Autism spectrum disorders (ASDs) are neurodevelopmental disorders. Many divergent pathogenetic views are currently present. Atypicality’s of structural and functional development of the brain have been used to explain ASD, but yet inconclusive. A recent paper tried to demonstrate these prenatally and perinatally (hypoplasia of the pons just after neural tube closure; and a deficient GABA developmental switch in the perinatal period) . Nevertheless, these specific prenatal and perinatal causes are expected to be infrequent. Yet ASD is common, affecting up to 2.25% of children [2,3], even prevalent with parents highly educated. Pathogenesis is also sought for genetic and environmental factors yet ASD etiology remains unknown .
The difficulty to find the etiology throughout the years may imply complex causes that work together in bringing forth an autistic child. And these factors may sequentially perpetuate the problem. Assembly of the developing nervous system for a final functional neural circuitry is dependent on a series of temporally regulated developmental processes.
Development follows senses and stimulation. Thus, as past socio-medical approach to ASD became more sophisticated, the social motivation theories were used to explain the ASD manifestations of stereotypical behavior, communication, and social interaction deficits. The hypothesis suggests that early neurobiological difference in response to social input could lead to weakened social motivation, and in time motivation for restricted interests increases .
Carried these up the brain, cognitive models developed. These include domain-specific models elaborating primary deficit in social cognition, and domain general models elaborating
primary deficit in nonsocial or domain-general processing. The disrupted cerebral connectivity hypothesis postulates that its clinical symptoms originate from deficiencies in the way the brain coordinates and synchronizes activity amongst different brains regions .
The gut microbial community is dynamic during the first 3 years of life and then stabilizes to an adult-like state . Gut bacteria influence the central processes through their ability to synthesize neurotransmitters including gamma-aminobutyric acid, noradrenaline, and dopamine, modulate activation of the immune system, and produce metabolites, such as short-chain fatty acids that possess neuroactive properties . Research has demonstrated the association between gut microbiota and early cognition in human infants. Fecal microbial community diversity in infants affects later Mullen score (scale of early learning), visual reception scale, and expressive language scale at two years of age .
Early life stress during this critical period can induce alterations in many body systems. Time windows of microbial community might be critical in shaping the brain function and have long-lasting effects on behaviors. Perturbations in the delicate synergetic host- microbiota relationship may have serious consequences and lead to brain, digestive, and metabolic disorders .
The microbiota–gut–brain axis exerts a profound influence on key brain processes, such as neuroinflammation, activation of the stress axes, neurotransmission, and neurogenesis, in addition to modulating complex behaviors, such as sociability and anxiety .
Neuroinflammation-related brain injuries are associated with
 and cytokine imbalance is involved in ASDs . Neuroinflammation
contributes to a significant subset of ASDs .
During rapid volume growth of cortical gray matter in the
first 2 years of life, certain brain regions, notably those around
information processing sensory modalities, develop faster.
These regions include the inferior frontal gyrus and angular
gyrus, cortical regions involved with language, the fusiform
gyrus, involved with face recognition and color processing and
the inferior temporal gyrus, involved with higher-order visual
processing, including shape and faces. Oddly, the insula is also
one of the most rapidly growing regions. In fact, the insula is
involved with awareness of interoceptive or visceral sensations,
pain, body movement, emotions, vocalizations, and perhaps even
consciousness [15-16]. Visceral sensations develop as the enteric
nervous system (ENS) develops during interactions of the neural
crest-derived precursors (mostly vagal neural crest cells )
with the enteric microenvironment.
Luminal stimuli activate mucosal enteroendocrine cells
and initiate peristaltic and secretory reflexes . Besides the
mainframe brain, some called ENS the ‘little brain’. The ENS is a
division of the autonomic system put in close apposition to effector
systems it controls; enterohormones also co-working.
Hippocampal volume rapidly increases in the first two years
of life , though less in the first year compared with the other
subcortical structures. With more mobility of the child in the
second year of life, hippocampus becomes one of the faster growing
structures, as it supports the acquisition of episodic memory 
as well as spatial working memory and path integration abilities
The hippocampus is activated by enteric signals through the
vagus nerve between the intestinal tract and the brain . The
hippocampus is linked with learning and memory control and
with feeding behavior . Vagus nerve stimulation enhances
memory , facilitates hippocampal neurogenesis, increases
hippocampal expression of brain-derived neurotrophic factor
 and induce neuronal plasticity . Neurogenesis with new
neurons continues in the hippocampus to play an important role in
learning and memory and responses to stress, even till adulthood
Dopamine dysfunctions have been reported in ASD, and
autistic-like behavior could arise from dopamine dysfunctions
in midbrain dopaminergic modulatory systems affecting social
motivation and goal-directed motor behavior . Dopamine
affects plasticity, synaptic transmission and the network activity
in the hippocampal circuitry for memory . Findings suggest
that while memory representations are processed and activated
by the hippocampus in both ASD and controls during successful
retrieval, these are not searched for, transferred, or monitored in
an efficient way during episodic memory retrieval as a result of
widespread disrupted connectivity .
The developmental trajectory before the preschool years is
determined by a combination of internal biologic variables and
environmental influences . It depends on the performance
level at the onset and the rate of change and direction of deviation.
Memory deficits in ASD driven by retrieval-related impairments
reduce their probability of recollection success . As it
biases the individual’s social motivation in a more or less fixed
environmental structure, the individual conforms with a selfconcept
and self-worth in a fairly fixed trajectory pertaining to
himself. Though parenting style and learning environment can
have significant effects, the individual developmental trend of
mental functioning at a different level and discrimination tends
to be fixed. This could lead to diminished social motivation and
increased activation to stimuli associated with their restricted
interest and thereby the typical ASD manifestations.
Developmentally, visceral sensations and the enteric nervous
system develop together. Stimulation with external or internal
(visceral) information is important for developing functional
networks and refining synaptic plasticity. A study noted infants
with sleep restlessness starting after 3 months old can recover
with peaceful sleep by 3-5 courses every 7-10 days of chlorpheniramine
1mg and duphalac 2.5ml daily for 3 days . During
early development, time windows shaped by enteric microbial assembly
and cortical neuro connectivity may shift developmental
trajectories for brain function and behaviors.
ASDs having neuro-inflammation with deviations in gut
microbiota, and problems in acquisition of memory and path
integration abilities related to affected hippocampus neurogenesis,
could set up an aberrant developmental trajectory.
Successful treatment of ASD children with herbs, senna and
chlorpheniramine, by improving intestinal transit time, relieving
inflammation and improving sleep, noted first and early recovery
of the enteric system (appetite, speed of finishing feeds) .
Subsequently there was improvement in sleep restlessness,
concentration, temper, and school acceptance. Finally, the children
had restoration of normal school work and social interaction.
Together with the restoration of the internal environment and the
management of abnormal processes, ASD children could recover
with treatment and restore their useful activities and normal
Aberrant connectivity may lead to structural demonstrable
differences in many brain areas, especially for developmental
process involved in response to rewarding social input, which
in turn may lead to the diminished social motivation. Apart from the aberrant connectivity, other issues in ASDs may
perpetuate the problem. Brain development including brain cell
proliferation, apoptosis, myelination, neurogenesis, maturation
and differentiation depend on nutrition and immune development
from the gut . The temporal series of adaptive mechanisms
would pave the developing nervous system for a final functional
The treatment report, after enteric restoration, noted that
improvement of sleep precedes improvement of other problems
. ASD tends to be associated with difficulty in falling asleep,
wake up in the night frequently and a low frequency of saccadic
eye movement during REM sleep . Slow wave sleep is also
shortened in ASD, and sleeping time, particularly the proportion
of REM sleep, is reduced . Cerebral plasticity has an important
relationship with sleep .
Inadequate or poor sleep may foster lasting neural changes as
well as changes in functional connectivity after perceptual, motor,
or emotional learning tasks . Hippocampus and the ventral
striatum are activated during NREM sleep , and this may
help subsequent performance improvement  and consolidate
associative memory-reward information .
Noted in rats, REM sleep deprivation impairs hippocampal
neurogenesis and related memory formation . Emotional offrelevance
and motivational biases may misdirect this overnight
consolidation of declarative memory and skill learning .
Poor sleep, probably disturbed ENS visceral sensations, memory
deviations, emotional off- relevance and motivational biases,
associative memory-reward value-system, and neuro- inflammation
as well as habituated responses to environment make up a
set of factors in ASDs that perpetuate the aberrant development
trajectory. It deters useful interactions with the environment,
leads to the diminished social motivation, biased social skills and
restricted interests. Whether due to a circuit dysfunction in reward
and motivation, autistic brains would fail to register social
experiences as rewarding, further reducing social interactions and
social abilities, ultimately leading to heterogeneous social deficits
with this “aberrant development trajectory” .
ASD may arise from deviated hippocampus memory processing
related to brain-gut dysregulation. There is a critical window
in early life, when the cerebral cortical networks from neuroconnectivity
is adapting to changes, that microbial colonization can
influence neurogenesis, including that in the hippocampus. ASDs
are associated with neuro- inflammation, and alterations in the
gut microbiota can change the developmental trajectory of brain
function and behavior.
The vagus nerve of the intestine, with which the enteric
microenvironment inputs related memory to hippocampus, will
affect neural development for hippocampus. ASD children have
memory retrieval-related impairments that reduce the probability
of recollection success. These aberrant memory processes,
resulting in restricted interest and diminished social motivation. It
explains how ASD children have stereotypic interest and behavior,
their characteristic communication and social interaction deficits,
as well as the presence of atypical mixed picture of neural
The developmental trajectory of ASD with perpetuating
brain-gut dysregulation, working memory and path integration
deviations, poor restoration from sleep all result in related brain
function and behavior deviating from normal. A course of Chinese
and western medicines has been successful to restore intestinal
function, improve sleep, restore normal school work and social
interaction. Treatment that normalizes microbiota relieving
neuro-inflammation and management of the enteric system can
be useful in maintaining signals to the hippocampus and brain
for neurogenesis. Together, with improving sleep, restoration
of the internal environment and the management of abnormal
processes, it is very likely that ASD can be treated to restore their
useful activities and normal development trajectories of life.