Thursday, February 9, 2023

• “iatrogenic damage done by psychiatry and their Medical Model of so-called ‘treatment.'”

How can you be certain psychiatry and its medical model of treatment caused iatrogenic damage?

If psychological therapy results in a worsened mental state, is that classified as an iatrogenic illness?

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018936s108lbl.pdf

Prozac comes with a 35-page warning label. It’s hard to imagine BP is trying to withhold concerns about potential dangers of this SSRI.

More than 20 million prescriptions for antidepressants were written between October and December 2020 (that is 80,000,000 annually)— a 6% increase compared to the same three months in 2019 — according to statistics reported by the NHS Business Services Authority (NHSBSA).

Overall, the statistics showed that 23% more patients received an antidepressant item in the third quarter of 2020–2021 compared to the same quarter in 2015–2016.

It is hard for me to understand that anti-depressants do so little good and cause so much harm when 80,000,000 prescriptions are written for them yearly. What am I missing?

• “Not only are these discontinuation syndromes and this means that you are going too fast, and you have to slow down, but if there is withdrawal, you should think of relapse and continue the medication again.”

How do you distinguish them?

Without significant evidence, without double-blind, controlled studies, how can we know what causes what?

• You too.
I don’t understand what your point is by sharing what Insel said about the failures of NIMH and, why it is that you suspect I think differently. What does what he experienced have to do with me?
I will tell you for what it’s worth that I think what’s been written here, in general and specifically, has been harmful for many people and I’m mad at MIA. Maybe that’s what you sense. I don’t get it.
The human brain is extraordinary. We are just beginning to understand how it works. I believe new discoveries will compare with recognizing how bacteria and viruses were responsible for disease. We are just now getting a glimpse of how the brain produces thoughts. To me, that is one of the most profound mysteries in the universe. That somehow flesh and blood can create one thought. A thought from a lump of cells. How in the world does that happen? What is a thought? How do chemicals form even just a single word, or an A or B or anything abstract like that?
And there are 35 trillion times 10 billion ways for the brain to misfire, or to be lacking in something-maybe a few million proteins, or whatever, that creates all kinds of illnesses or malfunctions.

• If I cut if my hand, I still am able to think. If I soak my neurons in alcohol, my brain will malfunction. If I pump dopamine into my neurons through vigorous exercise, I feel better. If I deprive my neurons of oxygen, I will lose consciousness.
The mind and the brain are intertwined. To isolate them from each other doesn’t seem possible. I can damage my mind by sticking an iron bar through it. I can remove memories by shooting electricity in to the hippocampus.
When I feel better, my thoughts are less troublesome. I can act my way into better thinking and a better mood, too.

Personally, I don’t think a precise diagnosis is as important as relieving unbearable pain. even though there is no proof of pain. Do we refrain from offering chemicals to reduce pain because it cannot be measured scientifically?

• “Anyone who has had even the slightest experience working with children and families can attest to the fact that there are always alternative psychosocial explanations, if one is prepared to look for them. The reality, however, is that within the practice of psychiatry, these alternate explanations are almost never sought.” hickey

name three alternatives

“And the reason they are not sought is because psychiatry has effectively closed the door on these kinds of deliberations. Within the psychiatric framework, if a child (or adult) meets the arbitrary and inherently vague criteria listed in the DSM, then he has a brain illness called ADHD. So the notion of even looking for psychosocial explanations not only doesn’t happen, but would be seen within psychiatry as ridiculous.” hickey

How do you know?

Things are different today, Phil. Almost everything you have provided over decades to refute ADHD is dead wrong.

• “The youngest students in class get diagnosed with ADHD more often and receive more ADHD medication than their older classmates.”

Nick Kowalenko from the Royal Australian and New Zealand College of Psychiatrists said there was insufficient detail in the research

Too bad the older kids may have been overlooked.

“I’ve learnt of some situations where children are not allowed to return to school until they are medicated by a doctor. The doctor is then compromised…” A supporter of ant-ADHD rhetoric.

easterbeilbs responded:
Are you sure? I’ve read your comment base and you make a lot of excellent well-informed observations. However, in more than 25 years in schools, I’ve never observed what you describe.

Trixr agrees:
That’s completely misleading. Teachers do not “diagnose” – they are highlighting a potential issue.
Only doctors can diagnose, and I’d like to see evidence of schools mandating drugs. I can imagine that a school may want to see evidence that an extremely disruptive child is receiving some kind of therapeutic attention.

To support the previous poster, I’ve worked more than 20 years in schools (half that time in WA) and I’ve never known another teacher or principal to diagnoses ADHD. I have been asked, by parents, to complete observation forms for the doctor who is deciding on a diagnosis (forms which, to be completely honest, I have found to be unclear and not terribly useful).

Paul Harvey. Now for the rest of the story/

It is astonishing how much misinformation is spread around about ADHD. Many latch onto it like Paul said it. Much is taken out of context and framed is the worst possible ways.
We are encouraged to enjoy our addiction. They hope we enjoy killing innocent kids and forcing them to behave according to our Puritan desires. Restricting them. Punishing them severely for being themselves. Refusing to be open-minded, calling us lazy, clueless, without genuine concern for children. One writer for MIA insists that ADHD is the result of lousy parents.
I don’t believe I have ever heard a positive comment about a parent who is doing the best she can and reports her child is doing wonderfully on medication.

Today there is proof that, “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice” O. S. Birk

I hope someone will and I invite anyone to explain in detail exactly what this means, “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice”

• “The youngest students in class get diagnosed with ADHD more often and receive more ADHD medication than their older classmates.”

Nick Kowalenko from the Royal Australian and New Zealand College of Psychiatrists said there was insufficient detail in the research

Too bad the older kids may have been overlooked.

“I’ve learnt of some situations where children are not allowed to return to school until they are medicated by a doctor. The doctor is then compromised…” A supporter of ant-ADHD rhetoric.

easterbeilbs responded:
Are you sure? I’ve read your comment base and you make a lot of excellent well-informed observations. However, in more than 25 years in schools, I’ve never observed what you describe.

Trixr agrees:
That’s completely misleading. Teachers do not “diagnose” – they are highlighting a potential issue.
Only doctors can diagnose, and I’d like to see evidence of schools mandating drugs. I can imagine that a school may want to see evidence that an extremely disruptive child is receiving some kind of therapeutic attention.

To support the previous poster, I’ve worked more than 20 years in schools (half that time in WA) and I’ve never known another teacher or principal to diagnoses ADHD. I have been asked, by parents, to complete observation forms for the doctor who is deciding on a diagnosis (forms which, to be completely honest, I have found to be unclear and not terribly useful).

Paul Harvey. Now for the rest of the story/

It is astonishing how much misinformation is spread around about ADHD. Many latch onto it like Paul said it. Much is taken out of context and framed is the worst possible ways.
We are encouraged to enjoy our addiction. They hope we enjoy killing innocent kids and forcing them to behave according to our Puritan desires. Restricting them. Punishing them severely for being themselves. Refusing to be open-minded, calling us lazy, clueless, without genuine concern for children. One writer for MIA insists that ADHD is the result of lousy parents.
I don’t believe I have ever heard a positive comment about a parent who is doing the best she can and reports her child is doing wonderfully on medication.

Today there is proof that, “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice” O. S. Birk

I hope someone will and I invite anyone to explain in detail exactly what this means, “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice”

• Dr. Berezin, the 4 temperments you mention, from where do they come?

“We evolve as a species, and we evolve as individuals in relation to our salient environment. All throughout our development – the embryo, fetus, newborn, baby, toddler, child, and adolescent adapts to its emotional environment. There are only three relevant issues – responsiveness, emotional deprivation, and abuse. Each of us fields our experience through the unique constellation of our temperament. The four elements of temperament are Internalization/Externalization, Introversion/Extroversion, Active/Passive, and Participant/Observer.”

We must eat and breathe. Molecules must enter our bodies or our temperments disappear. Add toxic molecules to food and air and our temperments cease. The molecular level of brains is extraordinarily important.

• “More recently, however, experts have concluded that reacting to a placebo is not proof that a certain treatment doesn’t work, but rather that another, non-pharmacological mechanism may be present.”
“The power of the placebo effect”
Harvard Health
Aug 9, 2019

Bob, how do you account for the hundreds of millions of people whose lives have been spared through the drugs produced by BP? Certainly, not every one of them was helped through the placebo effect. If they weren’t having a considerable impact, coming off them wouldn’t be such a nightmare. If the drug trials are fixed in favor of the drug company, why do they spend millions developing them? Couldn’t they throw some innocuous chemicals together and achieve the same results?
When psychiatrists first found that chemicals could relieve some of the pain of depression, they were surprised. Didn’t they soon realize they were on to something potentially groundbraking?

• I wonder how small the measurable benefit has to be in order to provide relief. Placebos work. If we match the power of placebo, or exceed it even just a tad, we’ve achieved a significant result.

• I give value to money. I can crave it or love it and make it my god. I don’t have to. I decide what value to place on it so that, by itself, it doesn’t distort anything.

• to insist that problems with thought, emotions, drive, impulse control, cognition, perception, behaviour and so forth should be exempted from the rubric of illness, and the assertion that there is no such thing at all as psychopathology, seem entirely unjustified.
absolutely true

• Keep in mind the great news out of the Middle East. Reseachers there discovered, “Published: 26 October 2021
“CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice”
D. Halperin, A. Stavsky, R. Kadir, M. Drabkin, O. Wormser, Y. Yogev, V. Dolgin, R. Proskorovski-Ohayon, Y. Perez, H. Nudelman, O. Stoler, B. Rotblat, T. Lifschytz, A. Lotan, G. Meiri, D. Gitler & O. S. Birk

Also,
Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis;{Synaptogenesis is a process involving the formation of a neurotransmitter release site in the presynaptic neuron and a receptive field at the postsynaptic partners, and the precise alignment of pre- and post-synaptic specializations.} the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.

Many already has deduced that a physical flaw was causing ADHD symptoms. It only made sense. More break downs will be discovered as scientists zero in on brain structure due to this breakthrough discovery. The Decade of the Brain continues to reveal astounding information about the most complex 3lbs of matter on earth. We are on the verge of the most exciting science of all time. How the brain works, and doesn’t.

• They have 15,600 appointments with patients on average per year. What should the maximum number of scripts she can write for stimulants be each year?
The date was Oct 13 2015.

Writing 2000 plus rx’s for stimulants per year has no bearing on the fact that ADHD is a damnable, confusing, complex, real and most often treatable through medication that I can see. Thank heaven doctors are treating so many people who suffer horribly from it while undiagnosed and untreated. There is hope now that it is being recognized and addressed for the monster it is and people are finding relief for it, building self-esteem and being given a second chance to do all the things they could not do.

• There isn’t an ounce of evidence anywhere proving that ADHD isn’t real. Keep that in mind. If the DSM lacks evidence and makes false statements, ADHD stands by itself.

BY DOUGLAS MAIN ON 3/10/15 AT 2:44 PM EDT
RTR24P48
A glass of tap water in New York.
SHANNON STAPLETON / REUTERS

ENVIRONMENTAL HEALTH
New research shows there is a strong correlation between water fluoridation and the prevalence of Attention Deficit Hyperactivity Disorder, or ADHD, in the United States.

It’s the first time that scientists have systematically studied the relationship between the behavioral disorder and fluoridation, the process wherein fluoride is added to water to prevent cavities.

The study, published in the journal Environmental Health, found that states with a higher portion of artificially fluoridated water had a higher prevalence of ADHD. This relationship held up across six different years examined. The authors, psychologists Christine Till and Ashley Malin at Toronto’s York University, looked at the prevalence of fluoridation by state in 1992 and rates of ADHD diagnoses in subsequent years.

“States in which a greater proportion of people received artificially-fluoridated water in 1992 tended to have a greater proportion of children and adolescents who received ADHD diagnoses [in later years], after controlling for socioeconomic status,” Malin says. Wealth is important to take into account because the poor are more likely to be diagnosed with ADHD, she says. After income was adjusted for, though, the link held up.

Take Delaware and Iowa, for instance. Both states have relatively low poverty rates but are heavily fluoridated; they also have high levels of ADHD, with more than one in eight kids (or 14 percent) between the ages of four and 17 diagnosed.

In the study, the scientists produced a predictive model which calculated that every one percent increase in the portion of the U.S. population drinking fluoridated water in 1992 was associated with 67,000 additional cases of ADHD 11 years later, and an additional 131,000 cases by 2011, after controlling for socioeconomic status.

“The results are plausible, and indeed meaningful,” says Dr. Philippe Grandjean, a physician and epidemiologist at Harvard University. This and other recent studies suggest that we should “reconsider the need to add fluoride to drinking water at current levels,” he adds.

Thomas Zoeller, a scientist at UMass-Amherst who studies endocrine disruptors—chemicals that interfere with the activity of the body’s hormones, something fluoride has been shown to do—says that this is “an important observation in part because it is a first-of-a-kind. Given the number of children in the U.S. exposed to fluoridation, it is important to follow this up.” Since 1992, the percentage of the U.S. population that drinks fluoridated water has increased from 56 percent to 67 percent, during which time the percentage of children with an ADHD diagnosis has increased from around seven percent to more than 11 percent, according to the Centers for Disease Control and Prevention (CDC).

NEWSWEEK SUBSCRIPTION OFFERS >
RTX146EG
NACHO DOCE / REUTERS
Others felt more strongly. “The numbers of extra cases associated with a one percent increase in the 1992 artificial fluoridation [figures] are huge,” says William Hirzy, an American University researcher and former risk assessment scientist at the Environmental Protection Agency, who is also a vocal opponent of fluoridation. “In short, it clearly shows that as artificial water fluoridation increases, so does the incidence of ADHD.”

But scientists were quick to point out that this is just one study, and doesn’t prove that there is necessarily a causal link between fluoridation and ADHD. They also noted a number of important limitations: Individual fluoride exposures weren’t measured, ADHD diagnoses weren’t independently verified and there may be other unknown confounding factors that explain the link.

Dr. Benedetto Vitiello, a researcher at the National Institutes of Health, says that the link between the two may not be a causal one and could be explained by regional or cultural factors. Charles Poole, an epidemiologist at the University of North Carolina, says that this research suggests fluoride should be more carefully studied, but doesn’t show much of anything by itself. “I think the authors were quite cautious in their interpretation… and [accurate] in their statement of the study’s limitations,” he says. “So it would be ludicrous to draw a strong conclusion based on this study alone.”

Nevertheless, previous research has suggested that there may be several mechanisms by which fluoride could interfere in brain development and play a role in ADHD, says Dr. Caroline Martinez, a pediatrician and researcher at New York’s Mount Sinai Hospital.

Animal studies in the 1990s by researcher Phyllis Mullenix, at the Harvard-affiliated Forsyth Research Institute, showed that rats exposed to fluoride in the womb were much more likely to behave in a hyperactive manner later in life. This could be due to direct damage or alteration to the development of the brain. (Mullenix’s adviser told her she was “jeopardizing the financial support” of her institution by “going against what dentists and everybody have been publishing for fifty years, that [fluoride] is safe and effective,” and she was fired shortly after one of her seminal papers was accepted for publication, according to Grandjean and a book by investigative journalist Christopher Bryson called The Fluoride Deception.)

Multiple studies also suggest that kids with moderate and severe fluorosis—a staining and occasional mottling of the teeth caused by fluoride—score lower on measures of cognitive skills and IQ. According to a 2010 CDC report, a total of 41 percent of American youths ages 12 to 15 had some form of fluorosis. Another study showed structural abnormalities in aborted fetuses from women in an area of China with high naturally occurring levels of fluoride.

There have also been about 40 studies showing that children born in areas home to water with elevated levels of this chemical (higher than the concentrations used in U.S. water fluoridation) have lower-than-normal IQs. Grandjean and colleagues reviewed 27 such studies that were available in 2012, concluding that all but one of them showed a significant link; children in high fluoride areas had IQs that were, on average, seven points below those of children from areas with low concentrations of the substance.

One recent small study of fewer than 1,000 people in New Zealand suggested that water fluoridation didn’t decrease IQ. But that study had some serious errors, according to Grandjean, who writes that “a loss of 2-3 IQ points could not be excluded by their findings.” And only a small percentage of people in the study actually lived all their lives in areas without fluoridation, and even less didn’t use fluoride toothpaste, severely limiting the validity and relevance of the findings, he says.

About 90 percent of the fluoride that is added to the water takes the form not of pharmaceutical grade sodium fluoride but of a chemical called fluorosilicic acid (or a salt formed using the acid). This material is a byproduct of phosphate fertilizer manufacturing, according to the CDC. Several studies have suggested that this form of fluoride can leach lead from pipes, says Steve Patch, at UNC-Asheville. Other work shows that children in fluoridated areas have elevated blood lead levels, and fluoride may also increase the absorption of lead into the body, says Bruce Lanphear, an epidemiologist at Simon Fraser University. Lead itself is a potent neurotoxin and has been shown to play a role in ADHD, Lanphear adds.

There is also good evidence the fluoride impairs the activity of the thyroid gland, which is important for proper brain development, says Kathleen Thiessen, a senior scientist at the Oak Ridge Center for Risk Analysis, which does human health risk assessments for a variety of environmental contaminants. This could indirectly explain how the chemical could impair attentional abilities, she says.
Philippe Grandjean is an adjunct professor at the Harvard School of Public Health. (Philippe Grandjean)

New research finds exposure to fluoride in drinking water and several other common chemicals in early life diminishes brain function in children. Study lead author, Philippe Grandjean, tells host Steve Curwood fluoride, flame retardants, pesticides and and fuel additives may be affecting children’s intelligence.
RELATED STORIES
Water Fluoridation May Increase Risk of Underactive Thyroid Disorder
Just last month, a study was published in the Journal of Epidemiology & Community Health, which found that there were nine percent more cases of hypothyroidism, or underactive thyroid, in fluoridated versus non-fluoridated locations in England.

“Fluoride appears to fit in with a pattern of other trace elements such as lead, methylmercury, arsenic, cadmium and manganese—adverse effects of these have been documented over time at exposures previously thought to be ‘low’ and ‘safe,'” Martinez says.

Grandjean concurs, citing a 2014 study he co-authored with researcher Philip Landrigan in The Lancet that characterizes fluoride as a developmental neurotoxin. Others, like Lanphear, prefer to call the chemical a “suspected developmental neurotoxin.” One problem, he says, is that there is no formal process for determining whether or not something is toxic to the brain.

The CDC declined to comment on the study, but maintains the fluoridation is “safe and effective,” and calls fluoridation one of the “ten great public health achievements” of the twentieth century for its role in preventing tooth decay. The American Dentistry Association says that the process reduces decay rates by 25 percent. It should be noted, though, that in recent decades rates of cavities have declined by similar amounts in countries with and without fluoridation—and the United States is one of the few Western countries besides Ireland and Australia that fluoridate the water of a majority of the populace.

Limitations aside, the study suggests that there is a pressing need to do more research on the neurotoxicity of fluoride, Lanphear says. In fact, every single researcher contacted said that fluoridation should be better studied to understand its toxicity and low-dose effects on the brain. Some deemed the lack of research on the chemical concerning and surprising, given how long it’s been around—fluoride was first added to water supplies beginning after World War II.

Regarding whether or not fluoridation is a sound public health practice, he says that he “can’t make that decision for the public, but I’d certainly recommend that more studies are done, in an urgent fashion.”

• In general, “ADHD” is essentially a lack of personal discipline. And people who lack personal discipline often struggle with the demands of life.`

I challenge that conclusion and I’ll raise several. There is not a single drop of evidence proving that statement is true. Further, there isn’t a shred of evidence that in general tems parents are to blame across the board as Dr. Hiclkey claims. Parents are not to blame, though they can make an environment which is toxic and that makes everything more difficult for children. It is pure speculation on his part that a lack of training during a child’s youth is the basis overall for ADHD. Mcrea’s kids grew up in a wonderfully nurturing and structured environment, yet they posed enormous problems. Why? Obviously, we are born with predispositions.

Explain, Doctor, if you don’t mind, the results of Birk’s work.

• N-Cadherin belongs to a superfamily of calcium-dependent transmembrane adhesion proteins. It mediates adhesion in the intercalated discs at the termini of cardiomyocytes thereby serving as anchor for myofibrils at cell-cell contacts.

Just the briefest of definitions regarding N-Cadherin

• Not “a systematic, scientifically controlled way”

Research on long-term effectiveness
There are a number of studies that follow children for longer periods, even into adulthood, but the kids in these studies are not being treated in

{a systematic, scientifically controlled way}

so the results are not conclusive.

Bob, would you consider writing up a thorough review of the breakthrough news that, “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice”

Thanks

This is a star studded group of experts extraordinaire: D. Halperin, A. Stavsky, R. Kadir, M. Drabkin, O. Wormser, Y. Yogev, V. Dolgin, R. Proskorovski-Ohayon, Y. Perez, H. Nudelman, O. Stoler, B. Rotblat, T. Lifschytz, A. Lotan, G. Meiri, D. Gitler & O. S. Birk

• Facts?

Quote them, please. How much damage have prescribed stimulants caused?

How much good have they done, these stimulants helping people to see for the first time in their lives? What do you suppose that was like?

• “In any case, lots of good medications become ineffective eventually,” adds Michael Milham, MD, PhD…that doesn’t mean we don’t use them for as long as they work.”

“The largest of the controlled studies, called the MTA (or Multi-Modal Treatment Study of ADHD) study, treated nearly 600 children in the late 1990s for 14 months. The longest treated over 100 kids for 2 years. Both found that kids treated with stimulant medications had their symptoms significantly reduced, and the effect was more powerful than in kids treated with behavioral therapy.”

• “Drugging a kid” in the vernacular means to cause him to become in a drunken stupor, the opposite of what we want.

• But, it is medicine for the ADHD afflicted individual. Why don’t we listen to them? They are the “spoken about” sufferers. When was the last time a major newspaper or network gave an adult with ADHD the opportunity to share with the world what it was like before treatment, how their life changed with treatment anf how they are doing at the present? Quite a few have a tale to tell of tragic misunderstandings, profound helplessness and an almost lethal loneliness. They are used to having no one Really listen to them. They came through hell and had a breakthrough that is quite thrilling. They are sharp, articulate, often very funny.

Keep in mind, if one stimulant begins to lose its effacy, they can use a different one, change the dosage, increase exercise, or reduce their workload–persish the thought, right? They often feel obligated to make up for decades of failures and lost opportunities. One stimulant acts like a dam in the synapse, blocking and loading up dopamine to be released. Another acts as a flood, pushing more dopamine like a wave into where it is needed.
With Birks’ incredible discovery ADHD will undergo massive new studies, more meds will be developed, better testing equipment, more ACCURATE results

• I searched and didn’t find it. Can you quote the data you referenced? Thanks

• A Destructive Psychiatric Hoax
Dr. Phil,
Left undiagnosed it is destructive.
Who is destroyed, if we take it seriously?
There are many good, decent, intelligent, hardworking, well-informed psychiatrists who believe the evidence proving it is a bio-chemical problem, is overwhelming.
I introduced evidence that it is biochemically based. It is undeniable.
It responds to treatment. Long term studies done properly, which are very expensive and difficult to do, show its efficacy. Many LT studies lack credibility. Many participants dropped out. Many were hard to find. Many did not continue to take their meds as prescribed and the long-term outcomes, of tests performed according to high standards, though favorable, have nothing to do with the fact that ADHD is real.

• Published: 26 October 2021
“CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice”
D. Halperin, A. Stavsky, R. Kadir, M. Drabkin, O. Wormser, Y. Yogev, V. Dolgin, R. Proskorovski-Ohayon, Y. Perez, H. Nudelman, O. Stoler, B. Rotblat, T. Lifschytz, A. Lotan, G. Meiri, D. Gitler & O. S. Birk

• The legends “worded in the ancient tribal hymn”
Lie cradled in the seagull’s call
And all the promises they made
Are ground beneath the sadist’s fall

• You don’t believe psychiatrists save lives, relieve suffering, restore hope?

• If their anxiety is over the imminent return of Martians to continue to wage war against aliens from Zeneith, maybe they need to see a professional?

• Among men, the crime rate
was reduced by 32% (P<0.001) during treatment
periods, and the rate reduction ranged from 17 to
46% in all nine sensitivity analyses (in which the
comparison was significant in eight). We observed
a similar association among women, with a reduction in the crime rate of 41% (P<0.001) during
treatment periods.

• “The effectiveness of stimulants in treating ADHD has been well documented in randomized clinical trials.” The NEJM

You are right doctor. The most prestigious medical journal in the world agrees with you..
You have the most articulate, informed, researched point of view and decades of experience. Obviously, you are a very bright man with a top notch education. I am certain you have a large number of grateful and delighted, loyal patients. The NEJM confirms your position and that of many others. The folks I know who take their meds as prescribed (which includes remaining on them without discontinuing them for years on their own) can barely contain their joy and gratitude for the staggering improvements in their lives.
If there wasn’t a flaw of some kind in the biochemistry of the afflicted, the medicine wouldn’t work. It targets neurotransmitters. There is no reason to believe that our brains run perfectly. Every physical component of our bodies is subject to failure and decay.

Have you heard the very latest news? Some brilliant, brilliant Israelis just published the results of their exhaustive research and concluded, “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice” Hallowell basically said, “Of course. It is just further proof of what we already know.”
These people did all the the work: D. Halperin, A. Stavsky, R. Kadir, M. Drabkin, O. Wormser, Y. Yogev, V. Dolgin, R. Proskorovski-Ohayon, Y. Perez, H. Nudelman, O. Stoler, B. Rotblat, T. Lifschytz, A. Lotan, G. Meiri, D. Gitler & O. S. Birk

• “They do not have a disease or disorder. ADHD BEHAVIOR IS AN AUTONOMIC NERVOUS SYSTEM ATTEMPT TO MAINTAIN DOPAMINE HOMEOSTASIS.”

Then why is it so disruptive? If there is nothing wrong, why do they fail to pay attention so often? You know?

• “salt overload is taking its toll. The study concludes that about 1.65 million deaths from cardiovascular disease each year”

over 200 million men and nearly 300 million women have obesity.

At least 2.8 million adults die each year as a result of being overweight or obese.

I am going to have to die soon based on everything trying to kill me.

• Removed for moderation.

• I think you might enjoy these stats:

What is the mortality rate of aspirin?
Mortality rate was 5.57% (95% CI = 4.9-6.7), and 5.62% (95% CI = 4.8-6.8) in study 1 and study 2, respectively. Death rate attributed to NSAID/aspirin use was between 21.0 and 24.8 cases/million people, respectively, or 15.3 deaths/100,000 NSAID/aspirin users.

Nothing is a lethal as birth. Birth will kill everyone on our planet. Billions and billions

• That is correct.

“CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice” Birk

• Incorrect.

Driven To Distraction” Hallowell

• Incorrect.

“Driven To Distraction” Hallowell

It is a great read. Powerful.

• That is correct.

“CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice” Birk

• Today’s DSM, and the psych drugs it mandates, are infinitely more insidious than the witch hunter’s manual, and the Nazi holocaust, combined.

Would you mind defining “mandate” as used is this context?

“A love for money is a root of all kinds of trouble” is more accurate. How do you eliminate this evil?

• You assert that “It has been proven again and again that people with ADD have ‘different’ brains and literally cannot pay attention to certain stimuli no matter what they do.” If you would cite me the references to support this assertion, I would be happy to take a look, and if your assertion is founded, I will acknowledge this in a subsequent post. Dr. Hickey

ADHD is the inability to focus attention as needed.

• My point is simply this. Even though our economic systen is condemned in this article, thoroughly and completely, we were in a position to provide 5 billion dollars of help and we did. What an economy and what a country. Unreal

• “we had one doctor, identified through a register here, who had more than 2000 ‘patient’s’ (in a one year period) he was prescribing stimulants to for ADHD…”

What’s his name? Where was this and when, do you recall? What does that have to do with the topic?

• “Sometimes, we are so sick, we can’t sin.”
“Obviously for any of these behaviors to occur, there has to be corresponding neural activity. But there is no necessity that the neural activity is diseased or malfunctioning in any way.” Dr. Hickey

Neurons become diseased. Damaged neurons take choice away. We see the results all the time

• “Trying to make a child believe that they have something wrong with them is most certainly emotional child abuse.”

Do believe millions of parents have done just that? How many parents did not accuse their children of having fake illnesses? 10? 5? Any? out of millions?

• “Mad in America hosts blogs by a diverse group of writers.”

You mean background, geographic areas where they were raised, their occupations, ages, things of that nature, I believe. There is no diversity as far as holding psychiatry responsible for the “epidemic” at least that I’ve noticed. Is there one psychiatrist, is there anyone at all, ever, who writes for Mad who supports psychiatry?

• Flouridation began in the U.S. in 1945. Based on the Literature, there is a direct conection between the prevalence of ADHD and the consumption of flouridated water. The research was published over 5 years ago.

We evaluated 150 adolescents, 50 each from three different areas with water fluoride ranging from < 2.5 ppm to ~ 10 ppm (Scott–Sanchis method). We observed that in ~ 10 ppm group, clinically none had normal Dean fluorosis index and only 4% had above average intelligence scores on Bhatia Battery, as compared to 48% in ~ 5 ppm group.

There were significant differences on one-way ANOVA for attention/concentration (F = 13.879; p = 0.000), verbal memory (F = 36.197; p = 0.000), working memory (F = 3.078; p = 0.014) apart from IQ (F = 12.938; p = 0.000) suggesting the inverse relationship. Further, significant (p < 0.001) spectral progression of psychopathology was evident in domains of ADHD, childhood disruptive mood disorder, persistent defiant disorders, and specific arithmetic scholastic skills disorders.

• Something extremely painful to another human being needs no label for us to do our best to try to help

• The essential feature of humanity is to try to allieviate the suffering of people.

• Prozac would be an excellent choice to relieve the OCD symptom of Involuntary Public Displays of Digital Nostril Repeated Entrance and Exist Syndrom (IPDDNREES) like washing hands excessively

• Exactly. Based on Dr. Hickey’s well researched, informed accusations many/every psychiatrist in the United States must be arrested for attempted murder and conspiracy to commit First Degree Murder and First Degree Murder. Intentionally, with malice aforethought, conspiring across state and international lines and borders, is terrorism. Murder, of millions of innocents, in the first degree during non-war time is among the worst crimes of all. The World Court has at least partial jurisdiction, I believe.

• “It allows parents to evade any blame for their kid’s failing to become mature/responsible, since it wasn’t their fault, but merely “symptoms of brain disease”. Telling people what they want to hear has been very lucrative for psychiatry.”

How would you help a child who presents with hyperactivity, does not pay attention and is failing in school. Physical exam reveals nothing abnormal and there are no signs or history of abuse, etc. IOW, ADHD symptomology present for several years beginning in third grade, is the overriding concern.

Can you share what course of action you would take to improve his school performance and his interaction with peers?

• Anatomy of an Industry: Commerce, Payments to Psychiatrists and Betrayal of the Public Good
Enrico Rodriquez

Some stimulants serve as dams. Others push through like a river. If one becomes less effective, switch to the other and rotate them like this.

• Anatomy of an Industry: Commerce, Payments to Psychiatrists and Betrayal of the Public Good
Enrico Rodriquez

Thanks Bob for all your hard work covering this topic.
I have just one question. A child who was failing in school was diagnosed with severe ADHD and given a stimulant. He is thriving.
Should they take him off of it?
Thanks for your much appreciated thoughts on this matter.

• “Nowhere does Whitaker include references to the many studies showing structural brain abnormalities, neurological abnormalities, and neuropsychological deficits in individuals with schizophrenia who had never been treated with any medication.

He also includes statements that are patently erroneous. For example, he claims that “even moderately high doses of haloperidol were linked to violent behavior,” when, in fact, studies have shown that haloperidol and other antipsychotics decrease violent behavior in individuals with schizophrenia. Many of Whitaker’s errors originate in his liberal footnoting of Dr. Peter Breggin, who has acknowledged having received support from Scientology, as a source.

• Removed for moderation.

Bring out to the puiblic for others and prove

• “Psychiatry is nothing more than legalized drug-pushing. There is not one shred of intellectual or scientific validity to their so-called taxonomy. They invent these so-called illnesses to expand their turf, and then liberalize the criteria to expand it further.” Dr. Hickey

You accuse psychiatry of illegal, immoral, deceptive, racketeering, interstate conspiracy to defraud, and premeditated conspiracy to commit mass murder.

Dr., where is the evidence? Would you mind presenting it? From what you say all psychiatrists are wanted felons. Any psychiatrist could substitute her name for psychiatry. How do you condemn all of them, repeatedly, when you don’t know all of them?

• “After re-checking my post, I find your diminishment of the accomplishments described to be even more offensive.”

I was making a comment or two here, on this thread, and I’ve done so elsewhere, and then you show up out of the blue and demand that I interact with you. Why does it bother you what I think?

Would you mind ignoring me? Please?

• Is There Long-Term Benefit From Stimulant Treatment for ADHD?
Steven R. Pliszka, M.D.

Stimulant medications have been used to treat symptoms of attention deficit hyperactivity disorder (ADHD) for over 80 years, longer than the use of antibiotics to treat infection (1). Based on data from over 6 million individuals in an insurance database, the 2008 annual prevalence for filled stimulant prescriptions was found to be 4.6% for children ages 6–12 years, 3.7% for adolescents (13–18 years), and 1.6% for young adults (19–24 years) (2). These figures are in line with data from other studies (3) and are below the estimated 7% 1-year prevalence of childhood ADHD (4). The short-term efficacy of stimulants in ADHD is well established (5), yet despite eight decades of clinical use, there continues to be angst over it. Reviews call attention to the fact that there have been no long-term studies of stimulant use beyond 1 year (6), and this fact is often brought up by the lay media in discussions of the treatment of ADHD (7).

Previously, the Multimodality Treatment of ADHD study (MTA) found that after 14 months, structured medication management was superior to behavioral treatment alone or treatment as usual in the community (8). After the first year, all participants in the MTA sought whatever treatment was available, and as a result, the exposure to medication treatment was highly variable as the years wore on. The most recent follow-up examined medication usage, ADHD outcome, and growth at age 25 (9). Medication usage was assessed by interviewing the patient or caretakers—always an issue, as patients tend to overreport their adherence to medication regimens. The MTA defined being on “minimal” medication as taking 10 mg of methylphenidate (or its equivalent) per day more than 50% of the time. Based on this definition, the MTA sample was broken down into three groups: negligible (always below the minimum at all time points interviewed), inconsistent (below the minimum in most follow-ups), and consistent (above the minimum at all time points). This latter group consisted of only 35 individuals, or 7.3% of the sample. Not surprisingly, given this very low medication exposure, no relationship was found between ADHD outcome and medication usage.

The MTA could not address the question of the efficacy of stimulant medication use beyond 1 year, so there is a need to reliably establish the long-term benefits of stimulant use in ADHD treatment. There is also the practical clinical question as to how long to maintain a child or adolescent with ADHD on stimulants. A common question that is asked is whether the patient has “grown out of” his or her ADHD, such that the medication can be discontinued. In this issue of the Journal, Matthijssen et al. (10) report on the first double-blind placebo-controlled discontinuation study in ADHD patients who were continuously treated with methylphenidate for at least 2 years. The participants had to be on a stable regimen of either 36 mg or 54 mg of extended-release methylphenidate for the past 4 weeks; they then entered a blinded study in which they were randomly assigned either to remain on this dosage for 7 weeks or to undergo a 3-week taper to placebo followed by 4 weeks on placebo. Teacher, parent, and clinician assessments (all blind to study group) were performed at baseline and at 7 weeks.

Although the design was to enroll a sample of 120 participants, with 60 in each group, only 94 were enrolled, because of recruitment difficulties. As the authors state, “Many patients we approached did not want to participate in our discontinuation trial, as they argued that they ‘knew it still worked,’ based on experiences of stopping briefly or when they forgot to take their medication for a day.” This will not come as a surprise to clinicians, as many parents whose children have more severe ADHD are unequivocal about the medication’s efficacy and maintain their children on medication on weekends and during school vacations. At the end of the 7-week trial, 40.4% of the patients in the discontinuation group worsened, and only 15.9% of those who continued medication worsened. Furthermore, the authors found that the effect of continuing methylphenidate was significant in the younger participants (below the median age of 13.8 years) but not in the older group. This finding might be explained because ADHD symptoms may be more subtle in older patients and it may take longer for relapse to occur. Patients in the discontinuation group had worse scores on the ADHD Rating Scale, as rated by both parents (effect size=−0.23) and teachers (effect size=−0.52). The difference between parent and teacher ratings is also not surprising given the higher cognitive demands of the classroom. It is of note that 16% of the participants who remained on their stable medication regimen worsened, which is likely due to the “nocebo effect” of believing that one might be on a placebo.

Clearly, this study demonstrates that stimulant administration remains generally effective over 2 years of treatment; but what about the fact that 60% of those who were transitioned to placebo “did not worsen”? Will this finding result in headlines announcing that “60% of children with ADHD can be taken off medication after 2 years?” This conclusion would be premature, to say the least. All clinicians have had the experience of parents who have not restarted stimulant medication at the start of the school year, only to be called after the first 6-week grading period to restart medication because their child was failing several classes. The authors are correct in their conclusion that patients with ADHD should be assessed at least annually to see if discontinuation is possible, particularly for adolescents who seem to be functioning well when off medication. The medication should be restarted at the first sign of relapse.

Multiple other studies using large national or insurance databases are beginning to establish the long-term benefit of psychopharmacological treatment of ADHD. Relative to periods off medication, ADHD patients on medication have fewer motor vehicle accidents (11), have a lower risk of traumatic brain injury (12), are less likely to engage in criminal activity (13), have lower rates of suicidal behavior (14), and have lower rates of substance abuse (15). Thus the answer to the question “Is there long-term benefit from stimulant treatment for ADHD” is a definite “Yes!”

Department of Psychiatry, UT Health San Antonio, San Antonio, Tex.

• CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice
Birk

• Dr Berezin, if we remove all the brain tissue from the skull, depression will disappear; personality disorders, ADHD, bi-polar, anger, they won’t bother us a bit. Or say we remove all the neurotransmitters, same thing. Deprive our grey matter of oxygen for 8 minutes and mood disorders vanish.
Logic tells me with the few neurons I have left, that the brain must have something to do with us, you know?

• We are now being made aware of these issues. They’ve been around a long time. IMO

• ADHD was first identified in 1902 by British pediatrician Sir George Still. He described the condition as “an abnormal defect of moral control in children.” He found that some affected children could not control their behavior in the same way a typical child would. He did note, however, that these children were still intelligent.

• “Are stimulants safer than aspirin? Unequivocally, yes. Web MD lists 38 side effects of aspirin and many of them are potentially fatal. Taken daily as many do for various ailments, aspirin’s most lethal side effect is bleeding. It can lead to brain hemorrhage, bleeding in the stomach, hepatitis hemolytic anemia, decreased platelet cell ability to clot. Kidney difficulties, seizures, and life threatening allergic reactions are amongst other difficulties.”

Stuart L. Kaplan, M.D., is a clinical professor of psychiatry at the Penn State College of Medicine.

• “Look, we’re not going to agree on this. It’s a philosophical problem, not a scientific one. You have a set of assumptions, mostly that kids learn best by doing what they’re expected to in a regular classroom…”

Learning in a classroom stinks.

“it is the adults’ job to figure out the best setting for children to learn in and that adapting your approach to the children’s needs…” Amen!

I believe in doing everything possible to avoid medication. Special schools, the best teachers, experiential education, all the latest techniques, everything not to resort to meds.

I am a teatotaler, strictly. I hate what drugs/alcohol do to people. I don’t drink, smoke, drug, eat fatty foods, I exercise, blah, blah, blah.

I believe at this very momenbt there is a child somewhere who can’t do his schoolwork. He cannot learn. He fakes paying attention. He nods his head on the inflection of a voice. He smiles when someone nods his head. He smiles when he sees that others smiled at something. He compensates and has no idea what’s going on. He cannot follow directions; he doesn’t hear them. He’s tuned out and drifted off somewhere. He catches a word or two occassionally. He gets by the best he can. He simply cannot pay attention and he’s learning to despise himself. He is bored to death, almost literally. He assumes he must be as rotten as his folks tell him daily and his teachers reinforce constantly. Kids make fun of him and he gets into trouble and he has absolutely no idea, none, what he did wrong. He’s all alone and afraid and desperate.

I want him to know there’s hope. He is not at fault. He’s a good kid. Kids with ADHD often have big hearts and are extremely empathetic.

“People with ADD often have a special feel for life, a way of seeing right into the heart of matters, while others have to reason their way along methodically.”

The upside of being a person who feels so deeply, with such a high capacity for empathy, is that you’re often the best friend/parent/sibling/colleague, etc. that a person can have. You can read people well and understand what they’re feeling even before they express it.

– Dr. Hallowell

• Steve, where did you get the impression I oppose “open classrooms”? In many ways our public school system is a disaster. We need all kinds of improvements.
I built my own house. Had no experience. I read up on it. It was a lot of work but most people have the ability. I wanted to take what I learned and teach it in the field through schools as an experiential classroom. We would build a house together. To the extent that happened, the juvenile delinquents had a ball. They loved it.

I don’t want children or adults to be trapped by a very damaging disorder when there is help. It is painful for me to think that some may never know they had a true disorder. They are not to blame for their endless series of failures. It wasn’t their fault. Two nurses wrote a book, “You Mean I’m Not Lazy, Crazy, Or Stupid?”

• “why is it that study after study shows no improvements in long-term outcomes for medicated vs. non-medicated “ADHD”

“Is there long term benefit from stimulant treatment for ADHD?
Thus the answer to the question “Is there long-term benefit from stimulant treatment for ADHD” is a definite “Yes!” Department of Psychiatry, UT Health San Antonio, San Antonio, Tex.Sep 1, 2019”

• “How on Earth do you know that my children were “not as limited as many?” How could you possibly know that without meeting my children…”

Here’s how anyone can come to that conclusion, Steve. No presumption on the part of anyone. It is simple. Your kids were able to respond.

Blind people cannot see. No matter what they do or anyone else does, they cannot see. If a person has ADHD, he cannot improve his capacity to focus. Some suffer from severe ADHD. There is a continuum. Some have it mildly. Some are very intelligent. Some are below average. But, nothing they do changes their inborn neurologic flaw. Training, doesn’t change a thing, nor education, nor anything. Training education, support can make it easier to use whatever capacity the person has, but the flaw in our bodies remains. This is a neurologic deficit which means it is an abnormal function of a body area. This altered function is due to injury of the brain, spinal cord, muscles, or nerves.

Obviously, you disagree strongly. You insist no bio markers exist. That is not true, IMO. That’s why misdiagnosis is common. It is tricky. We know very, very little on the molecular level which disturbances yield.

• “There is, in my view, nothing offensive in the article. There is a widespread tendency among psychiatric adherents to confuse offense with disagreement. “I disagree with this” becomes “This is offensive.” If you feel that there is some sentence or passage that is offensive, please point it out and I will gladly take another look.” Dr. Hickey

You also said this: “You assert that “It has been proven again and again that people with ADD have ‘different’ brains and literally cannot pay attention to certain stimuli no matter what they do.” If you would cite me the references to support this assertion, I would be happy to take a look, and if your assertion is founded, I will acknowledge this in a subsequent post.” Dr. Hickey

I think it is only right that you reference your sources which document that “psychiatric adherents” confuse offense with disagreement. Regardless, she said she was ioffended. You offended her. She Felt offended. A book isn’t going to change how shje felt. Averages, statistics, manuals, theories, intellect, will not change how she felt when she read how you condemned people like her, that most people like her don’t have self-discipline.

• “I do agree 100% that different learning styles should be respected, and that more discipline to force “ADHD” kids into regular classroom environments is stupid. Of course, the real purpose of “medication” is to do exactly that, to force kids who don’t fit to modify their personalities and learning styles so as to be less inconvenient for the adults involved.” Steve Mcrea

That is insulting, unfair and nasty. You are condemning scores of people you’ve never met who worked just as hard as you and your family to help their children. That is a terrible thing to say.

Medication is intended to help the individual to pay attention. Then, he/she can learn through whatever style he/she may have.

• “In general, “ADHD” is essentially a lack of personal discipline.” Dr. Hickey

Doctor, would you explain to us how you came to this conclusion? I know people with ADHD symptomatology who are self-disciplined and it made a huge difference for them. They were very bright and had very mild symptoms. Others I’ve known couldn’t organize themselves no matter how hard they tried–until they took medication.

• “Others are passionately interested in their children’s welfare, but utterly clueless as to how to train them.” Dr. Hickey

Dr. Hickey, where can parents find the information you rely upon which will make them better parents? What sources do you recommend? Why did dedicated, educated parents like Mr and Mrs Mcrea have to work so hard to train their children?

• The diagnosis rests upon a careful history taken from the identified patient as well as at least one other person. This could be a parent, spouse, sibling, or close friend, as well as, if possible, teacher comments.

“And it needs to be noted particularly that since 1994, the only requirement under this item for adults and adolescents is that they experience feelings of restlessness!” Dr. Hickey.
That is incorrect. See below

That is one of 5 symptoms and the symptoms of hyperactivity and impulsivity must have been present for at least 6 months, and they are inappropriate for developmental level. Also, they be present by age 12.

As children grow older, they often develop strategies to help them control some of the more elementary forms of hyperactivity, but that uncomfortable urge to squirm and move about burns inside. Aerobically demaning activities often soothe that desire.

• I love kids. I want the best for everyone of them. I don’t want any child to be harmed in any way, ever. That’s where I’m coming from. I don’t want all kids to be moulded into a certain type. Last thing on my mind. I do want kids to reach their full potential, whatever that may be. A mind is a terrible thing to waste and if a child or an adult cannot process what is taking place around him, that limits his options to do and to be what he can do and who he wants to become. If orange juice was as effective as meds seems to be, I’d be advocating consuming thousands of gallons!

• You didn’t answer my questions.

“There is also an abundance of research going back to the 60’s that demonstrates clearly that children who are habitually inattentive, impulsive, and hyperactive even to an extreme degree, can be trained readily to behave in a more productive and less disruptive fashion”

What is meant by “more productive”? For herself or for others she is not disrupting? I am interested primarily in the documentation which shows that extreme examples of children manifesting hyperactivity, a lack of concentration and impulsivity are “readily” trained to be more productive. I would like to see how they quantified, specifically, their increased productivity.
Also, a child can be scared into being quiet. That is true and rather obvious. Remove the immediate threat and what happens? I will state with confidence that those children learned just as much when they were not trained. ADHD is a biological/chemical/electrical/organic malfunction of the brain and training will not and cannot improve concentration. A business advertising that claim got into hot water and had to stop.
In addition, would you cite the supporting research which shows that parents prior to the 1960’s knew how to raise their children better than succeeding generations, please.
Why don’t those “ADHD” children snap out of their funk immediately and permanently? Did something damage the structure of their brains? What is holding them back? Why do the majority of ADHDers respond immediately to the medicinal properties of stimulants and begin to concentrate instantly?

Thank you in advance for any cooperation

• Statements here are from MIA’s paper on long term impact of ADHD drugs.

The “Reply” button is not available often when others are directing questions my way. I cannot respond directly. I mentioned this before.

“However, the drugs have not been shown to improve classroom performance…”

“The APA first created a diagnosis called Attention Deficit Disorder in 1980, when it published the third edition of its DSM.”

It was discovered and called something else, MBD, over one hundred years ago.

“Given that there is no biological marker for the disorder”

there is now

“there is an obvious subjective element to making the diagnosis. What may be seen as a problem in one setting—by a parent, teacher, or pediatrician—may be considered normal behavior in another situation.” for example?

“whereas 13% of elementary-school children in the United States are said to have ADHD…”
Who says that? It is not the majority opinion.

“only about 2% of children in the UK are seen as exhibiting attention-deficit type problems”

“The long-term effects of ADHD drugs on the brain are not well understood, or even well studied” You see, there are a range of opinions on this.

“Is there long term benefit from stimulant treatment for ADHD?
Thus the answer to the question “Is there long-term benefit from stimulant treatment for ADHD” is a definite “Yes!” Department of Psychiatry, UT Health San Antonio, San Antonio, Tex.Sep 1, 2019”

Steve, I run across your opinions occassionally. I don’t know when you respond to something I’ve said to someone else. I notice you have not answered several questions I asked. People disagree about the long term benefits of treatment with meds.

Why do you believe your kids needed (and received, thank heavens) extraordinary care?

• Taking a daily aspirin is far more dangerous than was originally thought and causes more than 3000 deaths a year in Britain, a major study suggests. Millions of British pensioners take the blood-thinning pills to ward off heart attacks and strokes.

• Steve, why condemn others for insulting and condescending when you cheer on condescending and insulting comments? How do you suppose others feel who disagree with her point of view and when as a moderator you encourage it?

Kids learn differently. But, if they can concentrate, they learn. When you cannot pay attention, you are at a big disadvantage.

A REPLY button does not show up under your comments at times so I try to respond the best way I can

• I cannot respond to your most recent criticism through the reply mechanism. so I’ll try here. I can see what you mean and I apologize for presenting my viewpoint in a condescending, dismissive fashion.

WE disagree about the nature of this disorder. Your children were not as limited as many are and you did do a great job.

Many children cannot, no matter what anyone else does or doesn’t do, pay attention. They are like legally blind people. Often, they respond to medication when nothing else works.

That’s why I advocate for anything that will work to help them. ADHD is not just a matter of guessing. It is not loosely defined. It is not something that responds significantly, most of the time, to structure and training and carrots or jails.

Many who comment here condemn anyone who doesn’t hate psychiatry and psychiatrists, including you. You are a cheerleader, regularly, for the most nasty and vicious and hateful participants. and You are not open minded. No offense Steve, but you, for some reason believe you have all the answers, but you don’t. No one does. What you accomplished with your kids is astonishing, but most kids are not your kids. I fear you lose sight of that. Many condemn parents who have tried very hard, including you. Many condemn teachers, some who don’t deserve it, you included.

You suggest I like drugs. Caffeine is a drug don’t forget. I’ll tell you what I like best of all: to know that everyone who needs help gets it, whatever it is as long as it doesn’t do more harm than good and I know mant people who are different people today, so grateful for medication that saved their lives. I don’t see that you too are happy they have found such significant help. Why? Remember thius too. I was not directing my opinions at you. I think you are taking too personally differences of opinions, but I do apologize for implying you didn’t care about your own kids. Big oversight. Sorry bro.

• “In short term studies, ADHD medications have been shown to be effective in reducing core ADHD symptoms, such as task irrelevant activity (e.g. finger-tapping, fidgetiness, and and off-task behaviors), and classroom disturbance.” MIA

MIA recognizes ADHD exists and that the core symptoms respond favorably to medication. That is a bold thing to do.

So, it is! and can be managed initially, through the use of medication. Unfortunately, they don’t mention what else is is included in the list of the core symptoms that improve: the child’s ability to pay attention. Most likely for the first time in her life! For The First Time in Her Life!
The secondary benefits of medication are that the child’s behavior improves. Just like that, with no training, without instructions or anything else. That is certainly impressive, but again that is not what we hope to achieve ultimately for the child. Those are secondary matters. What MIA omits is by far the most important result, that is that the child’s brain starts to work. We are not drugging anyone. That is a perverse notion. We are giving the child the ability for the first time in her life to use her brain as intended, not to make her incoherent. Just the opposite. He can sit still and calmly participate in the school setting Because his brain can focus on what it is supposed to. That, to me, is miraculous. Nothing else is known to give that ability to anyone who cannot function due to ADHD. If someone is diagnosed with ADHD but does not need chemical intervention to gather, to focus on and to process information in order to manage her daily life within reasonable guidelines, they don’t need medicine.

What MIA has made clear at the beginning is as follows. ADHD is.

Forget all the rest for a minute. For one minute concentrate your attention on what MIA just acknowledged! What MIA has just stated clearly, officially, and formally, is just this: ADHD responds to proper medical intervention.

That is an excellent place to start a discussion and an analysis of what we can and need to do now. Children await our decisions. Their futures are are at stake every day.

(When I go to edit my comments, the content shows up in a square outline and it doesn’t include the margins. They get cut off and I can’t see everything I’ve written.)

• Steve, several times I have asked the person who wrote the particular comment for him or her to respond, not you. You are welcome to respond. I point this out for clarification. I hope the ones I asked questions will not be confused. I want their input, too.

• You have drifted off the topic. I am not just discussing the origins of ADHD directly.
If training is the answer as explained previously, I challenge that opinion through a few questions and examples. Bear in mind not every one who believes medication can be a valuable tool for many afflicted with this disorder is a cold blooded killer. Some of them love and care about children very sincerely. Not every argument they make in favor of using medication as called for and under the supervision of a competent, experienced, true-blue doct is made by greedy, psychopathic, crimminally minded, worthless, raving lunatics out to destroy children at any cost.

“Drugging children” is a horrible term. It is misleading and wildly inappropriate. I don’t want to send anyone into a stupor. I don’t want to control any one. My hope is that medication can serve like a pair of glasses. That’s all. If someone doesn’t want improved vision, fine. Should every child who has debilitating problems with their eyesight be offered a vision test? Sure. Should all of them be forced to wear glasses? Of course not, but some believe so. They misinterpret the others’ intentions. Ascribing the worst, most immoral motives to just about everyone who views ADHD as a medical matter is a terrible mistake, for the CHILD.

• I think they have gone too far for too long with Ms. S. Way too far. Way, way too long.
I think she endangered her family with risky, irresponsible, immature behavior frequently and she needed to grow up and get well before she could be in charge again.

• Trained, experienced professional health care workers can spot illness that may be hidden to others. People work tirelessly to build defense mechanisms to mask their raw selves.
I would would offer instead that our world is filled with people who have serious issues and there is much more awareness about these kinds of things today. So much more information is available today compared to 10, 20, 30, 40, 50 years ago.

I think most of us are pretty good at mistreating others as a rule.

• Your children functioned without medical intervention. Say they didn’t. Say nothing you did made it possible for them to learn in any setting? What then?

• This adhd thing you speak of is NOT an abnormality because you deem it as such.

What is it? What do you deem it as?

What do you recommend are the best ways to help a severely ADHD chikd? Any thoughts? Thanks

• Dr. Hickey, which treatment modalities have you had most success with as you worked with young children with so called ADHD? Have you assisted children to become more attentive? What worked best, what style or method yielded the best results? Did any of your most severely afflicted kids make significant progress which continues today?

• ADHD is an illness according to Birk. It is a disorder if nothing else, it is destructive, and it lasts for years, and most often responds to the introduction of powerful chemicals.
No matter how you classify ADHD, how would you help a third grader who no longer tries in school? He cannot follow along. He’s had excellent training and is of normal intelligence. His folks have sat next to him in class. First and second grade were wonderful experiences. In third grade the work became considerably more demanding. Nothing has worked. He is not disruptive. He is polite, sits still and isn’t learning. He is way behind. If he doesn’t turn this around immediately, he will never catch up.
Please be specific if you don’t mind, or at least give guidelines that you’ve found helpful with other children.

Thanks

• “The essential feature of illness is that there has to be biological pathology. Problems that do not stem from structural or functional biological pathology might be serious problems, but they are not illnesses.”

ADHD is an illness according to Birk. It is a disorder if nothing else, it is destructive, and it lasts for years, and most often responds to the introduction of powerful chemicals.
No matter what how you classify ADHD, how would you help a third grader who no longer tries in school? He cannot follow along. He’s had excellent training and is of normal intelligence. His folks have sat next to him in class. First and second grade were wonderful experiences. In third grade the work became considerably more demanding. Nothing has worked. He is not disruptive. He is polite, sits still and isn’t learning. He is way behind. If he doesn’t turn this around immediately, he will never catch up.
Please be specific if you don’t mind, or at least give guidelines that you’ve found helpful with other children.

Thanks

• Thanks. Appreciate all you said, Glad you are thriving. Walking in someone’s else’s shoes can make all the difference.
Unfortunately, I haven’t seen alternatives proposed for the individual who cannot concentrate that make sense. It is easy to criticize, but when it’s time to offer workable options, silence shows up.

• I am interested in the views of everyone here not just yours no offense intended. This subject is far from closed as far as I’m concerned. If you are done, thanks for your contribution.
The sgnificance in Rappaport’s study is not that both groups responded in the same fashion. That is irrelevant. What she observed but didn’t comprehend, apparently, is that people who were blind could see!
The “issue” regarding how the stimulants acted upon the different groups means nothing. Why wouldn’t the same chemicals impact most human beings similiarly? Why wouldn’t stimulants improve the mental acuity of everyone? Helping those who struggle to focus isn’t magic. Whatever is present in the brains of “normal” people seems to be in short supply or not working as intended in the brains of those who are really hindered by this problem. By introducing a particular chemical that can pass through the BBB, known to stiumulate “typical” brains, we are only observing what we would expect.

The almost immediate impact of a stimulant on the brain simply makes sense. It only takes a few moments for the chemical to be taken to the brain and into the neurons. Obviously, that is where the action is, or is supposed to be. If the poorly trained children are instructed to, “Sit up. Be quiet. Pay attention!” Why don’t they respond immediately? There’s nothing wrong with them, right? The kids who were inattentive because of “poor parenting” and given a stimulant don’t need to be told anything. (They’ve heard it millions of times before anyway!). Without a word from anyone they ARE paying attention–without even trying. That’s what brains are supposed to do. Infants pay attention. Children, little 2, 3, 4 year old kids learn to speak a language. No one trains them to pay attention so that they can master what adults find nearly impossible–learning a new language. They just do. Their brains are designed to pay attention.

• “Could you PLEASE respond to my very valid points regarding the CDH2 mutation NOT being established to exist in all or most or even any kind of percentage of so-called “ADHD” sufferers?”

I did respond. I’ll try again. What difference does it make if the cause of ADHD is reflected in people given that label? If everyone of them was misdiagnosed, how would that alter the known cause? What we do know now is that ADHD has at least one known biological cause. Again, if everyone so diagnosed before this discovery does not have this biological flaw, that would have no bearing whatsoever on the reality of ADHD.
There may be numerous other physical causes. We are just beginning to get a glimpse of all the various components that caused the form of ADHD discovered through this research. There are thousands of different cancers. We discovered one, so to speak. We are merely at the threshold of scientific breakthroughs. We have barely scratched the surface. However, if we never find another medical cause, we know without a doubt that ADHD is the result of flaws within the human organism.

My turn, if you don’t mind. What is the worst possible outcome for mankind and for you knowing what Birk’s research shows? Is there a specific reason that you are not rejoicing over this revelation? What is so awful, so terrible, so shattering for you personally? What difference does it make? The most important issue is applying what we learn to help others who struggle and often fail to concentrate when they need to? Shouldn’t we all be grateful for every piece of information that can be used to help others? Isn’t that what we are all striving for?

• ‘It is mostly up to us users and survivors to preserve the memory of those murdered in the name of psychiatry in our hearts.’

Users of psychiatry as practiced in Nazi Germany? Users of murdering psychiatrists since WW2? All psychiatrists are murderers? I’ll look for her biography.

• “There is also an abundance of research going back to the 60’s that demonstrates clearly that children who are habitually inattentive, impulsive, and hyperactive even to an extreme degree, can be trained readily to behave in a more productive and less disruptive fashion”

What is meant by “more productive”? For herself or for others she is not disrupting? I am interested primarily in the documentation which shows that extreme examples of children manifesting hyperactivity, a lack of concentration and impulsivity are “readily” trained to be more productive. I would like to see how they quantified, specifically, their increased productivity.
Also, a child can be scared into being quiet. That is true and rather obvious. Remove the immediate threat and what happens? I will state with confidence that those children learned just as much when they were not trained. ADHD is a biological/chemical/electrical/organic malfunction of the brain and training will not and cannot improve concentration. A business advertising that claim got into hot water and had to stop.
In addition, would you cite the supporting research which shows that parents prior to the 1960’s knew how to raise their children better than succeeding generations, please.
Why don’t those “ADHD” children snap out of their funk immediately and permanently? Did something damage the structure of their brains? What is holding them back? Why do the majority of ADHDers respond immediately to the medicinal properties of stimulants and begin to concentrate instantly?

Thank you in advance for any cooperation

• A few highlights of their research

The p.H150Y mutation we identified is within the recognition domain of the protease responsible for this endogenous modification, and as we demonstrate through biochemical studies, impacts this tightly regulated post-processing. Also, long-term expression of an aberrant N-cadherin was demonstrated to reduce synapse connectivity. Accordingly, our in-vitro results support deficits in synaptic formation as an intriguing mechanism underlying the patients’ clinical manifestations.

This stuff is beyond fascinating. What they are discussing are the very building blocks, miniscule, tiny, itsy-bitsy molecules that constitute human thoughts!

Thus, our data support the postulation that replacing histidine with tyrosine debilitates the anchoring of the peptide within the catalytic pocket of furin protease and putatively impairs N-cadherin protein maturation.

Goodness gracious! The depth of their testing and understanding of the microscpic inner workings of the most complex structure in the universe is phenomenal.

BTW, N-cadherin a calcium-dependent cell adhesion molecule, is essential for normal CNS development. Homophilic binding of N-cadherin depends upon a specific conformation assumed by the molecule when it binds calcium. N-cadherin is a substrate for a specific zinc-dependent protease. The reliance of N-cadherin on two cations for proper function makes it a potential target for toxicants which act by replacing or modifying calcium or zinc at ion-binding sites. Exposure of the developing brain to lead, an ubiquitous toxicant known to interact with calcium, disturbs neural tube closure and subsequent maturation of the nervous system. Preliminary data indicates that lead may induce these effects by direct interaction with N-cadherin. Numerous common toxicants, including metals and solvents, also perturb cadherins and cause defective CNS development. These data indicate that changes in the spatio-temporal expression of cadherin can result in profound alterations in neural structure and function, and may underlie CNS malformations caused by numerous toxic agents

• Ned Hallowell, who came from money, has ADHD (and dyslexia.)
The person you responded to was thrilled to be able to pay attention. He was shocked by the ability to do that. Shocked and thrilled. Paying attention doesn’t equal turning into what everyone else is anymore than giving glasses to everyone who needs them turns them into the same person.

We now know that ADHD is the result of the roles of certain CDH2 pathways. CDH2 mutation affects N-cadherin function and causes attention-deficit hyperactivity disorder in humans and mice. Familial ADHD is caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein.

“CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice”

It is not the end of the world that some people need medical help to pay attention. It isn’t disempowering, either. It is an opportunity to thrive.

• Hey, Thanks for the explanation. I appreciate it.

• The quote regarding long term improvements is from PubMed.
Birk and his team have left deniers behind. It is over for this very small but very vocal band of conspiracists. The debate about whether or not ADHD exists based on a biochemical flaw is done. It is finished. And, to pretend that ADHD is still somehow bogus, while simultaneously brutally condemning the parents for it, is beyond absurd. It is insane. “It isn’t real, but the p​arents are to blame for it.” “There is no such thing, but by golly, the parents are the ones responsible for it.”
There is no question that medical intervention conducted by experienced specialists reaps numerous and significant improvements/enhancements in the lives of the war torn.
The vast majority of thinking people recognize ADHD a serious neurological disorder that often requires medical intervention. It is not questioned by most respected, educated health care experts and with this breakthrough research, the few, small vestiges of doubt will vanish for good.
Adult survivors of various kinds of abuse, deprivation and horror are often the best sources to bring awareness to society of the reality of the terror they endured. So too, adult, mature survivors of life before proper treatment will convince the world what a nightmare ADHD has been. Innocent children and fearful adults will no longer be second class disabled citizens, rejected and dismissed, humiliated and scorned. That day is rapidly approaching. Thank you again, Dr. Birk.

• My responses aren’t directled solely to you but are intended to benefit all who are interested in this fascinating topic. I encourage anyone to raise questions. You are reaching. Your “arguments” are far removed from what is now known: “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice.”

This is a fact. It is proven through published research. Attack the research, vigorously, not matters that don’t acknowledge that fact. It is foundational. It may bear repeating dozens of times to allow it to sink in. This isn’t theoretical. It is not a hypothesis or a best guess.

You miss the point. Your concerns/objections have nothing to do with the facts which he proved. If you find fault in his testing protocol, in his math, calculations, etc., it is up to you to demonstrate what he/they did wrong. He established that 2 plus 2 equals 4. 1 plus 3 equals 4, but that is not what he prooved and it has nothing to do with his conclusion. He published peer reviewed, detailed explanations regarding each step (and more) he took to reach his conclusion. This reseacher proved “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice.” You have failed utterly to dispute that. Not one of your objections has anything whatsoever to do with this: “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice.” Discussing anything/everything else besides what he prooved has no bearing on that fact.
Trying desperately to deny reality doesn’t change a thing. He did it. He and his colleagues found the cancer. It is right there in black and white, you see. It does exist. It is real. He found it. It is an astounding, marvelous achievement. Many accepted it was only matter of time. Others, for some inexplicable reasons, assured everyone it could not be done; they were positive it was all explained away by poor parenting, poor diets, luke warm educators, greedy doctors and bigpharma.
This is a significant breakthrough and soon will be accepted throughout the scientific commuity and around the world. It is huge and I for one am delighted that such a dedicated and respected scholar, scientist, PhD, and a medical docotor without conflicts of interest, who studied this matter exhaustively, found the answer. It wasn’t easy. They worked extremely long and hard and deserve our gratitude.
I encourage you once again to take your concerns to him. You have nothing to lose.

• Have you, or, will you, consider that the child wants to learn? She goes to class eager to learn. She wants to follow along, to contribute. She wants to understand what is being taught and discussed. However, for some unknown reason she sits in class and tries to follow along, but she can’t. When she’s called on, she blushes and can’t respond. She’s laughed at. The teacher moves on to another student and the child is embarrassed, hurt, confused and feels all alone and afraid. What about her?

• What if the child is unable to pay attention in school or in sports?

• Sounds a lot like “blaming the victim” to me.

They are legally blind or nearly deaf, but no one understands these things including themselves. Blindness and deafness are not acceptable problems. They are excuses in this analogy. No one needs glasses or hearing aids or sign language. That’s what they run up against when they say they can’t see the blackboard or hear the teacher. They want to engage in life just like others do, but they can’t. They are held back by physical limitations. (But no one knows about this stuff.) They are bad and they hate themselves and they should. They are good for nothing spoiled bums. If they wanted to do well in class and have friends, they would straighten out. That’s what they are taught every where they go. “Try. Quit screwing around. You’re lazy. You just want to sit around all day and do nothing but watch t.v. and fart around with your loser friends.”

No one understands, including themselves. They buy into what others say about them and soon they hate. They hate themselves and everyone else. They are called stupid and excluded, all the while they long to participate, they long to engage in life.

One day mom takes her to what they call an “eye doctor”. She’s transformed over night, even though some don’t believe in eye doctors or hearing specialists or speech therapists.

• Have you, or, will you, consider that the child wants to learn? She goes to class eager to learn. She wants to follow along, to contribute. She wants to understand what is being taught and discussed. However, for some unknown reason she sits in class and tries to follow along, but she can’t. When she’s called on, she blushes and can’t respond. She’s laughed at. The teacher moves on to another student and the child is embarrassed, hurt, confused and feels all alone and afraid. What about her?

• They have nothing more to prove. It is done. They found what causes ADHD.
It is very simple.

Contact Dr. Birk if you disagree.

causes attention-deficit hyperactivity disorder in
humans and mice.”

• There is a tremendous shortage of school bus drivers nationwide. Things happen. We don’t always know why. Like Dylan said when asked about his burst of success and fame back in the early 60s. He shrugged his soldiers and said with a profound look of innocence, “It just happened. I don’t know. It just is. It’s the way things turned out, that’s all” or words to that effect.

Something that troubles me more and more is the carnage, the broken bodies torn asunder through the vicious, violent, debauchery promoted endlessly and enjoyed by millions every Sunday as boys try to prove they are men donning plastc armor and cheered on by half naked women.

• “CDH2 mutation affecting N-cadherin function
causes attention-deficit hyperactivity disorder in
humans and mice.”

This is a fact. It is proven through published research.

• “Outcomes from 351 studies were grouped into 9 major categories: academic, antisocial behavior, driving, non-medicinal drug use/addictive behavior, obesity, occupation, services use, self-esteem, and social function outcomes. The following broad trends emerged: (1) without treatment, people with ADHD had poorer long-term outcomes in all categories compared with people without ADHD, and (2) treatment for ADHD improved long-term outcomes compared with untreated ADHD, although not usually to normal levels.”

I think, therefore, I am. ADHD is defined, acknowedged, studied, prevalent, injurious, reported on, etc. I believe it is proper to say that, “it is.”
Two years may not be long enough to determine the long term outcome of treatment for ADHD.

I recommend personal interviews in addition to the other tools used to measure outcomes.

We now know there is a biochemical basis to ADHD. See Ohad Birk

• “CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice”

A summary of the data

• “The world punishes autistic people for displaying their autistic traits, leading to masking even without interventions. Being rejected, marginalized, and receiving the constant message that everything that is intrinsic to them is wrong or unacceptable is a continuous source of trauma: society rarely produces non-traumatized autistics. Chronic stress, masking, and having to constantly conform to neurotypical social expectations are often cited by autistic people as a major contributor to autistic burnout—a devastating and, for many autistics, recurring condition with substantial negative effects on functioning, wellbeing, and quality of life.”

Very interesting. Truly.
A question occured to me as I read your through your thoughtful concerns. Could you make the same observations about other groups of people who are marginalized, rejected, and told repeatedly they are intrinsically wrong? But, what if they agree? What if they view themselves with disdain and contempt, yet long to be “okay” one day, who crave change?
What if medical intervention could set them free? What if psychiatrists could relieve their suffering, from lives never lived, from potential never realized?

• To conclude, we demonstrate that a novel mutation in CDH2 is associated with familial ADHD, through impaired presynaptic vesicle clustering, attenuated evoked transmitter release, decreased spontaneous release, and reduction in dopaminergic distribution within limbic pathways. We thus delineate the role of CDH2-related pathways in the pathophysiology of ADHD.

Finally, let me encourage you again to study in its entirety the documented data published regarding this research.

Res ipsa loquitur

• My efforts to add data from the research appears to be rejected for excessive size.

Behavioral experiments – detailed
Open-field
The apparatus consisted of a square arena measuring 50X50X33cm under 15 lux illumination. The outer walls were wrapped with white paper to limit external stimuli and light gradients. Mice from both genotypes were allowed to explore the arena for 6 min, while their location was tracked and recorded by a video camera positioned overhead. The time spent in the central zone of the arena (10 × 10 cm) was extracted.

Elevated plus-maze
The apparatus consisted of four arms (30 × 5 cm each) extending from a central platform (5 × 5 cm). One set of arms, opposing one another, was enclosed by a 15-cm wall (‘closed arms’), while the other set was open with a 1-cm ledge on either side (‘open arms’). The maze was elevated 75 cm above the ground with illumination set 15 lux. Mice from both genotypes were placed in the central platform and allowed to explore the maze freely for 6 min. Entry into an arm was scored when the center of mass of the animal had entered an arm. The time spent and entries into each arm were extracted for analysis.

Y-maze
A spontaneous alternation test was performed to assess executive functions. The Y-shaped maze consisted of 3 plastic arms placed at 120° angles to each other. Mice were placed at the end of one arm and were allowed to explore the maze freely for 6 min without training, reward, or punishment. An alternation was defined as a complete cycle of consecutive entrances into each of the three arms. Percent alternation (PA) was calculated as follows: PA = number of alternations/(total number of entries into each arm – 2).

Resident-intruder
A test for aggressive social interaction. The intruder mouse is introduced into the cage of the test resident mouse following habituation. The observation starts when the resident first sniffs the intruder. The observation stops when the first attack (by either mouse) occurs, or when no attack has occurred by 5 min observation71.

Acoustic startle reflex (ASR)
This test evaluates an animal’s level of stress/arousal by measuring the extent of audible tone-induced flinching after acclimatization to background noise. Startle trials consist of a single noise burst (120 dB, 40 ms), thereafter the amplitude of animal flinch is recorded. Mean startle amplitude is calculated in a fully computerized, blinded, and unbiased measurement.

Pre-pulse inhibition (PPI) of the ASR
PPI is a measure of sensorimotor gating used to identify deficits in early-stage information processing. PPI trials consist of a pre-pulse of intensity 2, 4, 8, or 16 dB above background noise followed 100 ms later by a startling pulse (120 dB, 40 ms). Sessions are designed to include acclimation, pre-pulses, and pulse trials.

Rotarod
A test of motor abilities, which requires mice to balance on a rotating cylinder. The test consisted of three 4-minute trials. During each trial, rod rotation gradually increased up to 40 rotations/minute. The duration mice were balanced on the rod in each trial was measured. Trials were divided by at least 20-minute breaks, to avoid mice exhausting.

Three-chamber sociability test and social novelty test
Aims to evaluate animal levels of sociability (preference of an unfamiliar mouse over an object) and preference for social novelty (preference of a novel stranger over a familiar one). The device used in this test consists of three chambers (left, right, and central); the middle chamber is connected to the others via doors. In the habituation phase, the animal is allowed to explore the device freely for 10 min. In the second sociability phase, a stranger mouse is placed in one of the lateral chambers (inside a specially devised cup with bars). In the social novelty phase, another stranger is similarly introduced into the other lateral chamber. During phases 2 and 3, time spent in each chamber, the number of approaches to each stranger mouse and their frequency are tracked and recorded72.

Mice were administered with Methylphenidate hydrochloride (Biotechne 2 A/248099, UK)73; Methylphenidate (MPH) was dissolved in 0.9% normal saline and diluted to 1 mg/ml. Male 14-week-old C57BL/6JRcc WT (Envigo, Israel) and Cdh2H150Y(1/2) mice (n = 39) were weighed and injected with MPH or vehicle (0.9% saline solution) via intraperitoneal injection at 10 mg/kg body weight, 30 min before the initiation of tests. MPH dosages were chosen based on previous studies in rodents suggesting that these MPH dosages mirror those that are used in clinical practice15. MPH experiments were approved by the Hebrew University Ethics Committee on Animal Care and Use (Applications MD-20-16347-3).

Primary dense hippocampal cultures
Primary dense hippocampal cultures from P0-P2 pups of either sex were generated. Briefly, postnatal day 0–2 pups from WT and Cdh2H150Y littermates were decapitated and their brains quickly removed; hippocampi were dissected, sliced manually, and kept on ice in Hank’s Balanced Salt Solution (Biological Industries, Bet-Haemek, Israel) supplemented with 20 mM HEPES (termed HBSS; Biological Industries, Beit-Haemek, Israel) at pH 7.4. Hippocampus pieces were incubated for 20 min at room temperature (RT) within a digestion solution consisting of 5 ml HBSS, CaCl2 1.5 mM, EDTA 0.5 mM and 100 units of Papain (Worthington, Lakewood, NJ) activated with Cysteine (Sigma-Aldrich, Rehovot, Israel). Brain fragments were then gently triturated twice. Cells were seeded at a density of 80,000–100,000 cells per well on 12 mm #1 glass coverslips (CS; Bar-Naor Ltd, Ramat-Gan, Israel) coated with poly-D-Lysine (Sigma-Aldrich, Rehovot, Israel). Initially, cells were plated in a plating medium consisting of Neurobasal-A medium supplemented with 2% B27, 2 mM Glutamax I (Thermo-Fisher Scientific, Waltham, MA), 5% defined FBS and 1 μg/ml gentamicin (Biological Industries, Beit-Haemek, Israel). After 24 h, the plating medium was replaced by a serum-free culture medium consisted of Neurobasal-A, 2 mM Glutamax I, and 2% B27. Cultures were maintained at 37 °C in a 5% CO2 humidified incubator for about 12-15 days prior to staining and imaging.

Immunocytochemistry of hippocampal cultures
Days in-vitro (DIV) 8 and DIV 14 hippocampal neurons were fixed with 4% paraformaldehyde (EMS, Hatfield, PA) in PBS for 10 min, rinsed with PBS, permeabilized with 0.1% Triton X-100 in PBS for 2 min, blocked with 5% powdered skim-milk (Sigma-Aldrich, Rehovot, Israel) in PBS for 1 h, rinsed, incubated with the primary antibody for 1 h, rinsed, incubated with the secondary antibody for 1 h, rinsed, and mounted in immumount (Thermo Fisher Scientific, Waltham, MA). All steps were performed at RT. Primary antibodies used: rabbit polyclonal anti-Synaptobrevin 2 (1:1000, Synaptic Systems), goat polyclonal anti-vesicular glutamate transporter-1 (vGlut1, 1:1000, Synaptic Systems), mouse monoclonal anti-Glutamic acid decarboxylase-6 (GAD-6, 1:1000, developed by D.I. Gottlieb, obtained from the Developmental Studies Hybridoma Bank, DSHB). Secondary antibodies used: Donkey anti-mouse IgG and donkey anti-rabbit IgG, labeled with Northern Lights 637 or 557, respectively (1:1000, R&D Systems), and donkey anti-goat IgG, labeled with AlexaFluor 647 (1:1000, Abcam).

Semi-quantitative synaptic immunofluorescence
To allow for a semi-quantitative comparison of immunostaining intensity of synapses, WT, and mutated Cdh2H150Y hippocampal neurons were processed under identical conditions. Synapses were detected semi-automatically using an in-house iterative algorithm based on serially decreasing to thresholds implemented in NIS-elements software (Nikon). Fluorescence values for each synapse were obtained from an area of 3 × 3 pixels located on its center of mass and an image average was generated. Because intensity values can vary from session to session, a normalization value was determined from the WT experiments of each session and further used to normalize all images acquired during that session, both WT and mutants. The normalized values were either averaged or used to compute cumulative distributions. Puncta that were positive for GAD65 were deemed GABAergic since GAD (Gamma-Amino Decarboxylase) is a vesicular enzyme mediating convergence of glutamate to GABA74; otherwise, they were considered glutamatergic.

Fluorescence microscopy of neuronal cultures
Fluorescence measurements were performed on a Nikon TiE inverted microscope driven by the NIS-elements software package (Nikon). The microscope was equipped with an Andor Neo 5.5 sCMOS 12 bit camera (Oxford Instruments), a 40 × 0.75 NA Super Fluor objective, a 60 × 1.4 NA oil-immersion apochromatic objective (Nikon), a perfect-focus mechanism (Nikon), and EGFP and Cy3 TE-series optical filter sets (Chroma), as well Cy5 filter set (Semrock).

Synapse width analyses
Synapse width was measured by drawing a line starting in the axon and through the synapse punctum, and fitting it using a Gaussian function as follows75:

$$y={y}_{0}+A{e}^{-\frac{{\left(x-{x}_{c}\right)}^{2}}{2{w}^{2}}}$$
(1)
Where xc is the center of the punctum maximum, y0 is the fluorescence of the axon, w2 is the variance of the Gaussian, and A is its amplitude. The full width at half-maximum (FWHM) fluorescence intensity is calculated as follows:

$${FWHM}=2w\sqrt{{{{{{\rm{ln}}}}}}(4)}$$
(2)
Fitting was performed by the least-squares error method using Origin 2020 (OriginLab). Independent images were acquired from cells grown on various coverslips obtained from a minimum of three different cultures. A mean FWHM was determined for each image, and then a grand average was calculated for WT and mutant cultures.

Neurons were initially placed in normal saline (in mM: 150 NaCl, 3 KCl, 10 HEPES, 2 CaCl2, 2 MgCl2, 20 Glucose, pH adjusted to 7.35 with NaOH), then loaded with FM1-43 at a final concentration of 10 μM by depolarizing them for 2 min using hyperkalemic saline (90 KCl, 63 NaCl, otherwise as above) in the presence of the dye. The neurons were exposed to the dye in normal saline for an additional 5 min after depolarization, to allow labeling related to endocytosis to be completed. Afterward, neurons were washed with normal saline for 5 min, followed by 5 min washing with 1 mM ADVASEP-776 in normal saline. Finally, the cells were washed in normal saline and imaged. The cells were stimulated twice, once for 2 s at 20 Hz to access the size of the RRP and a second time for 120 sec to access the RcP, following a minute of recovery. The degree of unloading was calculated as the change in fluorescence (ΔF) normalized by baseline background-corrected fluorescence F0. Experiments were performed at RT in the presence of APV (50 μM) and DNQX (10 μM) to reduce destaining due to spontaneous network activity77.

Measuring vesicle cycling using sypHy
SypHy is a probe based on the internal fusion of a pH-sensitive GFP called pHluorin78 (pKa = 7.6), with the vesicular protein Synaptophysin I (SypI), so that pHluorin is located in the lumen of the synaptic vesicles (SVs) and allows the reportage of presynaptic activity31,79. Briefly, pHluorin fluorescence is quenched by the acidic pH of the intact vesicle lumen (pH~5.5). Upon stimulation, SVs fuse with the plasma membrane, thus exposing their lumen to the neutral pH of the extracellular environment (pH~7.3), causing an increase in the fluorescence of pHluorin. Following endocytosis, pHluorin is re-quenched due to the reacidification of the lumen by the vesicular proton pump (vATPase). Therefore, an increase in fluorescence reflects the exocytosis phase, and the subsequent decrease in fluorescence indicates the endocytosis phase of the vesicle cycle. The kinetics of exocytosis is determined by examining the time course of an upsurge in fluorescence upon stimulation in the presence of bafilomycin A, an inhibitor of the vATPase80, which inhibits neurotransmitter loading but not vesicle recycling81,82. In our experiments, 12-14 DIV neurons were field-stimulated in the presence of APV (50 µM) and DNQX (10 µM), in the presence or absence of bafilomycin A (Fig. 6a-c). After stimulation, the bath was perfused with saline in which 50 mM NaCl was replaced with NH4Cl. Ammonium ions are in equilibrium with aqueous ammonia, which is membrane-permeable and can diffuse into SVs to neutralize their lumen. Therefore, the combination of sypHy and NH4Cl reveals intact SVs within the terminals, and the size of the total SVs pool is measurable. The recycling vesicle pool (RcP) size is estimated by measuring the plateau of fluorescence intensity obtained during exhaustive stimulation (Fig. 6c), while the resting pool is that which completes the RcP to the total pool26. The baseline fluorescence intensity of sypHy (F0) in each synapse of interest was the average value measured in five successive images acquired before stimulation. The change in fluorescence (ΔF) at time t was calculated as F(t)−F0. Values for each synapse were normalized by the maximal fluorescence intensity (Fmax) measured after the treatment with NH4Cl (ΔF/Fmax).

Acute hippocampal slices
P18-P21 littermate mice for field-potential recordings and P28-P31 mice for whole-cell recordings from either sex were anesthetized with Isoflurane and decapitated. The brains were rapidly removed and placed in an ice-cold oxygenated cutting solution that contains (in mM): 252 Sucrose, 5 KCl, 1 CaCl2, 3 MgSO4, 26 NaHCO3, 1.25 NaH2PO4, and 10 Glucose; pH 7.3 when bubbled with 95% O2/CO2. Transverse slices (300 µm) were cut on a vibratome (Leica 3000) and placed into a holding chamber containing oxygenated aCSF at RT for at least an hour prior to the recordings. ACSF solution contains (in mM): 124 NaCl, 3 KCl, 2 CaCl2, 2 MgSO4, 1.25 NaH2PO4, 26 NaHCO3 and 10 glucose; pH 7.4 when bubbled with 95% O2/CO2.

Whole-cell recordings
Slices were viewed through 40X water-immersion lenses (Olympus) in a BX51WI microscope (Olympus) mounted on an X–Y translation stage (Luigs and Neumann). Somatic whole-cell recordings were made using patch pipettes pulled from thick-walled borosilicate glass capillaries (1.5 mm outer diameter; Science Products). Pipettes had resistances of 5–7 MΩ when filled with a whole-cell voltage-clamp solution that contains (in mM): 135 CsCl, 4 NaCl, 2 MgCl2, and 10 HEPES (cesium salt), pH adjusted to 7.3 with CsOH. Voltage-clamp recordings were made with a MultiClamp 700B amplifier (Molecular Devices). Data were sampled at 10 kHz, amplified (gain 5), filtered at 3 kHz then digitized and analyzed using Clampfit. Membrane access resistance was maintained as low as possible (5-10 MΩ) and was compensated at 80%. Recordings were not corrected for liquid junction potential. Recordings were performed at 30 °C in the presence of Tetrodotoxin (TTX, 1 nM, Alomone Labs) and Bicuculline (GABA A antagonist. 10 µM, Alomone Labs). Inter-event intervals (IEIs) were calculated per recording (per cell) and averaged across slices (up to 3 slices per mouse).

Two-photon reconstruction of neuronal morphology
At the end of physiological recordings brain slices from WT and Cdh2H150Y littermates, the slice that contained the cells filled with SBFI fluorescent dye (0.5 µM, Thermo Fisher) was placed in an aCSF perfused chamber. Slices were scanned with an Ultima IV two-photon microscope (Bruker) equipped with a Mai Tai DeepSee pulsed laser (Spectra-Physics) and Olympus water-immersion lens ×60. Using two-photon excitation at 740 nm, we focused on the cell and scanned 30–40 slices of dendrites, soma, and axon at 0.5-μm depth intervals. The resulting z-stacks were imported into ImageJ (US National Institutes of Health) for reconstruction and image processing.

• The balance of the data included in this publication exceeded the size permitted by this cite. Dr. Ohad Birk’s contact information is available.

• CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice
Article
Open Access
Published: 26 October 2021
CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice
D. Halperin, A. Stavsky, R. Kadir, M. Drabkin, O. Wormser, Y. Yogev, V. Dolgin, R. Proskorovski-Ohayon, Y. Perez, H. Nudelman, O. Stoler, B. Rotblat, T. Lifschytz, A. Lotan, G. Meiri, D. Gitler & O. S. Birk

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADH

Introduction
Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood-onset neuropsychiatric conditions, characterized by a persistent pattern of inattention, impulsivity, and hyperactivity, with complications often continuing into adulthood1. Affected individuals have difficulties in higher-level executive functions, which are mediated by late-developing frontal-striatal-parietal and frontal-cerebellar neuronal networks. These mainly include motor and interference inhibition, working memory, sustained attention, and temporal information processing2. Although its etiology is not well defined, ADHD appears to have substantial heritability, and as such, it has been the focus of considerable genetic research, with growing evidence that rare monogenic variants may possess an essential role in its pathogenesis3.

Here we describe three siblings of a consanguineous kindred presenting with severe ADHD, apparent as of early childhood. Through linkage analysis, whole-exome sequencing (WES), and biochemical studies, we identified a disease-associated homozygous missense mutation in CDH2, affecting proteolysis and maturation of the encoded N-cadherin adhesion protein, which is known to play a significant role in synaptogenesis, plasticity-induced long-term spine stabilization, and neurite outgrowth4,5. Notably, CDH2 has an essential role in regulating the proliferation of dopaminergic progenitors within the limbic system, primarily the ventral midbrain and prefrontal cortex6. Through generation and analysis of mice homozygous for the human mutation in the mouse CDH2 ortholog, we demonstrated hyperactivity and deficient sensorimotor integration in the mutant mice and delineated downstream physiological and molecular pathways mediating the phenotype, mainly alterations in synaptic properties and defects in dopamine neurotransmission. Thus, we identify the role of CDH2 and its downstream pathways in the pathophysiology of ADHD.

Results
Clinical characterization
Three siblings of consanguineous Bedouin pedigree (Fig. 1a) presented with severe ADHD, diagnosed as of early childhood. Patient II:6 was born at term following an uneventful pregnancy, whereas the non-identical twin patients II:3 and II:4 were born prematurely at 32 weeks (weight appropriate for gestational age; 1900 and 2200, respectively). By the age of three, all siblings presented with a similar manifestation of severe hyperactivity behavior, predominantly hyperactive/impulsive. By the age of four, all patients met the criteria for ADHD, as outlined in the DSM-5. Concisely, information about ADHD manifestations was collected from semi-structured interviews conducted with both parents. Additional information was obtained from observations, questionnaires, and supplementary assessments: Clinical Evaluation of Language Fundamentals 5th Edition7 and Conner’s Parent Rating Scales-Revised8. The following were excluded in all three patients: scoring below 80 on both the performance and the verbal scales of the WISC-III9, psychosis, bipolar affective disorder, Tourette syndrome, multiple chronic tics, and a first-degree relative diagnosed with bipolar affective disorder and schizophrenia. All affected siblings were medication-free for 24 h prior to assessment and cognitive testing. Patients II:3 and II:6 (ages 11 and 7, respectively) reached normal developmental milestones, had no other comorbidities, and are completely normal in terms of intellect. Patient II:4 demonstrated mild developmental delay with autism spectrum disorder manifestations. Brain MRI (patient II:6, at 21 months) was normal. Blood pH, lactate, pyruvate, creatine, phosphokinase, and amino acids, as well as urinary organic acids, were within normal limits. Screening for congenital glycosylation defects, karyotype, and chromosomal microarrays were normal. All three patients were treated with stimulants, neuroleptics, and 3-Quinuclidinyl Benzilate. Notably, both parents and other siblings (including II:1 and II:7) were normal in terms of hyperactivity, intellect, and general health.

Fig. 1: Pedigree and CDH2 mutation.
figure1
a Pedigree of the consanguineous kindred studied. Beneath each individual is the allele corresponding to the CDH2 mutation. C and T denote the WT or mutant nucleotide, respectively. b Homozygosity scores. Genome-wide single nucleotide polymorphism (SNP) distributions were collected for all nine family members by bead-chip (>750 k/sample). The distribution of homozygous regions in the genome was determined using HomozygosityMapper (http://www.homozygositymapper.org/). Genomic regions are ordered by chromosome (green numbers). The blue arrow indicates the single homozygous locus on chromosome 18 shared by affected individuals. c Sanger sequencing. Through whole-exome sequencing, a single homozygous variant was found within the segregating locus: c.355 C > T in CDH2. CDH2 sequencing results of an unaffected individual (II:2), an obligatory carrier (I:1), and an affected individual (II:3) are shown. d Protein MSA. To demonstrate evolutionary conservation within the vicinity of mutated p.H150Y residue, eight representative CDH2 orthologs were selected for MSA. The recognition motif RXK/R-R is located approximately five residues downstream of the identified site of mutation. MSA, multiple sequence alignment.

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Genetic analysis
Linkage analysis, testing all nine family members, identified only one locus shared by the affected siblings: a ~11 Mb homozygous segment on chromosome 18 between SNPs rs11082423 and rs1480438 (Fig. 1b). Homozygosity mapping delineated this segment as the only homozygous disease-associated locus segregating as expected for autosomal recessive heredity within the studied kindred. WES data of individual II:3 were filtered for normal variants as described in Methods. A single homozygous variant was found within the locus: c.355 C > T; p.H150Y in CDH2 (transcript variant 1; NM_001792.4). This variant, validated by Sanger sequencing (Fig. 1c), was found to segregate within the family as expected for autosomal recessive heredity; neither compound heterozygous nor other homozygous mutations were found to co-segregate within this locus. Screening of the variant in 400 ethnically matched controls identified a single carrier and no homozygous mutants. This mutation has not been reported in the Genome Aggregation Database (gnomAD), with only fifteen CDH2 loss-of-function (LoF) variants (stop gain, frameshift, or essential splice site mutations) reported to date, none in a homozygous state. Multiple sequence alignment demonstrated the p.H150 residue to be highly conserved (Fig. 1d).

CDH2 protein structural analysis
CDH2 encodes a 906 amino acid protein, neuronal cadherin (N-cadherin), that is broadly expressed in the brain. It is known to play an essential role in synaptogenesis, synapse function, plasticity-induced long-term spine stabilization, and cortical organization. Classical cadherins are initially synthesized bearing a prodomain, thought to limit adhesion during the early stages of biosynthesis, which is then endogenously cleaved within the Golgi apparatus10. N-cadherin protein modeling (Fig. 2a) revealed that the sequence linking the prodomain to the outermost extracellular cadherin domain is unstructured and can be found in variable conformational loops, enabling the anchoring of proteolytic enzymes, mainly furin protease11. Computational studies (Fig. 2b) demonstrated that the furin protease consensus cleavage site contains approximately 20 residues, harboring the recognition motif RXK/R-R12, located five residues downstream to the p.H150Y mutation site. Using prediction tools for protein-peptide interactions, we demonstrated that the wildtype (WT) p.H150 residue is anchored within the catalytic pocket of the furin protease active-site, putatively contributing to its stable docking. In contrast, the mutant tyrosine sidechain, in a right rotamer conformation, is predicted to project perpendicularly, away from the catalytic pocket due to its non-polar, uncharged sidechain. Therefore, the mutation is predicted to interfere with the proteolysis and maturation of the protein.

Fig. 2: Structural analysis and disrupted cleavage of CDH2-mutated peptides.
figure2
a In-silico protein modeling. Ribbon representation of N-cadherin extracellular domains allows assessing the location of the identified mutation. Red, prodomain; green, extracellular cadherin domains (CADs 1-5); Blue, unstructured linker. The identified p.H150Y mutation resides within the unstructured region. Modeling was predicted using the SWISS-MODEL server (https://swissmodel.expasy.org/) based on the crystal structure of protocadherin GAmmaB4 extracellular domain (PDB ID 6E6B). b Electrostatic density representation map of furin protease (PDB ID 4Z2A). Furin cleavage site harbors the recognition motif RXK/R-R, which resides in proximity to the identified p.H150Y mutation site. Modeling was done using the HPEPDOCK server (https://omictools.com/hpepdock-tool), predicting protein-peptide interactions. The WT and CDH2-mutated sequences are denoted in pink and light blue, respectively; WT p.H150 residue is denoted with magenta, mutant p.Y150 residue with cyan. c Illustration of furin protease digestion assay; WT and mutant 22 amino-acid peptides, harboring the RXK/R-R recognition motif, were synthesized. Both peptides (10 µg) were digested by 2U enzyme furin protease followed by 30 °C incubation. Reaction mixtures were deactivated and subjected to LC-MS analysis. Predicted molecular weight is shown beneath each sequence. d Chromatogram separation and detection. Decreased absorbance of the digested full-length WT peptide at four-time intervals (0, 30, 60, 180 min) with a concurrent increase in absorbance of a fragmented small peptide (same was done for the mutant peptide). Peptides were separated by LC with subsequent tandem MS analysis. X axis: retention time (min), Y axis: relative absorbance (uAU). e Normalized cleavage efficacy after 180 min. The full-length peptide area under the curve (AUC) from MS analysis was calculated based on the desired spectral match. The ratio between AUC over time and the initial AUC at t=0 was extrapolated to calculate cleavage percentage. Left: percentage of peptide cleaved at t = 30, 60, and 180 min. (n = 3 for t = 30 and 60, n = 4 for t = 180; n represents an independent peptide digestion experiment subjected to LC-MS analysis (see Methods); mean ± SEM data were acquired, two-sided Student’s t-test, at t = 30 ns p = 0.08; t = 60 ns p = 0.44; t = 180 ns p = 0.052). Right: normalized cleavage efficacy at t = 180. Cleavage disruption of the mutated peptide is demonstrated with digestion >20% weaker in comparison with the WT peptide. UV, Ultraviolet; LC, liquid chromatography; MS, mass spectrometry.

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Decreased cleavage efficacy of the mutated p.H150Y peptide
The proprotein convertase family of enzymes plays an important role in activating other proteins13. To test whether the p.H150Y mutation interferes with protein processing, we performed a biochemical peptide cleavage assay using furin protease, the prototypical proprotein convertase; WT and mutant 22 amino-acid peptides were synthesized (GL Biochem, Shanghai), harboring the aforementioned RXK/R-R recognition and cleavage motif, conjugated with FITC and biotin at their N and C-terminus, respectively (WT: FITC-SKHSGHLQRQKRDW-K-biotin, Mutant: FITC-SKYSGHLQRQKRDW-K-biotin; Fig. 2c). Following digestion by furin (Fig. 2d)14, peptides were cleaved into two fragments based on the recognition preference of the protease (Fig. S1). Liquid chromatography-mass spectrometry (LC-MS) analysis demonstrated that proteolytic cleavage of the mutated peptide was substantially decreased compared with that of the WT peptide (Fig. 2e). Thus, our data support the postulation that replacing histidine with tyrosine debilitates the anchoring of the peptide within the catalytic pocket of furin protease and putatively impairs N-cadherin protein maturation.

CRISPR/Cas9-mutated knock-in mice
As the human CDH2 shares a high degree of similarity with its murine ortholog (Fig. 1d), with notable evolutionary conservation in the vicinity of the consensus prodomain cleavage motif, we generated two founder lines of CRISPR/Cas9-mutated mice harboring the specific human p.H150Y substitution in the Cdh2 mouse ortholog; Selected KI F0 mice were bred with C57BL/6JRcc WT mice for two cycles to generate non-chimeric F1 KI heterozygotes. Heterozygote F1 offspring were then bred and F2 offspring of WT and mutant origin (Cdh2H150T and Cdh2H150Y(2) founder lines) were used for all further experiments (details in Methods). Thorough studies of the Cdh2 homozygous knock-in (KI) 10-week-old mutant mice, with a specific focus on the brain, demonstrated no anatomical or histological abnormalities Fig. S2).

Behavioral and cognitive phenotypes in Cdh2-mutant mice
To assess possible in-vivo effects of the Cdh2 mutation, we performed behavioral studies of the mutant mice. 10-week-old WT and homozygous Cdh2H150Y KI mutant male mice (n = 18, nine mice per group) underwent a 3-week cassette of extensive phenotypic assessment (see Methods). Cdh2H150Y mice exhibited significantly greater traveling distance, increased velocity, and prolonged mobility time in the open-field exploratory test (OFT), recapitulating motor-associated features of hyperactivity (Fig. 3a-f). No differences were observed when examining the duration mice spent in the center of the open-field arena, a measure inversely related to neophobic behavior, nor in the amount of center/border crossings. In addition, no difference was evident in the rotarod test (Fig. 3m), implying no significant effect on primary motor control. Regarding cognitive evaluation, a trend was observed in the spontaneous alteration test (Y-maze, Fig. 3h), suggesting a potential effect on executive functions and working memory. A significant difference was observed in the acoustic startle reflex test (ASR, Fig. 3j, k), demonstrating an elevated startle amplitude of the Cdh2H150Y(1) mice, commonly associated with differences in sensorimotor integration. A similar pattern was observed in the pre-pulse inhibition test (Fig. 3l), in agreement with deficits in early-stage information processing, although no difference was evident in the pre-pulse attenuation fraction itself. Also, as part of the anxiety-domain assessment, no difference was demonstrated in the elevated plus-maze test (Fig. 3g). Lastly, the results of social interaction tests were inconclusive; although a significantly shorter interaction time in the resident-intruder test may imply a propensity for aggression (Fig. 3i), no differences were observed in the three-chamber sociability test followed by the social novelty test (Fig. 3n).

Fig. 3: Behavioral experiments in Cdh2 knock-in mice.
figure3
Behavioral test results of Cdh2H150Y(1) and WT mice following cassette of motor, anxiety, cognitive and social interactions domains assessment. a–f Exploratory OFT consists of a square arena measuring 50X50X33cm. Mice explored the arena for 6 min, while their location was recorded. a OFT tracking visualization. Cdh2H150Y mice exhibited (b) significantly greater traveling distance (*p = 0.04), (c) increased velocity (*p = 0.04) and (f) prolonged mobility time (*p = 0.03). d, e No differences were observed examining the duration mice spent in the center of the arena nor at the amount of center/border crossings. g Elevated plus-maze test consisting of two sets of opposing arms extending from a central platform. One set of arms was enclosed by a 15 cm wall, while the other was open. No differences were observed examining the duration mice spent in each set of arms (ns p = 0.4). h Spontaneous alteration test (Y-maze) consisting of three arms in 1200 Y-shaped maze. An alteration was defined as a complete cycle of consecutive entrances into each of the three arms. WT mice exhibited more alterations compared to Cdh2H150Y(1) mice (ns p = 0.06). i Resident-intruder test assesses the time for aggressive social interaction. Cdh2H150Y(1) mice demonstrated significantly shorter interaction time (*p = 0.03). j–l ASR test consists of a single noise burst (120 dB, 40 ms); thereafter, the amplitude of the animal flinch is recorded. Cdh2H150Y mice demonstrated a significantly elevated startle amplitude (*p = 0.03). This pattern was consistent with the pre-pulse inhibition test. m Rotarod test, assessing motor abilities, demonstrated no difference between the groups. n No differences were observed in the three-chamber sociability test, followed by a social novelty test. For all experiments, mean ± SEM data were acquired; n = 18, 9 mice per group, two-sided Student’s t-test. OFT, open-field test; ASR, acoustic startle reflex.

Part 1
Contact Dr. Ohad Birk for further information

• The United States, for its part, has largely resisted direct military intervention in the conflict between the Assad regime and anti-government forces in spite of its varied interests throughout the Middle East, limiting its military operations to fighting the Islamic State of Iraq and Syria (ISIS). And while it largely resisted intervening militarily, the Obama administration opted to use foreign aid as its chief instrument in responding to the conflict. Since 2012, some $5.1 billion in humanitarian assistance has been given to various countries, intergovernmental organizations, and non-governmental organizations to address the growing humanitarian crisis. Of this,$2.6 billion has been allocated to groups operating within Syria itself. The remainder (approximately 50%) has been directed to countries and groups operating in the region surrounding Syria. In particular, several billion dollars have been allocated to more closely aligned states like Turkey, Iraq, and Egypt

Michael Flynn SAGE Journals 2020
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• There appears to be some good news for advocates of a biochemical cause for those who are diagnosed with ADHD. Nature published some data which identified pathology within CDH2, a mutatation affecting N-cadherin function

causes attention-deficit hyperactivity disorder in
humans and mice

We demonstrate that a novel mutation in CDH2 is
associated with familial ADHD, through impaired presynaptic
vesicle clustering, attenuated evoked transmitter release,
decreased spontaneous release, and reduction in dopaminergic
distribution within limbic pathways.

Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.

Birk, O.S. Following MD studies at Tel Aviv University, military service as a medical officer (Major) in the IDF and residency in Pediatrics at Sheba Medical Center, Birk did his PhD at the Weizmann Institute with Irun Cohen,[13] delineating hsp60 as a crucial autoantigen in type 1 diabetes and allograft rejection, effective in their prevention.[14][15][16] He then went on to do his training in clinical human genetics and post-doctorate with Heiner Westphal at the NIH, unraveling LHX9 as a gene critical for mammalian gonad formation.
Director, Genetics Institute, Soroka Medical Center
Scientific Director, National Institute for Biotechnology in the Negev
Head, Morris Kahn Lab. of Human Genetics,
Faculty of Health Sciences,
Ben-Gurion University, Beer-Sheva, ISRAEL
Phone: (972)-8-6403439

And
Dan Halperin
Professor of Computer Science, Tel Aviv University