NEUROBIOLOGY OF AUTISM

The most fitting description for autism is the word given to it in the Maori language: “takiwātanga”. It means “in his/her own space”.

ANTERIOR CINGULATE GYRUS
What is different about the autistic brain is how it functions in terms of its neurophysiology. In a neurotypical brain, the anterior cingulate gyrus (ACG) functions like an automatic transmission, seamlessly switching attention back and forth between the frontal lobes as required.

The core neurological deficit in the brain of a person with Asperger’s is a lack of social relatedness due to abnormalities in the amygdala and anterior cingulate cortex. The circuit between the anterior cingulate in the frontal cortex and the amygdala is not entirely connected. All individuals with autism have decreased metabolism in the anterior cingulate gyrus.

The dysfunctional anterior cingulate gyrus keeps the person trapped in their left frontal lobe, the intellectual, analytical, problem-solving part of the brain, with no ability to access the emotional/creative processing right frontal lobe, which plays a central role in spontaneity, social behaviour, and nonverbal skills. Some neurotypical people are left-brain dominant, whereas others are right-brain dominant. Autistic people, however, are left-brain exclusive.

The anterior cingulate cortex can be divided anatomically into cognitive (dorsal) and emotional (ventral) components. The ACC is especially involved when effort is needed to carry out a task, such as in early learning and problem-solving. It contains specialized neurons called spindle cells, which help address complex problems.

The dorsal cognitive portion is involved in certain higher-level functions, such as attention allocation, reward anticipation, decision-making, ethics and morality, and impulse control (e.g. performance monitoring and error detection).

The ventral part of the ACC is connected to the amygdala, nucleus accumbens, hypothalamus, hippocampus, and anterior insula, and is involved in assessing emotional and motivational information.

A typical task that activates the ACC involves a conflict that could result in an error. When the ACC receives conflicting input from control areas in the brain, it determines and allocates which area should be given control over the motor system. This evaluation is emotional and highlights the amount of distress associated with a specific error.

The ventral part of the ACC is believed to be more involved in affective responses to errors. Frustration occurs when making mistakes, and it may form the basis of self-confidence. It is likely the centre of free will in humans. It appears to be involved in the emotional reaction to pain rather than in the perception of pain itself. The ACC may also be involved in monitoring painful social situations, such as exclusion or rejection.

Abnormalities of the ACC are associated with emotional instability, inattention, akinetic mutism, schizophrenia, ADHD, obsessive-compulsive disorder, social anxiety, major depression, childhood trauma, and executive dysfunction. Impaired development of the anterior cingulate and the medial-frontal cortex may be the basis of the socio-cognitive deficits in autism.

HYPERFOCUS
This inherent neurophysiological anomaly in the anterior cingulate gyrus creates a perpetual state of hyperfocus, characterized by intense, single-minded concentration fixated on one thought pattern at a time, to the exclusion of everything else, including one’s feelings. Hyperfocus is the sole factor responsible for the autistic person’s withdrawal into an inner world that is entirely mental. Hyperfocus keeps a person’s awareness trapped in the intellectual and analytical left frontal lobe, with no ability to access whatever may be happening in the right frontal lobe, where emotions and social connectivity are experienced. Autistic hyperfocus explains all 11 traits of Asperger syndrome as first described by Lorna Wing, a British clinician whose ideas were years ahead of her American counterparts.

Being left-brain exclusive means that one can only process their emotions intellectually, by deduction or inference, a process that can take time. Failure to process emotions causes anxiety, which is an upsetting physiological response (different from emotion) that bypasses the intellect.

Hyperfocus is so intensely single-minded that an autistic person cannot divide attention between two trains of thought. An autistic person takes everything you say literally because s/he cannot also be running a second mental program questioning how you use words. While talking at length about a favourite topic, autistic people are incapable of running a second mental program asking how they are being received or perceived by their audience. Autistic individuals require structured activities because they struggle to divide their attention between what they are doing and trying to anticipate what may happen next.

Hyperfocus also causes various kinds of sensory overload. A sudden loud or high-pitched noise triggers hyperfocus on the noise, which the autistic person then experiences with many times the intensity that a neurotypical person does. Seeing too many words on a page can cause cognitive impairment, whereby the autistic person’s mind goes disturbingly blank. Too many products on shelves and overhearing unwanted conversations in stores can trigger anxiety. Lighting displays in hardware stores can trigger intense anxiety. For some, hyperfocus exaggerates the sense of touch, making close-fitting clothing irritating and hugs unbearable.

Non-communicative autistic children are the ones most intensely trapped in hyperfocus. Intensely autistic children cannot be taught to speak; however, some spontaneously start to talk on their own.

People with Asperger’s process emotional information differently than normal subjects. Functional MRI studies indicate that normal people activate the amygdala to judge the expression in another person’s eyes, but people with Asperger’s call on frontotemporal regions of the brain.

AMYGDALA AND HYPOTHALAMUS
The amygdala and hypothalamus are part of the limbic system, which is the part of the brain involved in our behavioural and emotional responses, especially when it comes to behaviours we need for survival, such as feeding, reproduction, caring for our young, and fight-or-flight responses. The left and right amygdalae, especially, play a central role in our emotional reactions, including feelings such as pleasure, fear, anxiety, and anger. The amygdala also attaches emotional content to our memories, thereby playing a crucial role in determining how robustly those memories are stored. Memories with strong emotional significance tend to remain more vivid.

The amygdala not only modifies the strength and emotional content of memories, but it also plays a crucial role in forming new memories, particularly those related to fear. Fearful memories are formed after only a few repetitions. This makes ‘fear learning’ a popular way to investigate the mechanisms of memory formation, consolidation, and recall. Suppressing or stimulating activity in the amygdala can influence the body’s automatic fear response, which is triggered when something unpleasant occurs, such as a startling noise.

FEAR
There are two different pathways in the brain that moderate fear, depending on whether the threat is external or internal.

External threats
Feeling fear is an evolutionary survival tactic in response to perceived external threats.
Fear is processed in the amygdala, and initiates the fight or flight response. All vertebrates, including mammals, birds, reptiles, amphibians and fish, possess an amygdala, and it is a huge aid to survival. The amygdala plays a role in organizing how we respond to the social world.
When it comes to external threats, the amygdala acts like an orchestra conductor, directing the other parts of the brain and body to produce a response. First, it receives information from the brain areas that process vision, smell, taste and hearing. If the amygdala detects a threat, such as an approaching burglar, snake or bear, it then sends messages to the hypothalamus, which then communicates with the pituitary gland, which in turn gets the adrenal glands to release cortisol and adrenaline into the bloodstream. This will cause your heart rate to go up, blood pressure to rise, and all the classic fight-or-flight symptoms of a typical fear response.

Damage to the amygdala
If the amygdala is damaged, and one is exposed to real-life threats, there is a pronounced lack of fear. Without this critical circuitry for navigating the external world, these animals put themselves into dangerous situations. They have an almost overwhelming curiosity, approach them, touch and interact with them. Animals in the wild will typically die within a matter of hours or days.
Humans learn not to touch a hot pan just out of the oven, but those with a damaged amygdala cannot be fear conditioned – that is, they don’t experience a racing heartbeat and surge of adrenaline when presented with a stimulus that has previously been associated with danger. They tend to approach people whom they should be avoiding, and can get into trouble as a consequence of their inability to sense the trustworthiness of individuals. They will go nose-to-nose with relatively unfamiliar experimenters, which is something that healthy control participants with an intact amygdala would essentially never do. One study investigated the distance at which they felt most comfortable. That preferred distance may be as short as 0.34m (1.1ft), almost half that of other volunteers. This suggests they are unusually comfortable with people being in their personal space. They are often extremely sociable and gregarious
They are also unable to recognize the fearful facial expressions of others, although they can pick out expressions of joy and sadness.

Urbach-Wiethe disease (lipoid proteinosis) is a very rare genetic condition with only about 400 people having ever been diagnosed with it. It is caused by a single mutation in the ECM1 gene, found on chromosome 1. ECM1 is one of many proteins crucial for maintaining the extracellular matrix (ECM), a supportive network that holds cells and tissues in place. When ECM1 is damaged, calcium and collagen begin to build up, causing cell death. One part of the body that seems to be particularly vulnerable is the amygdala.
Urbach-Wiethe disease is unique as it may almost destroy their amygdala while leaving other regions intact. People respond to different brain injuries in different ways. The age at which brain damage occurs can also play a role in how a person recovers.

Internal threats.
Studies of those with damaged amygdalas show us that not all fear is the same as they react to internal threats, often in an alarming way.
This type of fear occurs independently of the amygdala. If someone with a damaged amygdala breathes in carbon dioxide, it triggers a feeling of fear and suffocation, and they experience intense fear with a full-blown panic attack. It would be the most intense fear they had ever felt.

However, when it comes to internal threats, such as detecting raised levels of CO2 in the blood, the brain manages things differently. The body interprets the high CO2 as a sign of impending suffocation, as there aren’t any oxygen sensors in the brain. It is the brainstem, a region that regulates unconscious bodily functions such as breathing, that senses the rise in CO2 and initiates a sense of panic. The amygdala puts the brakes on this response, preventing fear; hence why patients like SM, who are missing their amygdala, have such an exaggerated response. Scientists still don’t know why, however, the amygdala behaves this way.
This highlights why we evolved fear in the first place. It is crucial for orchestrating fear in response to external threats, such as the mugger, the snake, the spider, the monsters jumping out of the haunted house, but it doesn’t seem to be responsible for triggering a very strong sense of panic in response to this more internal trigger.”
One of the questions is whether this primal emotion of fear may actually not be necessary in modern life. It may cause more harm than good, especially in Western societies where a lot of our basic survival needs are taken care of, yet we are seeing levels of stress and anxiety-related disorders that can be off the charts.

FRONTAL LOBE
It controls higher executive functions, including emotional regulation, planning, reasoning, and problem-solving.
Left Frontal Cortex/Lobe. In the autistic brain, alpha frequencies (8-12 Hz) predominate over beta frequencies (12.5-30 Hz), which is the exact opposite of the neurotypical brain. Higher alpha frequencies in the left brain appear to be compensating for the inability to access creativity and intuition from the right brain (Rowland).
Right Frontal Cortex/Lobe. There is regular brainwave activity in the right frontal lobe, with alpha frequencies predominating over beta frequencies.  However, the autistic person is unaware of anything that happens in their right frontal lobe, the place where emotions and social connectivity are experienced (Rowland).

FRONTOSTRIATAL CIRCUITS are neural pathways that connect frontal lobe regions with the basal ganglia (striatum). They process information to control social behaviour and executive functions, such as working memory, planning and organization, behavioural control, adaptation to changes, and decision-making. They are responsible for the elaboration of the plan of action responsible for goal-directed behaviour.

There are five circuits. Due to its role in affective-emotional processing, the circuit most pertinent to autism is the ventromedial prefrontal circuit, which connects the prefrontal cortex to the amygdala.

CEREBELLUM
Part of the hindbrain contains special neurons called Purkinje cells, which are capable of processing multiple signals simultaneously due to their highly complex dendrite branches. The cerebellum coordinates our sensations with our muscles, enabling most of our voluntary movements. It also coordinates the inner ear with muscle movement, thus helping us maintain balance and posture.

SENSORIMOTOR GATING
This is the standard protective mechanism in the brain by which a neural system screens or ‘gates’ irrelevant external (sensory) and internal (cognitive, motor) information from higher-order processing. This prevents information overload and the misinterpretation of sensory information, facilitating mental and behavioural integration. This enables coherent thought – the uninterrupted processing of the most salient aspects of the external and internal environment.

Filtering out relevant from irrelevant information is deficient in multiple neuropsychiatric disorders, including autism and Asperger’s, schizophrenia, and obsessive-compulsive disorder.

Sensorimotor gating is significantly impaired in Asperger’s due to abnormalities in frontostriatal pathways. Sensorimotor gating deficits in autism may reflect similar difficulties with cognitive gating, rendering the individual unable to inhibit or ‘gate’ the repetitive thoughts, speech, and actions characteristic of the disorder. The subsequent information overload may lead to higher cognitive difficulties, such as executive function and ‘theory of mind’ (ToM) abnormalities, common in autism. ToM conceptualizes the thoughts, feelings, knowledge, and beliefs of others. Neurotypicals use context, knowledge of the person, and whether a particular comment or action had benevolent or malicious intent to make character judgments. This is impaired in autism. It makes them naive and prone to be attracted to and imitate children who may not demonstrate good friendship skills.

ToM and executive function accounts of autism together explain quite well the socio‐communicative and flexibility problems in this disorder. However, neither account can explain why people with autism are so good at specific tasks.

Autism presents a strikingly uneven cognitive profile, with typical peaks on the Wechsler Block Design and Digit Span tests. One theoretical account of autism attempts to explain these skills in terms of a bias toward featural versus configural processing. This cognitive style of ‘weak central coherence is demonstrated through the success of individuals with autism on tasks favouring detail focus and relative inability on tasks requiring processing of information in context for global form or meaning. Impaired sensorimotor gating permits stimuli’s indiscriminate access to response output systems without regard for the context of presentation.

QUANTITATIVE MRI AND PPI TESTING
When healthy, unmedicated, intellectually able adults with Asperger’s syndrome are studied using quantitative MRI and PPI to measure sensorimotor gating to examine brain anatomy and are compared to healthy controls of comparable age, IQ, gender, and handedness, differences in the anatomy and function of limbic circuitry have been demonstrated. Abnormalities in the anatomy of this entire neural system have been shown in people with an autism spectrum disorder.

People with Asperger’s have significantly less grey matter in medial temporal and frontal lobe structures, as well as in cerebellar regions, and exhibit widespread differences in white matter. White matter projections to and from abnormal grey matter structures show white matter excesses are distributed bilaterally, but deficits appeared to be more prominent in the left hemisphere. This hemisphere typically develops later than the right, and, perhaps as a consequence of the evolution of speech pathways, frontotemporal pathways reach maturity later than those linking lower-order regions.

Thus, the neuro‐developmental delay in autism may particularly impact the left hemisphere and consequently explain some of the developmental language anomalies found in the disorder. Significant frontotemporal white matter deficits include the left superior temporal lobe speech area.

People with Asperger’s have significant reductions in the grey matter volume of the frontostriatal and cerebellar regions. In addition, people with Asperger’s syndrome have white matter excesses bilaterally around the basal ganglia, whereas they typically have deficits mainly in the left hemisphere. The concentration of abnormalities in the frontostriatal circuitry is most likely to have functional consequences. PPI is thought to depend in part on intact frontostriatal pathways and significant impairment in sensorimotor gating in Asperger’s.

The limbic circuitry, proposed by some as the biological substrate of autism, plays a vital role in sensorimotor gating. This mechanism is used to suppress motor responses to irrelevant stimuli, and similar processes may underlie cognitive gating.
These findings fit broadly with a growing consensus that limbic system and cerebellar abnormalities may be important determinants of autism.

Megaloencephaly is not a universal feature of autistic spectrum disorders, and no bulk regional brain volume differences between Asperger’s and controls have been found. Past reports of megalocephaly in autism may therefore reflect an effect of disease severity (e.g. mental retardation) that is not evident in the Asperger’s sample studied.
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Age‐related differences in whole brain and grey matter volume in the controls were not evident in people with Asperger’s. The reason for this is unknown but may include neurodevelopmental differences in neurogenesis and programmed cell death.

Frontal and striatal brain regions are reciprocally connected to the thalamus. Dysfunction in a system incorporating the basal ganglia and the mesial frontal lobe is responsible for the clinical symptoms of autism, including motor disturbances such as dystonia, bradykinesia and hyperkinesia, and impaired social communication.

The frontostriatal regions identified as abnormal are known to have intimate and reciprocal links with the cerebellum, and the cerebellum has been implicated in higher-order cognitive functions, including executive functions such as planning and shifting attention. Abnormalities in the cerebellum may be related to the behavioural phenotype of people with an autism spectrum disorder. Still, cerebellar pathology may be best viewed in the context of system-wide pathology rather than in isolation.

DIFFERENCES BETWEEN AUTISM AND ASPERGER’S
Autopsies reveal that in both autism and Asperger’s, there is immature development of the cerebellum, amygdala, and hippocampus. Autism has more immature hippocampus development than Asperger’s, which may explain the cognitive problems seen in low-functioning autism. The situation is reversed for the amygdala, a part of the brain that processes emotion – the Asperger’s brain is often more abnormal than the autistic brain. The more normal hippocampus preserves cognitive function in Asperger’s, and the less normal amygdala causes social problems.