Stem Cell Therapy for Learning Disability

*Alok Sharma, Nandini Gokulchandran, Hemangi Sane, Sakshi Desai, Pooja Kulkarni and Prerna Badhe*

## **Abstract**

Learning disabilities (LDs) are caused by genetic and/or neurological factors that alter brain functioning and affect processes related to learning, which include dyslexia, dysgraphia, and dyscalculia. It hinders the child's academic, social, and overall life skills. Current treatments for LD include medication and rehabilitation, focusing on management of symptoms. Thus, there is a need to explore newer treatments which will work at cellular level. Stem cell therapy is an evolving field of regenerative medicine and has shown great potential as a treatment strategy for various neuro-developmental and neurological disorders. It addresses the core underlying pathology and its benefits are enhanced when combined with standard treatments. This chapter focuses on various aspects of stem cell therapy in LD which includes the basics of stem cell therapy, rationale for use of stem cells, mechanism of action, monitoring tools like PET CT scan, and multidisciplinary rehabilitation. We have also enumerated our clinical experience and results of patients who underwent autologous bone marrow mononuclear cell transplantation combined with extensive rehabilitation. These patients showed a positive outcome, without any major adverse events. Nineteen out of 20 patients showed improvement in reading, writing, mathematical skills, attention, memory, problem-solving, comprehension skills, spelling, vocabulary, and overall increased academic performance.

**Keywords:** stem cell therapy, learning disability, bone marrow-derived mononuclear stem cells

## **1. Introduction**

Learning disability (LD) is an umbrella term that includes *dyscalculia* or difficulty in calculating numbers, *dysgraphia* or difficulty in writing, and *dyslexia* or reading difficulty [1]. Also known as Specific Learning Disabilities (SLD), it causes the inability to read and comprehend, which is a major obstacle to learning and may have long-term educational, social, and economic implications while interfering with children reaching their full potential [2]. SLD results not from a global intellectual deficit, but from impairments in one or more of the specific processes of speech, language, reading, spelling, writing, or arithmetic. This possibly results from cerebral dysfunction [3]. Neurological differences in brain structure and function affect a person's ability to receive, store, process, retrieve, or communicate information. While the specific nature of these brain-based disorders is still not well understood, considerable progress has been made in mapping some of the characteristic difficulties of

LD to specific brain regions and structures [4]. Hypoxia can lead to hypoperfusion of the brain and the reversal of hypoxia may lead to self-repair and neural proliferation, which is observed in many animal models of cerebral ischemia. Chronic cerebral hypoperfusion to a lesser degree is known to cause neurodegeneration over a period of months to years through neuronal apoptosis without acute infarction [5] and individuals with chronic cerebral hypoperfusion usually have cognitive deficits of varying degrees [6].

Currently, all treatments for LD involve medications and rehabilitative techniques that focus on managing the symptoms. Thus, there is a need to explore other treatments which will work at the cellular level. Stem cell therapy is a new evolving field of regenerative medicine and has shown great potential as a treatment strategy for various disorders such as autism, intellectual disability, and cerebral palsy among many neuro-developmental conditions. It addresses the core underlying pathology of LD. In experimental studies, stem cell therapy has been shown to repair the hypoxia-damaged neural networks and restore the lost neuronal connections [7]. Stem cells, when injected, migrate to the target tissue and differentiate into mature cells. Along with regenerating and restoring the neurons and glial cells, they have a neuroprotective effect [8]. Several vertebrates regenerate tissues and organs, like the salamanders, regenerate lost body parts through the dedifferentiation of specialized cells into new precursor cells. These de-differentiated cells then proliferate and later form new specialized cells of the regenerated organ. Stem cells or progenitor cells are the common denominators for nearly all types of regeneration [9]. The goal of stem cell therapy is thus to enable the localization of therapeutic cells to impaired/injured regions of the brain, to stimulate tissue repair and maintenance via a paracrine effect, and potentially even to generate new neurons [10]. Therefore, stem cells, through re-perfusion of the damaged brain regions in SLD can lead to improved neurological functions. This can increase academic performance and chances of employability in the future. Stem cell therapy has shown improved brain function and quality of life in similar neurological impairments such as autism spectrum disorder, cerebral palsy, intellectual disability.

This chapter focuses on the Regenerative capacity of Stem Cell Therapy in learning disability. It has a detailed description of what stem cells are, where they are obtained from, how they are injected into the body, and their mechanism of action. Furthermore, it explains how stem cell therapy results in a positive outcome in children with learning disabilities. We have included neuroimaging techniques such as PET CT brain scan as a monitoring tool to study the effect of stem cell therapy.

## **2. Unmet medical need**

With increasing awareness, the prevalence of learning disability has risen considerably. Most often LD is managed with medications and rehabilitative therapies which include behavioral therapy, alternate methods of learning like remedial education, individualized education plan (IEP), and intervention programs. However, these treatment strategies do not address the underlying neuropathology of LD. Hence, there is a need for a treatment that focuses on cellular repair and further addresses the cognitive deficit.

#### **3. About stem cells**

Stem cells provide the building blocks for every organ in the body. They have the unique ability to divide asymmetrically and to differentiate into the various cell *Stem Cell Therapy for Learning Disability DOI: http://dx.doi.org/10.5772/intechopen.101511*

types of the body. They simultaneously replicate to maintain a stem cell lineage. Stem cells are present in almost every human tissue. In embryos, they differentiate into all the tissues and organs of the body and provide a renewal capacity in most organs in fully developed humans. In neurological disorders wherein the neurons are damaged or defective, stem cell therapy repairs and replaces damaged/lost neurons [10]. Cell therapy is based on allogenic (patient receives stem cells from a healthy donor), or autologous transplantation (patient receives their own stem cells) of cells, with the goal of regenerating the damaged tissue or organ of the patient and replenishing specific stem cell populations [11].

## **3.1 Type of stem cells**

Classification of stem cells depend on major characteristics such as (**Figure 1**):


## *3.1.1 Based on the source of stem cells*

i. *Embryonic Stem Cells* **(ESCs)—**These are pluripotent, derived from the inner cell mass of the blastocyst, a stage of the pre-implantation embryo, 5–6 days postfertilization [12]. Our understanding of stem cells began with embryonic stem

**Figure 1.** *Types of stem cells based on differentiation potential and source.*

cells. They come from a ball of cells called the blastocyst, which forms 5 days after an egg is fertilized and develops into the embryo. In 1998, Professor James Alexander Thomson and his team at the University of Wisconsin-Madison grew the first human embryonic stem cells in a laboratory dish (in vitro). This allowed scientists to learn how the cells function [13]. ES cells have an unmatched capacity for self-renewal and pluripotential. These two factors continue to increase the relative potential of ES cells in cell replacement and regenerative therapies. However, their safety is questionable as they translate into tumors like teratoma and teratocarcinoma *in vivo* which remains the single greatest hurdle to successful ES cell-based therapies. Without rigorous elimination of this possibility, clinical transplantation of Embryonic stem cells will never be safe [14].


oncogenic potential is yet to be determined in long-term studies. Research in this area has been mainly confined to animal models and their extensive clinical application is yet to be tested. These stem cells have other limitations such as difficulty in identifying, purifying, and growing them consistently in labs [24].


## *3.1.2 Based on potency*


## *3.1.3 Routes of administration*


## **3.2 Mechanism of action of stem cells**

Stem cells have a unique property of homing and targeting specific damaged areas on administration. The homing mechanism is attributed to the expression of growth factors, chemokine, and extracellular matrix receptors on the surface of cells. On administration, they survive, migrate, proliferate, and differentiate into the required cell types [40]. They not only replace the damaged cells but also carry out the repair process via paracrine mechanisms [41]. Transplanted stem cells

### *Stem Cell Therapy for Learning Disability DOI: http://dx.doi.org/10.5772/intechopen.101511*

#### **Figure 2.** *Mechanism of action of stem cells.*

express paracrine signaling factors including cytokines and other growth factors, which are involved in the repair process through neuroprotection, increasing angiogenesis, decreasing inflammation, preventing apoptosis, activation of resident/ satellite cells, etc. (**Figure 2**).

## *3.2.1 Neuroprotection*

Stem cells secrete a vast array of neuroprotective growth factors including BDNF, nerve growth factor (NGF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor-2, and insulin-like growth factor type 1. These growth factors activate signaling pathways, enhance the differentiation, survival of neurons and maintain neuronal functions [42].

## *3.2.2 Increased angiogenesis*

Stem cells secrete signaling molecules like vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and basic fibroblast growth factor (FGF2) resulting in improved perfusion, regional blood flow, enhanced angiogenesis, and oxygenation [43].

## *3.2.3 Immunomodulation*

Stem cells impart an immunomodulatory effect as they reduce the levels of pro-inflammatory molecules TNF-α, IL-1β, IL-1α, IL-6 and increase levels of anti-inflammatory molecules such as IL-10 therefore, enhancing endogenous brain repair [44].

## *3.2.4 Activation of neighboring resident stem cells*

The resident stem cells may possess growth factor receptors that can be activated to induce their migration and proliferation and promote both the restoration of dead tissue and the improved function in damaged tissue. Transplanted cells stimulate these endogenous cells to carry out the repair process [45].

## **4. Published literature**

To our knowledge, there are no clinical studies of stem cell therapy in learning disability. However, it has been greatly explored in various pediatric neurological disorders such as autism, cerebral palsy, and intellectual disability [46].

Sharma et al. have established the safety and efficacy of bone marrowderived mononuclear cells in autism and intellectual disability. In 254 cases of autism spectrum disorder, 95.27% of patients showed an improved score on CARS while 94.48% of cases showed improvement in ISAA. Symptomatic improvements were observed in eye contact, attention and concentration, hyperactivity, sitting tolerance, social interaction, stereotypical behavior, aggressiveness, communication, speech, command following, and self-stimulatory behavior. Eighty six patients who underwent a repeat PET CT scan showed improved brain metabolism after intervention in areas that correlated to the symptomatic changes [47].

In intellectual disability, the outcome of 29 patients of the intervention group was compared to that of 29 patients from only the rehabilitation group and it was found that all patients in the intervention group showed improvement while there was no improvement in 20.69% of patients from only the rehabilitation group. Improvement was noted in cognition, memory, problem-solving, understanding of relationships, social inhibitions, toilet training, command-following, eye contact, aggressive behavior, and attention and concentration. Comparative PET-CT scan study in patients of the intervention group showed improved metabolism in the frontal, parietal cortex, thalamus, mesial temporal structures, and cerebellum. No serious adverse events were recorded [48].

## **5. Clinical data**

We have studied the outcome of autologous bone marrow-derived mononuclear cells in 20 individuals diagnosed with learning disability.

#### **5.1 Demographic data of study population**

Demographically, 14 male and 6 female patients were included, where 6 patients were within ages 1–10 years, 13 within 11–20 years, and 1 patient in the 21–30 years age range. Symptomatically, these patients presented with dysfunctions in academic performance, attention and concentration, reading, writing and mathematical skills, spelling, comprehension and recognizing words, problem-solving, and memory issues. Their functional capacity was measured by functional independence measure (FIM) and intelligence and/or social quotient through various tests such as BKT and VSMS measures.

#### **5.2 Procedure**

For the procedure of stem cell transplantation, autologous bone marrow mononuclear stem cells (BMMNCs) were selected as they were easily obtainable, safe, and did not involve any ethical issues. Intrathecal route of administration is a minimally invasive, safe, and effective procedure as compared to other routes. Studies have also shown that a mixture of cells exhibits more benefits as compared to a single subfraction of cells [49]. Hence, intrathecal autologous BMMNC transplantation was carried out in our study.

#### *Stem Cell Therapy for Learning Disability DOI: http://dx.doi.org/10.5772/intechopen.101511*

The patients were administered Granulocyte Colony Stimulating Factor (GCSF) before the harvest and transplantation of BMMNCs. On the day of the transplantation, 80–100 ml bone marrow was aspirated using a bone marrow aspiration needle from the right anterior superior iliac spine. This was collected in heparinized tubes and transported to the laboratory. Thereafter, in the culture laboratory, MNCs were separated by the density gradient technique. CD34 counts were performed and transported back to the operation theater in a cool sterile container. With the patient in a left lateral position, using a spinal needle, the thecal sac was punctured at L4-L5 space and the cells were injected through that spinal needle. Following this, Methylprednisolone 500 ml isolyte P was given intravenously, and the patient was observed for any adverse events.

After the stem cell transplantation, all patients underwent specialized rehabilitation such as special education, occupational and physical therapy, psychological counseling, and speech therapy.

## **6. Result**

No major procedure-related adverse events were recorded. One patient reported a slight increase in absence seizures, which was controlled with medications. On an average follow-up of 26 months, 94.7% patients showed an improved clinical status. Reading skills improved in 75% patients, writing skills in 88% patients and mathematical skills improved in 70% affected patients, attention increased in 94% patients, memory skills in 78.5% patients, problemsolving skills improved in 69% patients, and comprehension skills in 72.7% patients. Spelling and vocabulary skills improved in 75% and 60% patients respectively. Overall increased academic performance was reported in 70% patients (**Figure 3**).

#### **Figure 3.** *Improvements were seen in various areas in 20 patients with learning disability post stem cell transplantation.*

## **7. Role of rehabilitation in combination with cellular therapy**

Evidence suggests that exercise induces mobility in the injected stem cells, thereby helping in the migration of the cells and helping upregulate neural plasticity [50]. Exercise also improves oxygenation and blood supply to the brain. Hence, the synergistic effect of stem cell therapy and neurorehabilitation brings about maximum functional recovery. Post stem cell therapy, the aim of rehabilitation in individuals with LD is to address the specific deficits that impair their ability to learn through sensory integration therapy, context-specific training, psychological counseling, and vocational training. Occupational therapy interventions use sensory integration methods to enhance sensory processing skills such as understanding, attention, sitting tolerance, and memory skills along with higher cognitive skills like judgment and problem-solving skills. Focusing on fine motor hand functions, handwriting grip, and writing skills are facilitated. Making use of visual schedules and timers to enhance time organization. Some studies showed direct instruction and modeling of letter formation, combined with memory retrieval, self-evaluation, fluency, and/or orthographic coding activities, led to improvements in students' legibility and writing fluency in the studies [51–53], and improvements in correct word sequences [54]. Speech therapists may collaborate with instructors to incorporate instruction that involves multiple modalities to facilitate connections between letters and sounds, as well as between written and oral language that incorporates visual and auditory cues. Students with LD benefit from explicit and systematic instruction that is closely related to their area of instructional need [55]. Special education differs from general education for students with LD when it is more explicit, intensive, and supportive [49]. Some ways of facilitating improved academic performance and life skills are through controlling task difficulty, teaching students in small, interactive groups, modeling and teaching strategies for generating questions and thinking aloud while reading, writing, or working on a scientific or mathematical problem, direct and explicit instructional practices, higher-order processing skills and problem-solving along with learning when, where, and how to apply strategies, ongoing progress monitoring of specific skills, teaching the building blocks of reading and writing like phonemic awareness, writing speed, the process of writing and the organizational and mechanical aspects of writing [56–60]. These strategies enhance the specific skills of reading, writing, arithmetic and inculcate generalization of strategies in life. Alternatively, Art therapy can be used in people with SLD who have difficulties in expressing themselves. It is a form of psychotherapy using art media as its primary mode of communication. Making artwork can facilitate expression and communication for people who find it difficult to express their thoughts and feelings verbally, and it is an accessible approach for children and adults with learning disabilities [61].

## **8. Radiological imaging**

Brain tissue requires glucose for functional activity. The PET-CT scan records brain metabolism by using fluorodeoxyglucose (FDG) uptake. The active neural tissue absorbs glucose in direct proportion to its function. In turn, FDG uptake measures glucose metabolism and detects neuronal activity, which is the level of brain function. It is a promising technology to detect cellular effects of neurorestoration [62, 63]. In our study, a PET-CT scan was performed for all patients prior to cell transplantation to determine the dysfunctions in the brain. In the patients who underwent a repeat stem cell transplantation, PET images were compared to study the changes in brain metabolism after cell therapy. The images prior to stem cell therapy revealed hypo-metabolism in bilateral cerebellar hemispheres, medial temporal lobe, anterior

#### **Figure 4.**

*Improvements were seen in reduced hypometabolism in areas of cerebellum and basal ganglia 12 months post stem cell therapy (the blue hypometabolic areas turn green post cellular therapy).*

#### **Figure 5.**

*Improvements were seen in reduced hypometabolism in areas of the cerebellum, temporal and parietal lobes 8 months post stem cell therapy.*

and posterior cingulate gyri, and bilateral thalami with basal ganglia involvement, whereas hyper-metabolism was seen in the prefrontal cortex in many cases. These areas showed improved metabolism after cell therapy (**Figures 4** and **5**).

## **9. Conclusion**

Stem cell therapy in combination with standard treatment and rehabilitation is a novel therapeutic option for learning disability. Its safety and efficacy have already been established in other incurable pediatric conditions such as autism, cerebral palsy, intellectual disability. Likewise, the results of our study conducted on patients with a learning disability have demonstrated a positive outcome and is an excellent foundation upon which future research can be advanced. Future studies should focus on analyzing the benefits of different cell types, the number of cells, and the route of administration for optimal use of cell therapy in learning disability.

## **Author details**

Alok Sharma1 , Nandini Gokulchandran1 , Hemangi Sane2 , Sakshi Desai2,3\*, Pooja Kulkarni2 and Prerna Badhe4

1 Department of Medical Services and Clinical Research, NeuroGen Brain and Spine Institute, India

2 Department of Research and Development, NeuroGen Brain and Spine Institute, India

3 Department of Neurorehabilitation, NeuroGen Brain and Spine Institute, India

4 Department of Regenerative Laboratory Services, NeuroGen Brain and Spine Institute, India

\*Address all correspondence to: sakshidesai.work@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Stem Cell Therapy for Learning Disability DOI: http://dx.doi.org/10.5772/intechopen.101511*

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## *Edited by Sandro Misciagna*

Learning disabilities are a heterogeneous group of disorders characterized by failure to acquire, retrieve, and use information competently. These disorders have a multifactorial aetiology and are most common and severe in children, especially when comorbid with other chronic health conditions.

This book provides current and comprehensive information about learning disorders, including information on neurobiology, assessment, clinical features, and treatment. Chapters cover such topics as historical research and hypotheses of learning disorders, neuropsychological assessment and counselling, characteristics of specific disorders such as autism and ADHD, evidence-based treatment strategies and assistive technologies, and much more.

Published in London, UK © 2022 IntechOpen © photopsist / iStock

Learning Disabilities - Neurobiology, Assessment, Clinical Features and Treatments

Learning Disabilities

Neurobiology, Assessment, Clinical Features

and Treatments

*Edited by Sandro Misciagna*