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A little over two years, researchers reported a simple and quite remarkable discovery that could radically improve the treatment of foals with a condition known as neonatal maladjustment syndrome.
The behavioral abnormalities seen in these foals seem to resemble some of the symptoms in children with autism. The newborn foals seem to detach, fail to recognize their mothers, and have no interest in nursing.
The condition, also known as dummy foal syndrome, occurs in 3 to 5 percent of live foal births.
With around-the-clock bottle or tube feeding, plus intensive care in a veterinary clinic for up to a week or 10 days, 80 percent of the foals recover. But for horse owners, that level of care is grueling and costly.
The disorder has puzzled horse owners and veterinarians for a century.
For years, it was attributed to hypoxia — insufficient oxygen during the birthing process. However, this explanation had problems. Hypoxia usually causes serious, permanent damage, while most foals with the maladjustment syndrome survive with no lingering health problems.
Researchers at the the University of California, Davis, began looking for other potential causes, and attention turned to naturally occurring neurosteroids.
Neurosteroids are crucial to sustaining pregnancies in horses, especially in keeping the foal “quiet” before birth – effectively acting as sedatives for the unborn foal.
However, immediately after birth, the infant horse must make an equally important transition to consciousness – a transition that involves a complex withdrawal of consciousness inhibitors and an increase in neuroactivating factors that support awareness.
UC Davis veterinary professor John Madigan and veterinary neurologist Monica Aleman surmised that somewhere between the time a foal entered the birth canal and the moment it emerged from the womb, a biochemical “on switch” must be flicked that enabled the foal to recognize the mare, nurse and become mobile.
The pair suspected that the physical pressure of birth may be that important signal – that the pressure of the birth canal during the second stage of labor, which is supposed to last 20 to 40 minutes, signaled the foal to quit producing the sedative neurosteroids and “wake up”.
Were foals at risk of developing the syndrome when they did not receive enough physical pressure to trigger the change in neurosteroids?
Their theory was supported by the fact that maladjusted foal syndrome appeared more frequently in horses delivered via cesarean section and in those that experienced unusually rapid births.
Their theory was strengthened when they found that sedative neurosteroids persisted, and their levels often rose, in the bloodstream of foals born with symptoms of the maladjustment syndrome. These neurosteroids are known to be able to cross the blood-brain barrier and impact the central nervous system, acting on the same receptor as do sedatives and anesthetics.
What they then discovered was that maladjustment symptoms in foals could be reduced by using several loops of a soft rope to gently squeeze the foal’s upper torso and mimic the pressure normally experienced in the birth canal. When pressure is applied with the rope, the foal lies down and appears to be asleep.
After 20 minutes — about the same time a foal would spend in the birth canal — the rope is loosened and the squeeze pressure released. In initial cases, foals responded well to the procedure and recovered, some rising to their feet within minutes and then bounding over to join the mare and suckle.
The researchers suspect that the pressure triggers biochemical changes in the central nervous system that are critical for transitioning the foal from a sleep-like state in the womb to wakefulness at birth.
Research around the protocol, now called the Madigan Foal Squeeze Procedure, has been published this week in the open-access journal Animals.
In their paper, Aleman, Madigan and Kalie Weich set out to compare reported outcomes of conventional medical therapy alone to this squeeze procedure, with or without medical therapy.
“The results revealed some foals that received the squeeze procedure recovered faster than those that received medical therapy only,” the trio reported.
The use of the non-invasive squeeze method together with primary treatment may improve animal welfare by hastening recovery, they said.
“This would also avoid or reduce costs arising from hospitalization associated with veterinary and nursing care that sometimes leads owners to elect for euthanasia.”
In their study, the researchers conducted an online survey in which veterinarians, veterinary technicians and farm managers involved in foal births were invited to participate. Some pursued conventional therapies for the condition and some applied the Madigan squeeze.
Information on how to apply the squeeze was given to those in the “squeeze” group, who were told how to apply 20 minutes of pressure using a soft rope looped around the thorax.
The survey ultimately reached beyond the United States to include colleagues worldwide.
Information about medical treatments used such as intravenous fluids, medications and antimicrobials were collected, along with nine questions that focused on the time it took for foals to respond to medical treatment only versus the squeeze procedure.
There were 51 respondents to the survey, 86.6% of whom were veterinarians. Eighty-six percent of the respondents were from the US. The remaining 14% were from Africa, Australia, Canada, and Europe.
The number of foals diagnosed with the syndrome per respondent ranged from one to more than eight. Information was available for 195 foals.
All foals exhibited abnormal behavior, mentation, and/or sucking, typical of the syndrome. In all, 108 foals were not squeezed and 87 received the Madigan squeeze.
Fifty-eight foals (66.7%) were squeezed once, whereas 23 (26.4%) and 6 (6.9%) were squeezed twice and more than twice, respectively.
“There were statistically significant differences at different time points regarding time to respond positively to treatment between the non-squeezed group and the squeezed group,” they reported.
“Foals that received the squeeze procedure with or without medical therapy were 3.7 times more likely to recover faster than foals that did not receive a squeeze.
“Foals that were squeezed had significantly faster and higher recovery rates at different time points.
“Foals that were squeezed were 15.1 times more likely to recover in less than 1 hour than foals that were not squeezed.
“Foals receiving only squeeze treatment were 17.5 times more likely to recover within the first 24 hours than foals treated with only medical treatment.”
However, recovery did not occur in 12% of all foals and in 14% of squeezed foals.
There were no complications with the squeeze procedure in 86 foals, although one was reported to have brought up some milk after the procedure.
The overall recovery rate was 86% for the squeeze group and 87% for the non-squeeze group. However, crucially, the squeeze procedure appeared to be useful in decreasing the time to full recovery.
Discussing their findings, the researches said: “The squeeze procedure can have several advantages including avoiding referral of uncomplicated cases to veterinary intensive care institutions, reduction of costs of nursing care, reduction of time and effort spent by attending care givers and veterinarians, and faster recovery.
“Further, the option of euthanasia due to financial constraints, lack of personnel or resources to provide adequate nursing and intensive care, and/or perception of poor prognosis due to severity of signs, can potentially be avoided.”
They said it would not be sensible to use of the squeeze procedure in foals with the likes of respiratory problems, neuromuscular disease such as botulism, cardiomyopathies, and broken ribs.
They continued: “The concept that neonatal maladjustment syndrome in some foals results from a delay in clearance of sedation-producing compounds or a reversion to persistent production of sedative neurosteroids could explain the historical finding of full recovery in 80% of neonatal foals with NMS without residual neurological deficits when provided with nursing and supportive care.
“Such nursing care is expensive and it is not known how many foals with NMS die in the field when access to such care is not available or affordable to the owner.”
If a lack of oxygen during birth was behind the condition, some long term brain or spinal cord compromise would be likely, they said. This was not the case among survivors.
So, what of the potential links of the condition to autism? Autism includes a group of complex brain-development disorders.
While the symptoms vary, these disorders are generally marked by difficulties with social interactions, verbal and nonverbal communication, and repetitive behaviors.
The question has caught the attention of Isaac Pessah, a professor of molecular biosciences at the UC Davis School of Veterinary Medicine and a faculty member of the UC Davis MIND Institute, which investigates environmental factors that may play a role in the development of autism in children.
“There are thousands of potential causes for autism, but the one thing that all autistic children have in common is that they are detached,” he said.
“The concept that a disruption in the transition of fetal consciousness may be related to children with autism is intriguing,” Pessah noted in 2015, when the initial findings about the Madigan squeeze were first reported.
Pessah noted that the behaviors seen in the maladjusted foal syndrome truly were reminiscent of those in some autistic children.
He said some children with autism did outgrow autistic behaviors by the time they reached their teen years. Could this be a parallel to the recovery of the foals with the maladjustment syndrome?
A group called the Comparative Neurology Research Group, consisting of veterinarians, physicians, epidemiologists and basic-science researchers, was formed to pursue further studies in this area.
Madigan is working with researchers at the Stanford School of Medicine, exploring the mechanisms of post-birth transitions of consciousness related to neonatal care of infants.
Using data from the foal research, Pessah and Madigan are working with environmental epidemiologist Irva Hertz-Picciotto at the UC Davis MIND Institute to investigate neurosteroids in children with varying degrees of autism, ranging from some developmental delay to full-spectrum autism.
The researchers are exploring whether abnormal regulation of neurosteroids during the time around childbirth could be one of many factors that might contribute to autism and related neurodevelopmental disorders. A recent study has reported elevated levels of neurosteroids in children with autism spectrum disorder.
Foals are unconscious in the womb, including in the final countdown to being born, explains a leading animal welfare scientist, Professor David Mellor.
Mellor, who is with New Zealand’s Massey University, has provided an overview of changes in the balance between inhibition and activation of cerebral cortical function before, during, and after birth to accompany the paper.
During at least the last one-third of pregnancy, cerebral cortical electrical activity indicates the states of fetal unconsciousness, which require less oxygen to sustain than consciousness, he says.
At least nine neuroinhibitory factors unique to life in the womb apparently contribute to this: high circulating and/or cerebral concentrations of adenosine, progesterone, allopregnanolone, pregnanolone, prostaglandin D2, and a placental neuroinhibitory peptide, plus warmth, buoyancy and cushioned tactile stimulation.
“Nevertheless, fetal movements continue to occur until labor begins.”
These factors, he says, play a part in fetal cortical inhibition.
However, adenosine — which is released very rapidly during periods of abnornally low levels of oxygen in the blood (hypoxemia) — is particularly capable at switching off cerebral cortical electrical activity, thereby protectively reducing cortical oxygen consumption by at least 95% during marked oxygen shortages.
Reoxygenation within about 6 minute reverses these effects without neural damage.
“This has relevance to episodes of transient hypoxemia during labor as well as after severance of the umbilical cord and before the successful onset of breathing.”
Inhibition of brain function continues during labor as a result of these factors.
However, two potent hormonal neuroactivators begin to kick in. The first is estradiol-17β, whose fetal plasma concentrations rise throughout labor. The second is noradrenaline, stimulating extensive areas throughout the brain and acting to bring about arousal.
Potent stimuli to noradrenaline release include low oxygen levels in the blood and carbon dioxide retention, strong tactile stimulation of the head and body (squeezing), and injury-induced pain, which may all occur during labor and delivery.
These factors presumably prime the brain to spark the onset of arousal and consciousness soon after birth, aided by the withdrawal of the neuroinhibitors that exerted an influence in the womb.
After birth, key neuroinhibitors are withdrawn rapidly. Thus, thoracic compression ceases immediately and elevated adenosine concentrations due to low oxygen levels caused by labor decline as oxygenation of newborn tissues markedly increases with the start of breathing.
Likewise, the supply of placental peptide neuroinhibitor and any remaining placentally-sourced progesterone ceases with severance of the umbilical cord.
Withdrawal of other inhibitors, including allopregnanolone and pregnanolone, is slower. It is apparent, however, that a raft of factors is enough to spark consciousness or awareness – and not just hormones.
Such factors include estradiol-17β and noradrenaline, as well as the cold air temperature, gravity, unfamiliar contact with hard surfaces and air, changes in the quality of sound, the experience of sight, contact with the mother, and other sensory inputs.
Evidence suggested that applying the thoracic squeeze procedure to foals with neonatal maladjustment syndrome for 20 minutes would simultaneously elicit two responses.
The first is reflexive inhibition of physical movement and electrocortical activity leading to immobility and sleepiness. The second response is the release of noradrenaline.
If so, it is apparent that the former reflex-induced sleepiness would dominate the activation of the locus coeruleus − that’s the part of the brain that produces noradrenaline − that would continue throughout the duration of the compression.
“Withdrawal of that inhibition after 20 minutes of locus coeruleus neuroactivational priming would rapidly free the cerebral cortex to express consciousness.”
More details on applying the Madigan Foal Squeeze can be found here.
Survey of Veterinarians Using a Novel Physical Compression Squeeze Procedure in the Management of Neonatal Maladjustment Syndrome in Foals
Monica Aleman, Kalie M. Weich and John E. Madigan.
Animals 2017, 7(9), 69; doi:10.3390/ani7090069 http://dx.doi.org/10.3390/ani7090069