental Science, 9(4), 338–349
[ It seems there is no specific time for hypoxia to influence motor coordination - in the rat from prenatal to neonatal timing - the equivalent of human prenatal timing.]
(6). Golan, H. Kashtutsky, I. Hallack, M. Sorokin, Y. and Huleihel, M. (2004) "Maternal Hypoxia During Pregnancy Delays of development of motor reflexes in newborn mice" Developmental Neurosicience 26, pp24-29
(7).Hernan Picard, Isabelle Amado, Sabine Mouchet-Mages, Jean-Pierre Olie, and Marie-Odile Krebs (2007) The Role of the Cerebellum in Schizophrenia: an Update of Clinical, Cognitive, and Functional Evidences, Schizophrenia Bulletin Advance Access published June 11, 2007
(8). Matthew Derrick, Ning Ling Luo, Joanne C. Bregman, Tamas Jilling, Xinhai Ji, Kara Fisher, Candece L. Gladson, Douglas J. Beardsley, Geoffrey Murdoch, Stephen A. Back, and Sidhartha Tan Preterm Fetal Hypoxia-Ischemia Causes Hypertonia and Motor Deficits in the Neonatal Rabbit: A Model for Human Cerebral Palsy? The Journal of Neuroscience, January 7, 2004, 24(1):24-34; doi:10.1523/JNEUROSCI.2816-03.2004.
(9).Matthew Allin, Hideo Matsumoto, Alastair M. Santhouse, Chiara Nosarti, Mazin H. S. AlAsady, Ann L. Stewart, Larry Rifkin and Robin M. Murray (2001) Cognitive and motor function and the size of the cerebellum in adolescents born very pre-term Brain, Vol. 124, No. 1, 60-66, January 2001
(9b) E.B. Mukaetova-Ladinska , J. Hurt a, W.G. Honer, C.R. Harrington, C.M. Wischik (2002) Loss of synaptic but not cytoskeletal proteins in the cerebellum of chronic schizophrenics. Neuroscience Letters 317 161–165
 (10). Long-Term Prenatal Hypoxia Alters Maturation of Brain Catecholaminergic Systems and Motor Behavior in Rats, DAVID PERRIN,* JULIE MAMET, HELENE SCARNA, JEAN CHRISTOPHE ROUX, ANNE BEROD, AND YVETTE DALMAZ SYNAPSE 54:92–101, p99 (2004).
(11). Murray, Robin M., and Fearon, Paul (1999). "The developmental 'risk factor' model of schizophrenia," Journal of Psychiatric Research, 33, 497-499.
(12). MARY CANNON1, PETER JONES, MATTI O. HUTTUNEN, ANTTI TANSKANEN AND ROBIN M. MURRAY (1999) Motor Co-ordination Deficits as Predictors of Schizophrenia Among Finnish School Children, Hum. Psychopharmacol. Clin. Exp. 14, 491±497
(13) Mary Cannon, MD, PhD; Avshalom Caspi, PhD; Terrie E. Moffitt, PhD; HonaLee Harrington, BS;Alan Taylor, MSc; Robin M. Murray, MD, DSc; Richie Poulton, PhD
. Evidence for early-childhood pan-developmental impairment specific to schizophreniform disorder: results from a longitudinal birth cohort. Arch Gen Psychiatry. 2002;59:449–457.
(14). Neurological "soft signs" in children and adolescents, Paola Iannetti; Mario Mastrangelo; Sara Di Netta Journal of Pediatric Neurology; 2005; 3, 3 p123
(15). Studies trying to estimate the prevalence of future schizophrenics in childhood neurological soft signs do so at seven years of age, which the study in the previous study showed, will not vary with controls, and these studies don't indicate if severity of motor coordination deficit is related to schizophrenia. Two different studies of age seven Neurological Soft Signs on a small number of subjects, both resulted in only one schizophrenic Neurological soft signs. Their relationship to psychiatric disorder and intelligence in childhood and adolescence, D. Shaffer, I. Schonfeld, P. A. O'Connor, C. Stokman, P. Trautman, S. Shafer and S. Ng, Archives of General Psychiatry. Vol. 42 No. 4, April 1985 "Early soft neurological signs and later psychopathology by Shaffer, D. Stockman, CS. O'Connor, PA, Shafer S, Barmack, JE. Hess S, Spelton, D. and Schonfeld IS, "Early Soft Neurological Signs and Later Psychopathology in Life-span Research on the Prediction of Psychopathology By L. Erlenmeyer-Kimling, Nancy E. Miller Contributor Nancy E. Miller Published by Lawrence Erlbaum Associates, 1986 p42
(16). Rosso, I.M., Bearden, C.E., Hollister, J.M., Gasperoni, T.L., Sanchez, L.E., Hadley, T. and Cannon, T.D. (2000) "Childhood neuromotor dysfunction in schizophrenia patients and their unaffected siblings: a prospective cohort study," Schizophrenia Bulletin, 26(2), 371-374.
(17). Hypoxic-ischemia-related fetal/neonatal complications and risk of schizophrenia and other nonaffective psychoses: A 19-year longitudinal study
Gwen L Zornberg, Stephen L Buka, Stephen L Buka, Ming T Tsuang The American Journal of Psychiatry Feb 2000 Vol. 157 Iss. 2 pg. 196.
(18). NATURE NEUROSCIENCE VOLUME 11 NUMBER 8 AUGUST 2008 Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans - p899 Roger Pocock & Oliver Hobert
(19).,NATURE NEUROSCIENCE VOLUME 11 NUMBER 8 AUGUST 2008 Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans - p899 Roger Pocock & Oliver Hobert
(20) Oliver D. Howes, Colm McDonald, Mary Cannon, Louise Arseneault, Jane Boydell and Robin M. Murray, (2004) Pathways to schizophrenia, the impact of environmental factors, International Journal of Neuropsychopharmacology (2004), 7 (Supplement 1), S7–S13.
(21). MARY CANNON and ROBIN M MURRAY, Neonatal origins of schizophrenia Arch. Dis. Child. 1998;78;1-3
(22). M. Isohanni, P.B. Jones, K. Moilanen, P. Rantakallio, J. Veijola, H. Oja, M. Koiranen, J. Jokelainen, T. Croudace, M-R. Jarvelin. (2001) Early developmental milestones in adult schizophrenia and other psychoses. A 31-year follow-up of the Northern Finland 1966 Birth Cohort Schizophrenia Research 52 p2
(23).Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort Jones, Peter; Rodgers, Bryan; Murray, Robin; Marmot, Michael The Lancet; Nov 19, 1994; 344, 8934 pg. 1398
(24). Khalida, I (2003) Children, neurological soft signs and schizophrenia. B R I T I S H J O U R N A L O F P S YC H I AT RY ( 2 0 0 3 ) , 1 8 2 , 3 6 2 ^ 3 6 9.
(25). Prabakaran, S., Swatton, J. E., Ryan, M. M., Huffaker, S. J., Huang, J. T., Griffin, J. L., Wayland, M., Freeman, T., Dudbridge, F., Lilley, K. S., Karp, N. A., Hester, S., Tkachev, D., Mimmack, M. L., Yolken, R. H., Webster, M. J., Torrey, E. F. and Bahn, S. (2004). "Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress," Molecular Psychiatry, 9, 684-697.  This study has a lot of rigor as the results were reproduced: "Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations;" says the abstract.
(27). Schmidt-Kastner R, van Os J, Steinbusch HWM, Schmitz C. (2006). "Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia," Schizophrenia Research, 84(2-3), 253-271
(28).Mallard, E.C., Rehn, A., Rees, S., Tolcos, M. and Copolov, D. (1999). "Ventriculomegaly and reduced hippocampal volume following intrauterine growth-restriction: implications for the aetiology of schizophrenia," Schizophrenia Research, 40, 1, 11-21.
(29). Jucaite, A., Fernell, E., Halldin, C., Forssberg, H., & Farde, L. (2005). "Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity," Biological Psychiatry, 57(3), 229-238
(30) . MJ Decker and DB Rye (2002) Neonatal Intermittent Hypoxia Impairs Dopamine Signaling and Executive Functioning Sleep and Breathing Volume 6, Number 4 p205
(31), Kunugi, H., Urushibara, T., Murray, R.M., Nanko, S., and Hirose, T. (2003). "Prenatal underdevelopment and schizophrenia: A case report of monozygotic twins," Psychiatry and Clinical Neurosciences, 57, 271–274.
(32).Learning Disabilities: From Identification to InterventionBy Jack McFarlin Fletcher, G. Reid Lyon, Lynn S. Fuchs, Marcia A. BarnesPublished by Guilford Press, 2007
(33). Kobayashi, S., Conforti, L., Zhu, W.H., Beitner-Johnson, D., and Millhorn, D.E. (1999). "Role of the D2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells," Pflügers Archiv, 438, 750-759.
(34).Anibal Cravchik Dagger , David R. Sibley and Pablo V. Gejman Dagger (October 1996) Functional Analysis of the Human D2 Dopamine Receptor Missense Variants jbc online Volume 271, Number 42, Issue of October 18, 1996 pp. 26013-26017 - the mention of two factors converting to d2low are the two uncoupling agents.
(35). Rainald Schmidt-Kastner, Jim van Os, Harry W.M. Steinbusch, Christoph Schmitz (2006) Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia Schizophrenia Research, Volume 84, Issues 2-3, June, Pages 253-271
(36). Mátyás Trixler, Tamás Tényi and György Kosztolányi, (2005) Minor Physical Anomalies and Chromosomal Fragility as Potential Markers in Schizophrenia. Preliminary Report. Int J Hum Genet, 5(3): 173-177
(37). Fresh air is good for nerves: hypoxia disturbs axon guidance Chun-Liang Pan & Gian Garriga Nature Neuroscience v11 N8 Aug 2008, p861
(38). S Mah1,4, MR Nelson1,4, LE DeLisi2, RH Reneland1, N Markward1, MR James3, DR Nyholt3, N Hayward3, H Handoko3, B Mowry3, S Kammerer1 and A Braun1 (2006) Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia Molecular Psychiatry (2006) 11, 471–478
(39) Oxygen levels affect axon guidance and neuronal migration in Caenorhabditis elegans Nature Neuroscience Nature Publishing Group August 2008, Volume 11 No 8 pp894-900 Roger Pocock & Oliver Hobert
(40).Pre-eclampsia: Etiology and Clinical Practice By Fiona Lyall, Michael BelfortContributor Fiona Lyall, Michael BelfortPublished by Cambridge University Press, 2007 p143. http://books.google.com.au/books?id=-pbF6NCy2-cC&printsec=frontcover as at 16-11-08
(41)Murray, G (2005) Early Development and Adult Cognitivie Function in Schizophrenia and the General Population - A longitudinal perspective. Tiivistelmä suomeksi. Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium F101 of the Faculty of Medicine (Aapistie 7), on November 25th, 2005,at 12 noon O U L U N Y L I O P I S TO, O U L U 2 0 0 5 University of Oulu, 2005. ISBN 951-42-7891-7. ISBN 951-42-7892-5 (PDF). URI http://herkules.oulu.fi/isbn9514278925/.
(42). Mauricio Castillo (2007) Selective vlunerability and the cerebellum in neonates AJNR Am J Neuroradiol 28:20 –21 Jan 2007 www.ajnr.org.
(43). Rajaprabhakaran Rajarethinam, MD, Konasale Prasad, MD, and Matcheri S. Keshavan, MD, (2004) The Nature of Brain Abnormalities in Schizophrenia: What Do We Really Know? p51
(44) http://www.gproteins.com/showabstract.php?pmid=12697836 as at 15-09-08 J Cell Sci (2003) 116: 2247-60.
(45a) http://www.imt.ie/clinical/mental-health-cns/the-societal-link-to-adhd.html at 12-12-08
(46)http://www.nmihi.com/p/antisocial.htm 12-12-08
48. Striatal Level of Regulation of Learned Forepaw Movements in Rats I. A. ZHURAVIN, N. M. DUBROVSKAYA, S. A. PLESNEVA Physiol. Res. 51(Suppl 1): S67-S76, 2002.
(49). Miriam M. Menkes M.D.1, Jane S. Rowe M.D.1, and John H. Menkes M.D.1A TWENTY-FIVE YEAR FOLLOW-UP STUDY ON THE HYPERKINETIC CHILD WITH MINIMAL BRAIN DYSFUNCTION PEDIATRICS Vol. 39 No. 3 March 1967, pp. 393-399 .
(50). Nancy Andreasen, The Neuroscience of Individual Differences in Your Brain and Yourself Perspectives on Our Golden Age of Neuroscience
2007 The William A. Haseltine Foundation for Medical Sciences and the Arts
(45). James J. Levitt, M.D., Robert W. McCarley, M.D., Chandlee C. Dickey, M.D., Martina M. Voglmaier, Ph.D., Margaret A. Niznikiewicz, Ph.D., Larry J. Seidman, Ph.D., Yoshio Hirayasu, M.D., Ph.D., Aleksandra A. Ciszewski, B.A., Ron Kikinis, M.D., Ferenc A. Jolesz, M.D., and Martha E. Shenton, Ph.D.MRI Study of Caudate Nucleus Volume and Its Cognitive Correlates in Neuroleptic-Naive Patients With Schizotypal Personality Disorder Am J Psychiatry 159:1190-1197, July 2002.
(51). Jones, Peter, Rodgers, Bryan, Murray, Robin, Marmot, Michael. The Lancet. London: Nov 19, 1994. Vol. 344, Iss. 8934; p. 1399 Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort.
(52). ZAVITSANOU K. HUANG X. F. (2002) Decreased [3H]spiperone binding in the anterior cingulate cortex of schizophrenia patients: An autoradiographic study, Neuroscience, 2002, vol. 109, no4, pp. 709-716 (1 p.1/2)
(54). A Jablensky (2006) Subtyping schizophrenia: implications for genetic research. Molecular Psychiatry (2006) 11, p827
(55). Matti Isohanni, Irene Isohanni, Hannu Koponen, Johanna Koskinen, Pekka Laine, Erika Lauronen, Jouko Miettunen, Pirjo Mäki, Kaisa Riala, Sami Räsänen, Kaisa Saari, Pekka Tienari, Juha Veijola and Graham Murray, (2004)Developmental precursors of psychosis. Current Psychiatry Reports. 6(3) May 2004, 168-175. as at 22-09-08.
(56). John D. Aplin Hypoxia and human placental development J. Clin. Invest. 105(5): 559-560 (2000).
(57). Russell Foster,1 Apsara Kandanearatchi,2 Claire Beasley,3 Brenda Williams,4 Nadeem Khan,4 Magne K. Fagerhol5 and Ian P. Everall6 Calprotectin in microglia from frontal cortex is up-regulated in schizophrenia: evidence for an inflammatory process? European Journal of Neuroscience, Vol. 24, pp. 3561–3566, 2006
(58). N Laforgia, ME, ME Baldassarre 1 , G Pontrelli 1 , F Indrio 1 , MA Altomare 1 , G Di Bitonto 1 A Mautone 1 Calprotectin levels in meconium Acta Paediatrica, 92 (4) pp463-466. Online 2 Jan 2007.
(60). Rick M. Dijkhuizen, MSc; Siert Knollema, PhD; H. Bart van der Worp, MD; Gert J. Ter Horst, PhD; Dick J. De Wildt, PharmD, PhD; Jan Willem Berkelbach van der Sprenkel, MD, PhD; Kees A. F. Tulleken, MD, PhD; Klaas Nicolay, PhD; Dynamics of Cerebral Tissue Injury and Perfusion After Temporary Hypoxia-Ischemia in the Rat Stroke. 1998;29:695-704.
(61). Beginning child psychiatry, Paul L. Adams, Ivan Fras - 1988,Published by Routledge Mental Health, 1988 ISBN 0876304935, 9780876304938 p417.
(62).Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia
Khanum Ridler*, Juha M. Veijola†‡, Paivikki Tanskanen§, Jouko Miettunen†¶, Xavier Chitnis , John Suckling* ̈
Graham K. Murray*, Marianne Haapea†, Peter B. Jones*,**, Matti K. Isohanni†, and Edward T. Bullmore*††
"Proceedings of the National Academy of Sciences" PNAS October 17, 2006 vol. 103 no. 42 15651-15656;
(63).Fenoldopam for renal protection in patients undergoing cardiopulmonary bypass . Journal of Cardiothoracic and Vascular Anesthesia , Volume 17 , Issue 4 , Pages 491 - 494 P . Caimmi
(64). E.T. Bullmore *, S. Frangou, R.M. Murray, The dysplastic net hypothesis: an integration of developmental and dysconnectivity theories of schizophrenia, Schizophrenia Research 28 (1997) 143 156, (p152).
(65). Neuropsychologia. 2002 ;40(4):384-400 Deficits in executive functions and motor coordination in children with frontal lobe epilepsy. Hernandez MT, Sauerwein HC, Jambaqué I, De Guise E, Lussier F, Lortie A, Dulac O, Lassonde M
(66) Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a dmodel psychosis in humans", F.X Vollenweider, P Vontobel, I Oye, D Hall and K.L Leenders, in Journal of Psychiatric Research 34(2000) p 35
(67) I took this site to mean that arrestin stops the activation (or production of inhibitory G protein to the d1 receptor) while it was continuously stimulated by dopamine.
Annual Review of Physiology Vol. 69: 511-534 (Volume publication date March 2007) (doi:10.1146/annurev.physiol.69.022405.154731)

Physiological Roles of G Protein–Coupled Receptor Kinases and Arrestins

Richard T. Premont1 and Raul R. Gainetdinov2.
A simultaneous stimulation by dopamine from hypoxia and Gs explains why when medicine is added the stimulation is not totally removed in all cases.
(68) Sequential neural changes during motor learning in schizophreniaLaura M. Rowland,a Reza Shadmehr,b Dwight Kravitz,c and Henry H. Holcombad*
Psychiatry Res. 2008 May 30; 163(1): 1–12.
(69). http://esciencenews.com/articles/2008/08/25/looking.beyond.drug.receptor.clues.drug.effectiveness as of 30-11-08
(70).Neurodevelopmental Mechanisms in Psychopathology By Dante Cicchetti, Elaine F. WalkerPublished by Cambridge University Press, 2003 ISBN 0521002621, 9780521002622 (p131)
(71) Neuropsychopharmacology (2001) 25 915-924.10.1038/S0893-133X(01)00304-9 A Compensatory Mirror Cortical Mechanism for Facial Affect Processing in Schizophrenia Javier Quintana1,2 MD, Ph.D, Tom Davidson1,2 BA, Edward Kovalik1,2 BS, Stephen R Marder1,2 MD and John C Mazziotta3,4,5,6 MD, Ph.
(72). C-section birth per se or followed by acute global asphyxia altered emotional behaviour in neonate and adult rats
Behavioural Brain Research, Volume 168, Issue 1, 15 March 2006, Pages 56-63
Aldina Venerosi, Debora Cutuli, Flavia Chiarotti, Gemma Calamandrei
(73). Long-term effects of acute perinatal asphyxia on rat maternal behavior
Neurotoxicology and Teratology, Volume 25, Issue 5, September-October 2003, Pages 571-578
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(74) Critical Care Obstetrics By Gary A. Dildy, Michael A. Belfort, George Saade, Jeffrey Phelan, Gray Hankins, Steven L. Clark
Published by Blackwell Publishing, 2004
ISBN 0632046325, 9780632046324
(75). Javier Quintana, M.D., Ph.D., Tom Davidson, B.A., Edward Kovalik, B.S. , Stephen R. Marder, M.D, and John C. Mazziotta, M.D., Ph.D.A Compensatory Mirror Cortical Mechanism for Facial Affect Processing in Schizophrenia NEUROPSYCHOPHARMACOLOGY 2001–VOL. 25, NO. 6, p995
(76)(76)76. DAVIDSON M. ; REICHENBERG A. ; RABINOWITZ J. ; WEISER M. ; KAPLAN Z. ; MARK M. (1999) Behavioral and intellectual markers for schizophrenia in apparently Healthy male adolescents. The American Journal of Psychiatry. 1999, vol. 156, no9, pp. 1328-1335 (62 ref.)
(77). CHRIS HOLLIS, MRCPsych, (2003), Developmental precursors of child- and adolescent-onset schizophrenia and affective psychoses: diagnostic specificity and continuity with symptom dimensionsThe British Journal of Psychiatry (2003) 182: 37-44.
(78) Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis Philip Seemana,b, David Weinshenkerc, Remi Quiriond, Lalit K. Srivastavad, Sanjeev K. Bhardwajd, David K. Grandye, Richard T. Premontf, Tatyana D. Sotnikovag, Patricia Boksad, Mufida El-Ghundia, Brian F. O'Dowda, Susan R. Georgea, Melissa L. Perreaulth, Pekka T. Männistöi, Siobhan Robinsonj, Richard D. Palmiterj,k, and Teresa Tallericol
PNAS March 1, 2005 vol. 102 no. 9 3513-3518 .
(79) http://www.schizophreniaforum.org/new/detail.asp?id=1459 as at 14-12-08.
(80)  Physiol Rev (1998) 78: 189-225. Dopamine receptors: from structure to function. C Missale, SR Nash, SW Robinson, M Jaber, MG Caron   http://www.gproteins.com/showabstract.php?pmid=9457173&redirect=yes&terms=vascular+control+d1+d2+link as of 16-12-08.
(81)    Neurobiology of Aging 29 (2008) 379–396  Arrestins and two receptor kinases are upregulated in Parkinson’s disease with dementia E.R. Bychkov a,d , V.V. Gurevich a , J.N. Joyce b , J.L. Benovic c , E.V. Gurevich
(82) (This broken link between schizophrenic D1 and D2 receptors was reiterated by Dr Seeman in a recent issue of Synapse.  He said a more direct route between the two receptors may be possible.  In 2007 an article found that a G protein did indeed mediate between d1 and d2 receptors in hetero-oligomers).  It seems arrestins will try to prevent all actions of the d2 receptor - even those mediated by an agonist such as L-dopa (81).  Arrestins seem to prevent mental function and not muscular, as this study (81) showed increased arrestin for Parkinson's Disease with Dementia over simple Parkinson's disease.  I have read that arrestin does not block some signalling cascades.
(82) Mol Pharmacol 72:450-462, 2007,

Desensitization of the Dopamine D1 and D2 Receptor Hetero-Oligomer Mediated Calcium Signal by Agonist Occupancy of Either Receptor Christopher H. So, Vaneeta Verma, Brian F. O'Dowd, and Susan R. George
(Another possibility is that calcification if bought on by hypoxia; and that calcification producing complications can break the d1, d2 relationship in heterooligomers .)
(83)Schizophrenia doubles stroke risk in young peopleBy Eleanor McDermid09 May 2008Schizophr Res 2008; 101: 234-241
(84)   SYNAPSE 47:250 –254 (2003) Link Between Dopamine D1 and D2 Receptors in Rat and Human Striatal Tissues PHILIP SEEMAN1,2* AND TERESA TALLERICO2
(85)European Journal of Endocrinology (2004) 151 U49–U62 ISSN 0804-4643 Prenatal glucocorticoids and long-term programming Jonathan R Seckl
(88) (Stroke. 1998;29:1149-1154.) © 1998 American Heart Association, Inc.  Original Contributions Cerebral Blood Flow Velocity in Acute Schizophrenic Patients
A Transcranial Doppler Ultrasonography Study Ammar Owega, MD; Jürgen Klingelhöfer, MD; Osama Sabri, MD; Hanns Jürgen Kunert, PhD; Matthias Albers, MD; Henning Saß, MD ́ ́ ́ ́

(113) Carole Planès, Marcel Blot-Chabaud, Michael A. Matthay, Sylviane Couette, Tokujiro Uchida, and Christine Clerici Hypoxia and 2-Agonists Regulate Cell Surface Expression of the Epithelial Sodium Channel in Native Alveolar Epithelial Cells
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(114)Pathology: Basic and Systemic By Neville Woolf Published by Elsevier Health Sciences, 1998 ISBN 0702022918, 9780702022913 p25
(117)Striatal Size and Relative Glucose Metabolic Rate in Schizotypal Personality Disorder and Schizophrenia Lina Shihabuddin, MD; Monte S. Buchsbaum, MD; Erin A. Hazlett, PhD; Jeremy Silverman, PhD; Antonia New, MD; Adam M. Brickman; Vivian Mitropoulou, MA; Melissa Nunn; Michael B. Fleischman; Cheuk Tang, PhD; Larry J. Siever, MD
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(118) Modulation of Glucose Metabolism Inhibits Hypoxic Accumulation of Hypoxia-Inducible Factor-1α (HIF-1α) Adrian Staab1, , Jürgen Löffler2, Harun M. Said1, Astrid Katzer1, Melanie Beyer2, Bülent Polat1, Hermann Einsele2, Michael Flentje1 and Dirk Vordermark1 Strahlentherapie und Onkologie 183(7) 366
(119)Cerebral glucose metabolism during 30 minutes of moderate hypoxia and reoxygenation D. Kintner, J. H. Fitzpatrick Jr, J. A. Louie and D. D. Gilboe Am J Physiol Endocrinol Metab 245: E365-E372, 1983
(120)The effect of antipsychotic medication on relative cerebral blood perfusion in schizophrenia: Assessment with technetium-99m hexamethyl-propyleneamine oxime single photon emission computed tomography Biological Psychiatry, Volume 41, Issue 5, 1 March 1997, Pages 550-559 Del D. Miller, Karim Rezai, Randall Alliger, Nancy C. Andreasen
(121b) The effects of neuroleptic medications on basal ganglia blood flow in schizophreniform disorders: a comparison between the neuroleptic-naïve and medicated states
Biological Psychiatry, Volume 52, Issue 9, 1 November 2002, Pages 855-862 Patricia Westmoreland Corson, Daniel S. O’Leary, Del D. Miller, Nancy C. Andreasen
(121) Psychopharmacology (Berl). 2004 Oct;175(4):487-93. Clozapine and olanzapine, but not haloperidol, reverse cold-induced and lipopolysaccharide-induced cutaneous vasoconstriction.

(136)J Physiol. 2005 July 15; 566(Pt 2): 613–62 Differential responses to CO₂ and sympathetic stimulation in the cerebral and femoral circulations in humansPhilip N Ainslie,¹ Jon C Ashmead,¹ Kojiro Ide,¹ Barbara J Morgan,² and Marc J Poulin¹(137)Cardiovascular Physiology ConceptsBy Richard E. KlabundeEdition: illustrated Published by Lippincott Williams & Wilkins, 2005 ISBN 078175030X, 9780781750301 235 pages (p200)
(137) BIOLOGY OF REPRODUCTION 69, 483–488 (2003) Published online before print 16 April 2003. DOI 10.1095/biolreprod.102.012641 Effects of Sex Chromosome Dosage on Placental Size in Mice1Hitoshi Ishikawa,3,4 Aine Rattigan,3 Reinald Fundele,5 and Paul S. Burgoyne2,3
(140) http://www.springerlink.com/content/v4844q23t7m81765/ as at 6 Feb 2009.
(145)Is there an active mechanism limiting the influence of the sympathetic system on the cerebral vascular bed? Evidence for vasomotor escape from sympathetic stimulation in the rabbit Brain Research, Volume 164, Issues 1-2, 23 March 1979, Pages 81-102 R. Sercombe, P. Lacombe, P. Aubineau, H. Hamo, E. Pinard, A.-M. Reynier-Rebuffel, J. Seylaz

(151) Preterm Fetal Hypoxia-Ischemia Causes Hypertonia and Motor Deficits in the Neonatal Rabbit: A Model for Human Cerebral Palsy? Matthew Derrick,1 Ning Ling Luo,3 Joanne C. Bregman,1 Tamas Jilling,1 Xinhai Ji,1 Kara Fisher,1 Candece L. Gladson,2 Douglas J. Beardsley,3 Geoffrey Murdoch,4 Stephen A. Back,3,5 * and Sidhartha Tan1 * The Journal of Neuroscience, January 7, 2004, 24(1):24-34; doi:10.1523/JNEUROSCI.2816-03.2004

(153)Clinical Study Guide for the Oral Boards in PsychiatryBy Nathan R. StrahlEdition: 3Published by American Psychiatric Pub, 2008ISBN 1585622931, 9781585622931

512 pages - (p24)
(154)Who are the patients with schizophrenia who drink alcohol? European Psychiatry, Volume 22, Supplement 1, March 2007, Page S53 A. Dervaux

(156) Maternal Iron Deficiency and the Risk of Schizophrenia in Offspring Beverly J. Insel, DrPH; Catherine A. Schaefer, PhD; Ian W. McKeague, PhD; Ezra S. Susser, MD, DrPH; Alan S. Brown, MD, MPH Arch Gen Psychiatry. 2008;65(10):1136-1144.
(157)SEEMAN Philip ; SCHWARZ Johannes ; CHEN Jiang-Fan ; SZECHTMAN Henry ; PERREAULT Melissa ; MCKNIGHT G. Stanley ; RODER John C. ; QUIRION Rémi ; BOKSA Patricia ; SRIVASTAVA Lalit K. ; YANAI Kazuhiko ; WEINSHENKER David ; SUMIYOSHI Tomiki Psychosis pathways converge via D2^High dopamine receptors Synapse 2006, vol. 60, n^o4, pp. 319-346
(158) Alan S. Brown and Ezra S. Susser Prenatal Nutritional Deficiency and Risk of Adult Schizophrenia Schizophrenia Bulletin Advance Access published on August 4, 2008 Schizophr Bull 2008 34: 1054-1063; doi:10.1093/schbul/sbn096.
(159)"Breakthrough" Dopamine Supersensitivity during Ongoing Antipsychotic Treatment Leads to Treatment Failure over Time Anne-Noël Samaha,1 Philip Seeman,2,3 Jane Stewart,4 Heshmat Rajabi,4 and Shitij Kapur1,2The Journal of Neuroscience, March 14, 2007, 27(11):2979-2986; doi:10.1523/JNEUROSCI.5416-06.2007
(162) BMJ 1994;309:699-703 (17 September) Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11 D J Done, T J Crow, E C Johnstone, A Sacker
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(166) New Directions for Mental Health Services Volume 2000 Issue 88, Pages 49 - 60 Relapse prevention in serious mental illnessDavid P. Walling 1, Professor Diane T. Marsh 2
(168) (Nature 365, 441 - 445 (30 September 1993);  Dopamine D4 receptors elevated in schizophrenia
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(169) Acta Psychiatrica Scandinavica. 2004 Jul;110(1):29-35.) NEUROLOGICAL SOFT SIGNS DISCRIMINATING MOOD DISORDERS FROM FIRST EPISODE SCHIZOPHRENIA.
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(170) Comprehensive Care of Schizophrenia: A Textbook of Clinical ManagementBy Jeffrey A. Lieberman, Robin Murray Edition: illustrated, large printPublished by Informa Health Care, 2001ISBN 1853178934, 9781853178931(p42)
(171)Reduced size of the pre-supplementary motor cortex and impaired motor sequence learning in first-episode schizophrenia  Schizophrenia Research, Volume 84, Issues 2-3, June 2006, Pages 386-396 Cornelia Exner, Godehard Weniger, Carsten Schmidt-Samoa, Eva Irle

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(332) Shock: December 2004 - Volume 22 - Issue 6 - pp 569-574 Basic Science Aspects Tsc for Hemorrhagic Shock: Effects on Cytokines and Blood Pressure Stennett, Amanda K; Gainer, John L

(333) Learning and Memory Systemic blockade of D2-like dopamine receptors facilitates extinction of conditioned fear in mice  Ravikumar Ponnusamy1, Helen A. Nissim3, and
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(334) Learn. Mem. 2005 12: 399-406 Ravikumar Ponnusamy, Helen A. Nissim and Mark Barad Systemic blockade of D2-like dopamine receptors facilitates Ravikumar Ponnusamy, Helen A. Nissim and Mark Barad Systemic blockade of D2-like dopamine receptors facilitates

(335) Development and Psychopathology, 11 (1999), 467–485  A prospective cohort study of neurodevelopmental processes in the genesis and epigenesis of schizophrenia TYRONE D. CANNON,a ISABELLE M. ROSSO,b CARRIE E. BEARDEN,ba ISABELLE M. ROSSO,b CARRIE E. BEARDEN,b LAURA E. SANCHEZ,b AND TREVOR HADLEYbb AND TREVOR HADLEYb
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(337) Br J Psychiatry. 2001 Jun;178:524-30.Neurodevelopmental indices and the development of psychotic symptoms in subjects at high risk of schizophrenia.Lawrie SM, Byrne M, Miller P, Hodges A, Clafferty RA, Cunningham Owens DG, Johnstone EC.

(338) Developmental Medicine & Child Neurology Volume 27 Issue 5, Pages 578 - 587 THE CONTRIBUTION OF FETAL-NEWBORN COMPLICATIONS TO MOTOR AND COGNITIVE DEFICITS
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(339) Karimi, G., Hosseinzadeh, H., Khaleghpanah, P., 2001. Study of antidepressant effect of aqueous and ethanolic of Crocus sativus in mice.Iranian Journal of Basic Medical Sciences 4, 11–15.Crocus sativus in mice.
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(401)Seminars in Perinatology, Volume 28, Issue 6, Pages 425-432 Mechanisms of Hypoxic–Ischemic

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(402)The effects of dopamine and epinephrine on hemodynamics and oxygen metabolism in hypoxic anesthetized piglets
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