Effects of RTMS on Cognitive Functions and Behavior in Individuals with Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with core symptoms that include impairments in social communication and restricted and repetitive behaviors, interests, and activities. Social cognition is a broad term used to understand, perceive, and interpret information about others and ourselves in a social context. Impairments in social cognition are often highlighted as a potential mechanism underlying social disability in autism spectrum disorder. High-order cognitive functions, such as Executive function (EF) and social cognition, rely on neural network oscillations in the gamma frequency (30-80 Hz) band. It has been proposed that GABA-inhibitory interneurons in the dorsolateral prefrontal cortex (DLPFC) contribute to the synchronization of pyramidal neurons, which is necessary for EF performance. Impaired GABAergic neurotransmission within the DLPFC has been linked with altered gamma oscillatory activity and working memory deficits. Transcranial magnetic stimulation (TMS) is one method used to deliver electrical stimuli through the scalp in conscious humans. Recently, rTMS is not only for the treatment of major depressive disorders, but it has also been advanced as a potential therapeutic technique to treat neurologic disorders such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, and many other neuropsychiatric disorders. It is still undetermined whether it is possible to improve the symptoms of ASD individuals through noninvasive neural modulation. Previous studies in ASD indicate that rTMS applied to DLPFC can modulate gamma oscillatory activity.

In this study, the investigators aim to examine the effectiveness of low-frequency rTMS in improving social cognitive function and emotion recognition in ASD individuals.

Further understanding of the effect of low-frequency rTMS in altering the cognitive function in ASD individuals may help to achieve some answers related to the mechanism behind ASD. This stimulation protocol could be a vital therapeutic strategy for the treatment of ASD in future clinical practice.

Statement of the Problem:

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Core ASD symptoms include impairments in social communication and restricted and repetitive behaviors, interests, and activities. ASD may also present with secondary signs, including hyperactivity, self-injury, and co-occurrence of some psychiatric conditions, e.g., anxiety and major depression. The symptoms of ASD are persistent and typically appear during the first three years of life. It can be recognized and clinically evident in early childhood.

In most cases, but not all, ASD symptoms might follow a steady course without remission. However, deficits and impairment in social skills and behavioral patterns may not be noticed and diagnosed as symptoms of ASD until the child faces significant life demands such as social, educational, and occupational tasks. Moreover, this functional limitation may vary among persons with ASD and could develop over time.

In the past 50 years, ASD's description has changed from a rare disease of childhood-onset to a well-publicized, advocated, and researched lifelong condition, recognized as relatively common and very heterogeneous. Since the 1970s, several studies have reported increased ASD cases. The report documented that the male/female ratio is approximately 4 per 1. According to the Centers for Disease Control, the prevalence of ASD increased from 1 in 80 (1.25%) in (2011-2013) to 1 in 45 (2.24%) in 2014. In the Gulf countries, systematic review studies of the epidemiology of autism revealed a prevalence ranging from 1.4 to 29/10,000 persons. In a study in Taif, Saudi Arabia, the estimated prevalence of autism in primary school children aged 7-12 years was 0.035%. Reviews of the literature have revealed no recent prevalence statistics for children with autism/ASD in Saudi Arabia. The Saudi Ministry of Health has indicated that one in every 160 children has an ASD.

ASDs are a financial, emotional, and social burden. An autistic child's care causes more emotional burden to the parents than that of parents, compared to that of parents taking care of terminally ill children.

Social cognition is a broad term that describes cognitive processes related to perceiving, understanding, and implementing linguistic, auditory, visual, and physical cues that communicate emotional and interpersonal information. It is also defined as the perception of others, the perception of self, and interpersonal knowledge. It's the ability to understand, perceive, and interpret information about others and ourselves in a social context. It includes a wide range of processes that allow people to perceive and interpret rapidly changing social information and respond appropriately to social stimuli quickly, effortlessly, and flexibly. Also, social cognition ability gives meaning to the actions of others.

Assessment of social cognition, primarily focusing on four key domains, like theory of mind (ToM), emotional empathy, and social perception and behavior, has been increasingly evaluated in clinical settings, given the potential implications of impairments of these skills for therapeutic decision-making. Cognitive impairment is defined as when a person has trouble remembering, learning new things, concentrating, or making decisions that affect their everyday life. The common signs of cognitive impairment may include loss of memory. Asking the same question frequently or repeating the same story over and over, unable to recognize familiar people or places, having trouble exercising judgment, such as knowing what to do in an emergency, changes in mood or behavior, difficulty in vision, difficulty planning or carrying out tasks, such as following a recipe or keeping track of monthly bills.

Studies showed that alterations in social cognition ability were associated with autism, autism severity, and autistic traits. Impairments in social cognition are often highlighted as a potential mechanism underlying social disability in autism spectrum disorder. Different social skills programs have been developed for autistic adults based on the assumption that improving social understanding and ability will improve functional outcomes.

Transcranial magnetic stimulation (TMS) is one method used to deliver electrical stimuli through the scalp in conscious humans. Generally, single-pulse TMS (including paired-pulse TMS) is used to explore brain functioning. In contrast, repetitive TMS (rTMS) is used to induce changes in brain activity that can last beyond the stimulation period. Therefore, TMS and rTMS are indirect and non-invasive methods to induce excitability changes in the motor cortex via a wire coil, generating a magnetic field that passes through the scalp. TMS Non-invasive TMS of the motor cortex leads to a twitch in the target muscle, evoking motor-evoked potential (MEP) on electromyography. As per the literature, TMS might help regulate gamma oscillations, reduce behavioral symptoms, and normalize executive and autonomic dysfunction signs. TMS is a valuable technique for assessing the underlying neurophysiology associated with several neuropathologies. It is a unique tool for establishing potential neural mechanisms responsible for disease progression. Recently, rTMS has been advanced as a potential therapeutic technique to treat selected neurologic disorders. Such neurological disorders include Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis.

Moreover, worldwide, multiple studies have repeatedly demonstrated that TMS has antidepressant effects more significantly than sham treatment and that these effects are clinically meaningful. For diagnostic uses, TMS is a potential diagnostic tool in movement disorders. TMS is used worldwide and represents a novel technique with both diagnostic and therapeutic potential. TMS is used to study cortical excitability and intracortical inhibition and investigate cortical and cortico-spinal plasticity mechanisms implicated in ASD pathophysiology. Published studies showing promising results concluded that specific rTMS protocols targeting particular regions of the cortex might lead to improvement in specific behavioral deficits in some individuals with ASD; both the investigative and therapeutic results have been mixed. rTMS and other electrical stimulation devices can modulate the brain's functioning in either a facilitatory or suppressive manner and, when applied over several sessions, can have an additive effect lasting several months. If theories are correct that cortical mechanisms of excitability, connectivity, and plasticity are abnormal in ASD, then rTMS can modulate these mechanisms. Overall, in the hands of trained technicians, rTMS might have great potential as both a diagnostic and therapeutic tool for ASD.

Eligibility Criteria:
Target population:

* Autistic individuals
* previously Diagnosed with ASD using the American Psychiatric Association's DSM-V criteria
* previously Diagnosed using the Autism Diagnostic Observation Schedule (ADOS).

Inclusion Criteria:

* Male and female ASD individuals
* age between 5 and 11 years old
* diagnosed with ASD on prior clinical assessment using the American Psychiatric Association's DSM-V criteria and corroborated by assessment using the Autism Diagnostic Observation Schedule (ADOS).
* Normal hearing ability based on past hearing screens.
* Participation will be limited to higher functioning (intelligence quotient \[IQ\] \>70) to maximize successful completion of tested paradigms, maintain alertness/attention, furthermore, the ability to follow instructions.

Exclusion Criteria:

* Individuals that are known to have epilepsy ( including Hx. of febrile convulsion) or have a family history of epilepsy.
* Any individual with a previous Hx. Of head injuries
* Any individual has been diagnosed with psychiatric illness, including ADHD, depression, psychosis, bipolar disorder, anxiety disorders, or OCD.
* Individuals using one or a combination of Psychotropic Medications known for their significant seizure threshold lowering potential, for example, and not as a limitation: Bupropion, Citalopram, Duloxetine, Fluoxetine, Fluvoxamine, Mirtazapine, Paroxetine, Sertraline, Venlafaxine, Tricyclics, Olanzapine, Quetiapine, Aripiprazole, Ziprasidone, and Risperidone.
* The presence of metallic objects, e.g., cranium clips or implanted biomedical devices.