Evaluation of the combined effect of reading training and tACS on reading-related cognitive abilities in developmental dyslexia: an investigation by neuropsychological assessment

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Introduction 
This work aims to provide an analysis of the effect of the combination of behavioral 
training and transcranial Alternating Current Stimulation (tACS) on reading skills and 
related cognitive processes in subjects with Developmental Dyslexia (DD). 
Reading may seem a simple task. Nevertheless, it involves attention processes, motor 
control (eye movements), and visual information processing that leads to decoding 
graphic symbols representing letters and recognizing and fusing these into words. 
Although known hypotheses establish the core deficit of DD at the level of phonological 
representation, awareness, and subsequent processing (Bailey & Snowling, 2002), there 
is considerable evidence of the presence of visual (Boden & Giaschi, 2007) and 
visuospatial deficits as well. It is possible to define Developmental Dyslexia as a 
multifactorial disorder that specifically impairs reading skills (Gori et al., 2016). In this 
regard, brain-functional imaging analyses and scientific literature point to a central 
system of visual and linguistic areas underlying the decoding of words and pseudowords 
as a possible cause of the deficits and have shown that the impaired reading network is 
associated with both auditory-phonological and visual-tactile obligations (Habib, 2000). 
As dyslexia represents a persistent and chronic condition (Kemp et al., 2009), the 
investigation of dyslexia in adults has become a topic of great relevance and interest for 
several reasons: in the first place, to understand which aspects of reading continue to pose 
challenges even when the decoding process becomes more automatic; secondly, to 
identify the most appropriate assessment techniques and intervention strategies for adults 
with dyslexia to alleviate the difficulties they face and enable them to experience a 
rewarding college and work life. Therefore, this work aims to analyze from a clinical and 
neuroscientific point of view possible novel interventions to improve reading skills in 
adult individuals with DD. 
After this brief incipit, the following paragraphs will delve into the cognitive aspects that 
characterize dyslexia. Chapter 1 will describe the main etiological hypotheses of 
developmental dyslexia with a section devoted to the main neuropsychological tests that 
can be administered for behavioral assessment. Chapter 2 will discuss the neuronal 
substrates involved in this multifactorial neurological deficit. Chapter 3 will then briefly 
examine neural oscillations alterations in Dyslexia and electrical brain stimulation 
techniques, while chapter 4 will focus on the use of tACS in DD. To conclude, chapter 5
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will present the study testing the combination of a reading acceleration training with tACS 
in adults with DD and its effect on difference cognitive abilities, assessed with 
standardized neuropsychological tests before and after the training. 
 
 
CHAPTER 1: Developmental Dyslexia and its cognitive aspects 
 
The DSM-5 describes developmental dyslexia as "a pattern of learning difficulties 
characterized by problems with accurate or fluent word recognition, poor decoding, and 
poor spelling skills" (American Psychiatric Association, 2013). The main criteria for the 
diagnosis include the persistence of learning difficulties for at least six months and the 
individual's academic abilities quantitatively assessed below what expected based on 
one’s age. Moreover, difficulties tend to begin during the school years and are not better 
accounted for by intellectual disabilities or other mental disorders (American Psychiatric 
Association, 2013). Moreover, it persists despite an average and appropriate intelligence, 
education, and socio-cultural environment (American Psychiatric Association, 2013). 
The original concept of dyslexia was first introduced in 1878 by German neurologist 
Adolph Kussmaul, who noticed that some adults with reading problems had difficulty 
reading correctly and misused words. Kussmaul coined "word blindness" to describe this 
condition associated with neurological disabilities (Stein, 2018). Then in 1887, German 
ophthalmologist Rudolph Berlin introduced the term "dyslexia" to precisely describe the 
pathological condition of a child with severe difficulties in learning to read and write, 
even though his intelligence and physical abilities were "within the normal range." Based 
on Coltheart's two-way reading model, Seymour and Elder identified (Seymour & Elder, 
1986) the following subtypes of developmental dyslexia: 
1. Phonological dyslexia: difficulties occur in processing and reading words that are new, 
pseudo-words, rare, and those with orthographic regularity. 
2. Morphological-lexical or superficial dyslexia: difficulties in reading everyday words 
and those with irregular spelling structures are encountered. 
3. Mixed or deep dyslexia: there are difficulties in reading new, rare, and everyday words, 
pseudo-words, as well as those with both regular and irregular spelling structures. 
The percentage of adults with Dyslexia is not known. However, it appears to be 
approximately 4% according to the APA, DSM-5, 2014. These data show us how adults
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with Dyslexia were often misdiagnosed or not diagnosed at all during childhood due to a 
lack of awareness and understanding of Dyslexia in the past. This may cause Dyslexia to 
remain unrecognized or hidden as it is often regarded as a disorder that predominantly 
affects children, so there is less attention paid to adults, and from this, there may be a lack 
of understanding of the disorder and a lack of awareness about it. However, it is essential 
to note that in recent years, there has been an increased focus on Dyslexia in adults. This 
means that more resources are available for adults with Dyslexia, adult-specific 
diagnostic tests such as the BDA 16-30 battery (Ciuffo et al. l, 2019), LSC-SUA battery 
(Montesano, Valenti & Cornoldi, 2020) and specific intervention programs such as the 
“SuperReading” program (Cole, 2009). With these new tools, it is feasible to identify 
individuals with Dyslexia in adulthood, even if they demonstrate an adequate level of 
compensation. 
In 1997, Professor Thomas Richard Miles, a pioneer of developmental dyslexia studies, 
proposed a simple but structured and comprehensive model involving three levels of 
causal description to identify the significant components of the reading deficit. This 
causal modeling framework consists of a cognitive, biological, and behavioral description 
pathway interconnected by a space for environmental influences that unites and connects 
the three levels on one cohesive plane (Frith, 1999). The cognitive level refers to the 
mental mechanisms of information processing; in particular, the author of the model 
refers to difficulties in visual, auditory, and temporal processing; the biological level 
allows us to assume that the deficit of dyslexia has genetic origins and is associated with 
physiological and structural brain impairments (Pugh et al., 2001). The biological 
influence hypothesis is confirmed in a review conducted by DeFries, Alarcon, and Olson 
in 1997, who examined various evidence supporting physiological dysfunction of the 
brain in people with dyslexia during reading or reading-related activities (Knopik, et all 
1997). 
One study cited in the review was conducted by Rumsey et al. in 1992. This study used 
positron emission tomography (PET) to detect brain activity during reading in dyslexic 
individuals. The results showed reduced activity in the left temporal lobe, which is 
involved in language processing, in dyslexic participants compared to controls. 
Another study conducted by Shaywitz et al. in 1998. This study used fMRI to examine 
brain activity during reading in dyslexic individuals before and after an intensive reading
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intervention. After the intervention, the results showed normalization of brain activity in 
the right angular circumvolution, suggesting that intensive training can help improve 
neurological dysfunction in the brains of people with dyslexia. (Shaywitz, S. E., et all., 
1998). 
Overall, these analyses indicate the presence of physiological brain dysfunction in people 
with dyslexia during reading or reading-related activities. 
The behavioral level concerns all observable manifestations and, for example, we can 
find difficulties and slowness in reading, comprehension problems, challenges in 
memorization and synthesis of the content read. Many adults, then, have issues with time 
management, difficulties with planning and organization, or inadequate vocabulary. In 
conclusion, about environmental causes, we consider teachings obtained, cultural 
attitudes, and socio-economic conditions. The 3-level model shows us that there is a wide 
gap between brain functioning and behavior, emphasizing that external influences can 
affect the clinical picture (Frith, 1999). Evidence on the biology of dyslexia obtained from 
genetic studies, postmortem anatomical analysis, and brain imaging appear distinct from 
behavioral attributes, and the connections between them tend to be weak. The cognitive 
level is regarded as a bridge between the biological and behavioral levels: cognitive 
theories must build on the current understanding of brain function while systematically 
considering environmental factors that influence behavior. In this context, hypotheses 
about mental causes serve as a critical link in cause-and-effect models and can suggest 
possible intervention strategies. Suppose there is an abnormality at the neurological level 
in a specific brain system. In that case, it is expected that there will be abnormalities in 
the mental processes that depend on this system. It is important to note that this 
consequence is not necessarily inevitable, as protective factors may be present. Brain 
plasticity allows some flexibility, and the cognitive system may be sufficiently redundant 
to avoid further negative consequences (S. E. Shaywitz et al., 1998). The 3-level model 
thus meets the authors' goal of devising a neutral framework to compare different DD 
theories. According to Frith et al., these levels would not conflict with each other but 
rather collimate and intersect ideally with each other. It follows that it would not be 
correct to confine dyslexia to a single theoretical explanation, and this would explain the 
need for the consideration of developmental dyslexia as a multifactorial disorder.
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1.1. Etiological hypotheses of Developmental Dyslexia and related tests 
 
Various experts have formulated etiological hypotheses to try to understand the causes of 
this condition. Its exact causes are not yet fully understood. Nevertheless, its complex 
nature has led to the formulation of several hypotheses that have been put forward to try 
to explain its origins. Below, four of the most relevant ideas will be presented, 
accompanied by the relevant evidence. Empirical evidence supports the idea that dyslexia 
is a neurobiological disorder caused by genetic and environmental factors. 
Genetic Hypothesis 
One of the main etiological hypotheses of dyslexia is the genetic hypothesis: The genetic 
theory suggests that developmental dyslexia may be due to genetic factors. Studies 
conducted on identical twins and siblings have shown that the presence of the disorder is 
more significant among first-degree relatives of dyslexic patients than in the general 
population. In addition, some genetic association studies have identified specific gene 
variants related to dyslexia. Specifically, family, twin, and heredity studies have shown 
that there is a genetic predisposition to dyslexia. Children of parents with dyslexia have 
been found to have a higher risk of developing the disorder than the general population 
(Van Bergen et all., 2014). 
In addition, several genes have been identified that appear to play a role in determining 
susceptibility to dyslexia. For example, the DCDC2 gene has been associated with an 
increased risk of developing this disorder as well as other cortical defects could result 
from genetic changes in the DYX1C1 gene located on chromosome 15, as well as in the 
KIAA0319 and DCDC2 genes located on chromosome 6, and in ROBO1 located on 
chromosome 3. These alterations could lead to reduced activity in the left temporal region 
of the brain, more specifically involving the lateral temporal cortex and ventral 
occipitotemporal area (Scerri & Schulte-Körne, 2010). 
Phonological Hypothesis 
The phonological hypothesis argues that the primary deficit in developmental dyslexia 
lies in correctly processing spoken language sounds, which can affect reading, writing, 
language comprehension, and verbal memory. According to this hypothesis, phonological 
facility, that is, the correct manipulation of speech sounds, underlies developmental 
dyslexia and consequently suggests that the primary deficit in dyslexia is in the ability to 
correctly process and manipulate the sounds of spoken language and phonemes.
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According to this hypothesis, individuals with dyslexia have difficulty distinguishing and 
using oral language sounds, known as phonological skills, recognizing and distinguishing 
individual word sounds, and understanding how these combine to form meaningful words 
and sentences. Some studies have also found a correlation between phonological 
awareness skills in the preschool period and success in learning to read and write. 
Dyslexic children often make errors in reading and pronouncing words, swapping similar 
phonemes or omitting them altogether, and several pieces of evidence show that these 
issues often persist in adulthood. These errors are attributed to their inability to correctly 
distinguish and identify phonemes, which are the basic units of sound in language. This 
hypothesis also suggests dyslexic individuals may have difficulty memorizing the 
phonological rules of language, such as the correspondence between sounds and letters 
of the alphabet. This may lead to poor performance in reading and writing as they may 
struggle to decode written words and transform them into corresponding sounds. In 
addition, the phonological hypothesis of dyslexia argues that phonological difficulties 
may also affect other language skills, such as spoken language comprehension and verbal 
short-term memory. Since spoken language sounds play a key role in understanding the 
meaning of words, people with dyslexia may have difficulty understanding verbal 
instructions or remembering a series of words or oral information. 
Rapid auditory processing 
According to the auditory processing theory paradigm of dyslexia, the phonological and 
reading difficulties observed in the dyslexic context are attributed to an impairment in 
processing auditory information characterized by the rapid flow. (Tallal & Merzenich, 
1993; Tallal & Benasich, 2002; Temple 2002; Tallal & Gaab, 2006). This auditory 
processing deficit may manifest as difficulty remembering, producing, discriminating, 
and sequencing short, fast-moving auditory information (Tallal & Gaab, 2006). The 
authors argue that the inability to process this short and fast auditory information 
adequately can cause deficits in the ability to perceive and distinguish different phonemes 
within words. This skill is critical for learning grapheme-phoneme mappings, which are 
necessary to develop an effective reading strategy. 
Magnocellular Hypothesis 
The magnocellular deficit hypothesis as a cause of developmental dyslexia is supported 
by a great deal of empirical evidence. Stein (1997) documented structural and functional
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abnormalities in the magnocellular visual system, known as the M system, and formulated 
his "magnocellular deficit hypothesis" to explain the symptoms of dyslexia (Stein, 2001, 
2018, 2019, 2021). According to this hypothesis, reading, fluency, and spelling 
difficulties result from abnormal functioning of magnocellular cells. Eden et al. (1996) 
suggested that magnocellular deficit could be used as a discriminative diagnostic sign for 
dyslexia. The magnocellular deficit theory focuses on the role of perceptual deficits in 
developmental dyslexia. Studies have shown that dyslexic children exhibit decreased 
sensitivity to visual motion and reduced neuronal responses to moving visual information 
(Stein, 1997). These findings support the idea that perceptual problems may affect 
reading. Theory suggests that people with dyslexia show defects in the magnocellular 
system responsible for recognizing short, moving visual stimuli (Stein, 2001, 2018, 2019, 
2021). 
In conclusion, the magnocellular deficit hypothesis as a cause of developmental dyslexia 
is based on empirical evidence demonstrating abnormalities in the magnocellular visual 
system. Several studies have found defects in visual motion sensitivity and neuronal 
responses in dyslexic children, supporting that perceptual problems may affect reading. 
The magnocellular deficit theory proposes that abnormal magnocellular cell functioning 
can be a discriminating diagnostic sign for dyslexia (Eden et al., 1996). 
Cerebellar Hypothesis 
The cerebellar hypothesis is based on the involvement of the cerebellum in developmental 
dyslexia. The cerebellum is involved in motor processing and balance control. Recent 
studies have also shown its importance in reading and writing. Some functional Magnetic 
Resonance Imaging (MRIs) show reduced cerebellar activity in dyslexic children during 
reading tasks, suggesting dysfunctional involvement of the cerebellum in the disorder 
(Richlan, F. 2019). The cerebellar hypothesis of developmental dyslexia is a theory that 
suggests that dyslexia may be dysfunction or underdevelopment of the cerebellum. 
According to this hypothesis, developmental dyslexia could result from reduced activity 
or malformation in the cerebellum, which may adversely affect the ability to process 
language information. A damaged cerebellum could interfere with properly encoding and 
decoding verbal stimuli, making it difficult for a dyslexic individual to read or write 
correctly. The cerebellar hypothesis finds support in neuroanatomical evidence, where 
structural and functional differences have been found in the cerebellum of dyslexic