Categories
Health and Disease

Language Development and Communication and Neuroanatomical Differences in Children with ASD

By Preethi Nalluru

Published 11:23 EST, Sat October 23rd, 2021

Abstract

Autism Spectrum Disorders (ASD), characterized by deficits in social communication and restricted repetitive behaviors, is a neurodevelopmental disorder affecting approximately 1 in 54 children. Differences in producing and processing language are common in those with ASD and impact social development. Usage of communication tools, including gestures and cues such as gaze, are affected in children with ASD. In addition to behavioral differences, the main neuroanatomical differences in those with ASD that affect language are cortical thickness differences and differences in the amount of gray matter. Autistic children often reach developmental milestones later than typically developing children, and they often have flatter growth in early childhood with steeper growth in adolescence. They also show reduced gestures with a later onset and differences in cortical thickness.

Introduction

Autism Spectrum Disorders is a neurodevelopmental disorder characterized by deficits in social communication and restricted repetitive behaviors. According to the Centers for Disease Control and Prevention, almost 1 in 54 children can be reliably diagnosed with ASD by the age of two (2020a, 2020b). According to the National Institute of Mental Health, parents and educators request a diagnosis for any abnormal development seen in children. This is followed by an evaluation by a group of doctors or other health professionals like speech-language pathologists with experience in diagnosing ASD (2018).

There is high heterogeneity in autistic people with the symptoms of ASD, including language. Due to this variety, delayed development of language is common but not in all autistic individuals. Evidence supports the fact that language develops separately from autistic traits (Gernsbacher et al., 2016). In autistic individuals, there is often reduced language and the onset of language is often delayed. The delayed onset of language is the most pressing concern for autistic children’s parents (Mayo et al., 2013). Echolalia, repeating expressions word to word, and pronoun reversal, using I when you is meant, are common in autistic individuals (Gernsbacher et al., 2016).

  This review will address the ages at which autistic individuals reach developmental milestones and the different developmental trajectories that the language of autistic children follow social communication differences, and neuroanatomical differences affecting language.

Developmental Milestones and Trajectories 

    Throughout childhood development, there are many language milestones to reach: speech-like production, first words, first phrases, and understanding. Children with ASD often reach these milestones at a later age than typically developing (TD) children. Some children with ASD do not develop expressive language (language production), but this review will only address those who do.

Young children with ASD often demonstrate reduced sensitivity to human voices. Specifically, they appear unable to orient or respond to vocal cues, even though they show responsiveness to other non-vocal stimuli (Sperdin and Schaer, 2016). They also show unresponsiveness to their name (Figure 1). 

Figure 1 (Sperdin and Schaer, 2016) | Early language delays and impairments (unresponsiveness to name, delayed canonical babbling, more non-speech productions, less speech-like vocalizations, the delayed occurrence of the first words) that indicate a higher risk of ASD are shown by the red dashed rectangles.

    Typically developing infants reach the language milestone of canonical babbling at around 10 months of age. Canonical babbling is strings of syllables that include a vowel and a consonant. Young children with ASD (aged 16-48 months) show low canonical babbling production even when matched for expressive language subgroups. A study reviewed home videos of children from birth to two years, and concluded that typically developing children were more likely than children with ASD to have reached the canonical babbling stage at both the age ranges 9-12 months and 15-18 months. In addition, the infants who were later diagnosed with ASD demonstrated significantly lower total vocalizations than typically developing infants (Patten et al., 2014).

Studies of human language development have taught us that typically developing children form their first words at an age of 12-18 months. By comparison, children with ASD typically develop their first words at an average age of 36 months. A study referring to retrospective parent reports on the age of first words showed that when comparing children who had and had not produced first words by a benchmark age, the verbal children consistently scored higher on cognitive assessments (Mullen Scales of Early Learning Visual Reception, Expressive and Receptive Language), and communicative skills (Vineland Adaptive Behavior Scales Communication domain) and lower on autism severity (Childhood Autism Rating Scale total score) even though the group performance of all the autistic children was still below average (Mayo et al., 2013).

    Another study involving retrospective parent reports on the age of onset of the first phrases showed that the group with phrase speech by 24 months achieved higher levels of verbal ability, nonverbal ability, and IQ at school age. The group was also less likely to have sentence repetition deficits and impairments in adaptive communication (Kenworthy et al., 2012). Another study concluded that those with earlier first words had higher levels of language production in the future and, after controlling for the age of first words, those who reached the milestone later gained adaptive skills faster. Although the age of first words predicted expressive language and adaptive skills, it did not predict receptive language (language understanding) or nonverbal cognition (Kover et al., 2016). 

    It was also demonstrated in other studies that children with ASD show more impairment in receptive language, and that expressive language might proceed ahead of receptive language in children with autism. Three-year-olds with ASD showed reduced initiations, use of interrogative questions (who, what, when, where, and why), and responses to parents even though their parents initiated interactions with their children just as often as other parents. In comparison, toddlers with language delays also spoke less, but they had the same rates of responses to parents, use of interrogative questions and interactions initiated as typically developing children. This supports the fact that toddlers with ASD struggle more with the social aspects of language than they do with rules like grammatical markings (Bacon et al., 2019). 

    A behavioral study designed to assay social feedback in the context of language came to the conclusion that compared to typically developing children, children with autism produce fewer speech-related vocalizations, and responses are less dependent on whether the cue vocalizations are speech-related. In both typically developing and autistic children, the subsequent vocalization was more likely to contain speech-related material if the previous speech-related vocalization received an adult response. (Warlaumont et al., 2014). Highlighting the significance of the responses of adults, another study addressed the relationship between adult’s expressions and attention to child vocalization rate. Previous behavioral work with young TD children suggests that a parent’s still face, demonstrating a withdrawn state, tends to increase vocalization rate as infants wish to engage their withdrawn parent. The question of whether this is the same case in children with autism is yet to be answered (Patten et al., 2014). The reduced contingency of the responses of the autistic children’s parents provides fewer opportunities for the children to learn and later improve their language. In the future, improving the contingency of response on speech-relatedness of vocalization can help improve the language of the children (Warlaumont et al., 2014).

    A study that included 6 home visits with a 30-min semi-structured parent-child play session showed that the autistic children with higher verbal skills (ASD-HV) had a growth trajectory similar to that of typically developing children on several language measures, while those with lower verbal skills (ASD-LV) had flatter trajectories. ASD-HV children and typically developing children showed improvement in most language measures over time, whereas ASD-LV kids demonstrated a lower level of progress. ASD-LV children increased only in total utterances and in five of the 14 grammatical morphemes (Tek et al., 2014).

    Overall, the developmental trajectories of children with autism are flatter than those of typically developing children; however, there is steep growth observed at later time points. When compared with typically developing children with a similar size vocabulary, the vocabularies of children with ASD contain similar relative proportions of words from different grammatical and semantic categories. There is also an overlap in the words spoken most often. Still, the heterogeneity of language in children with autism must be emphasized (Gernsbacher et al., 2016).

Social Communication

A common finding among several studies is that gesture comprehension and gesture production plays a role in the later development of spoken language. Early-onset of gesture production was significantly correlated with higher language abilities later in life. Brooks and Meltzoff (2008) explain that gestures provide infants with a communicative tool that prompts caregivers to say the name of the object the toddler is referring to. It has been shown that infants vocalize more frequently when pointing with the index finger rather than the whole hand, which is practical because the declarative motive is to share a thought about the object being referred to. While typically developing infants begin to point around 9-12 months, children with ASD show a delay in the onset of gesture production (Ramos-Cabo et al., 2019).

    Children with ASD had significantly lower gesture rates than typically developing children, and pointing gestures were negatively affected the most. In addition, the children with ASD showed a lower variety of gestures (Ramos-Cabo et al., 2019). An outcome of primarily nonverbal communication at an age of 3 years was best predicted by a deficit in understanding, rate of communication acts for behavior regulation, inventory of conventional gestures, consonant inventory, inventory of conventional play actions, and stacking blocks in children with ASD between 18 and 24 months of age. Verbal communication skills at 3 years of age were best predicted by acts for regulating another person’s behavior, and inventory of consonants (Wetherby et al., 2007).

Evidence shows that children with ASD do not differ significantly from TD children in the first year of life in social-communication skills, possibly reflecting a developmental trajectory where ASD emerges as a behavioral decline in social engagement in the second year (Ramos-Cabo et al., 2019). It could be noted here that, according to the Centers for Disease Control and Prevention, by age two, a diagnosis of ASD can be considered reliable, although many children do not get diagnosed until approximately four years of age (2019, 2020a).    

Through analyzing home videotapes of first birthday parties, Osterling and Dawson (1994) discovered that at 1 year of age, a lack of pointing, showing, looking at the face of another, and orienting to name differentiated autistic children from TD children. Additionally, in a follow-up study, decreased use of gestures and increased repetitive behaviors were found to have separated autistic children from TD children, but not from developmentally delayed (DD) children (Wetherby et al., 2007). In another study, Wetherby et al. (2004) found that children with ASD differed significantly from TD and DD children by demonstrating a lack of appropriate gaze, lack of warm, joyful expressions with gaze, lack of sharing enjoyment or interest, lack of response to name, lack of coordination of gaze, facial expression, gesture, and sound, lack of showing, usual prosody, repetitive body movements, and repetitive movements of objects. The children with ASD differed significantly from the TD group but not the DD group with a lack of pointing, lack of vocalizations with consonants, and lack of conventional play with toys.

    In a study assessing eye gaze, autistic children were presented with images of faces below two candy bars, one looking forward and the other looking at a candy bar. The children were able to see the gaze shift but were unable to answer which candy bar the face wanted, suggesting that they were unable to take the meaning from the direction of the gaze (Redcay, 2008). Gaze interpretation is not automatic in autistic children. In the terms of the autistic children’s eye gaze, they show fewer gaze shifts and gestures integrated with vocalizations and eye gaze than DD children (Mayo et al., 2013). Another study showed that, compared with TD and DD children, children with ASD showed less social gaze in response to the adult’s distress, fewer gaze shifts as responses to the activation of the mechanical toys, and less imitation of modelled actions. During free play, the autistic children presented fewer gaze shifts between people and objects compared to the DD and TD children and spent less time looking at people (Wetherby et al., 2007). This highlights the significantly less joint attention in those with ASD compared to TD and DD children (Mayo et al., 2013). In summary, autistic children display fewer acts of communication: expressions, gaze shifts, and gestures.

Neuroanatomical Differences

    The first studies that investigated auditory language processing used positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) and found reduced temporal activation and left lateralization of activation in those with ASD compared to controls. A study that looked at fMRI activation during a language task in adolescents with ASD found a correlation in left frontal and temporal activation in controls but not in ASD individuals. This suggests less efficient connectivity in those with ASD because of differences in communication between important language areas (Knaus et al., 2008). Electroencephalography (EEG) and fMRI studies of individuals with autism have seen disrupted connectivity, which results in the brain functioning as a less cohesive unit (Saffin and Tohid, 2016).

In a large scale MRI study, the ASD group showed increased cortical thickness compared with the control group, especially in the left hemisphere. All cortical regions adjacent to the arcuate fasciculus, including Broca’s area (speech production) and Wernicke’s area (speech comprehension), showed increased cortical thickness. It is important to note here that the left hemisphere of the brain that mainly controls language. The relation between the severity of social and communication symptoms and the cortical thickness was strongest in regions next to the left arcuate fasciculus (Khundrakpam et al., 2017).

Several imaging studies showed that the difference in total gray matter volume in people with ASD compared to TD individuals was larger in early childhood (about 12% at 2 years) compared to early adulthood (about 2% at 19 years), with those with ASD having a higher volume. During adolescence, cortical thickness gradually declines in TD individuals, while it declines more rapidly in individuals with ASD, with little difference in cortical thickness by about 35 years of age. This increased size is suggested to have been due to a delay in regressive neurodevelopmental processes (synaptic pruning), abnormal macroautophagy and a high number of synaptic spines, which trigger unusually high neural losses (Khundrakpam et al., 2017). In another MRI study, both children with autism and their discordant co-twins showed reduced volumes of frontal, temporal, and occipital white matter (Mitchell et al., 2009).

Greater than normal cortical thickness was also found in the fusiform face area, posterior superior temporal sulcus, and frontal eye fields – areas involved in changing aspects of face processing. In a post hoc analysis of a different study, a significant positive correlation was found between residual cortical thickness and the severity of social affect and communication symptom in the left precentral and postcentral gyri, left supramarginal and fusiform gyri, right inferior frontal and middle frontal gyri, and bilateral inferior frontal gyri (Khundrakpam et al., 2017). In addition, negative associations were found between amygdala volumes and social reciprocity, with younger, less affected autistic subjects proposed to have normal to enlarged amygdala volumes, and older, more affected individuals having smaller amygdala volumes (Mitchell et al., 2009). 

Studies support the fact that the mirror neurons communicate through various networks including the amygdala-hippocampal circuit, caudate nuclei, cerebellum, and frontal-temporal regions – regions found to be damaged in ASD. EEG and fMRI studies of individuals with autism have seen a lack of activity in the mirror neuron system. It must be noted that the mirror neuron system has previously been associated with empathy, social reciprocation, verbal and non-verbal communication, and language (Saffin and Tohid, 2016).

The superior temporal sulcus (STS) responds most strongly to stimuli that are significant to communication, especially a stimulus that is human voice-specific, and complex. Decreased concentrations of gray matter were found in areas near the STS. Analysis of cortical sulcal maps in autistic children showed right anterior shifting of the STS interpreted by the authors as delayed or incomplete sulcal development. Social stimuli like facial expressions and voices evoke less STS activity in autistic individuals over controls, possibly due to the lack of taking social communicative meaning from gaze directions, expressions, or vocal sounds. In TD individuals, greater activation is seen in the STS during inference of the goal or intention of another person, compared to simply perceiving biological motion. This contributes to the implication of the STS in the theory of mind perception (Redcay, 2008). Theory of mind, the cognitive ability to infer the mental states of others, is often impaired in those with ASD (Senju, 2012). 

In summary, there are changes in activation (left lateralization) and structure (gray matter volume, white matter volume, cortical thickness) the brains of those with ASD. These changes are especially there in language areas in the frontal and temporal lobes and the degree of the change correlates with the severity of the symptoms.

Discussion

Individuals with autism often reach developmental milestones later than typically developing children. Evidence supports the idea that the later a child reaches a developmental milestone, the worse their cognitive ability and adaptive skills will be in the future. This opposes the “wait and see approach” and strengthens the “watch and see” ideology during which development is monitored over short periods of time and intervention given as soon as delayed development is observed (Mayo et al., 2013).

  Autistic children also have lower gesture rates, similarly to how they often have lower speech-related vocalizations (Warlaumont et al., 2014). They also differed from TD children with their lack of proper gaze, lack of coordination of gaze, expression, gesture, and sound, lack of sharing interest, and repetitive movements (Wetherby et al., 2007). Gesture production and comprehension are part of the later onset of speech: infants usually first name objects that were referred to with gestures and later transition to the two-word stage with gesture-speech combinations (Ramos-Cabo et al., 2019). This suggests that possibly addressing lower gesture rates or late gesture production in young children may better their language development in the future.

In the brain, there are differences in connectivity, gray matter volume, and cortical thickness. These differences are especially seen in language areas in the frontal and temporal lobes. In the future, it is possible that these neuroanatomical differences may be used to diagnose ASD and the degree of difference could predict the degree of the symptoms. These differences might help physicians diagnose ASD reliably at an earlier age, allowing earlier treatment.

    The differences in synaptic pruning and the large differences in brain size before that raise a question about the role of the synaptic pruning in helping the symptoms of ASD improve. Gernsbacher (2016) wrote that, in the first few years of life, the developmental trajectories of children with autism are flatter with a steep growth observed later. The question of whether inducing synaptic pruning early in childhood when the disorder is known could help the symptoms is yet to be answered.

    The heterogeneity of ASD must be emphasized again, as every child with ASD is different in their symptoms and in their responses to intervention. Some of the findings mentioned may not be accurate about some children but they may be accurate about other children. This field has only begun to understand why there is reduced socialization in autistic individuals; decreased communicative acts could be due to impaired motor skills, less motivation to communicate, abnormal brain structure and activation, or any combination of such factors (Warlaumont et al., 2014). Further research is needed to truly shed light on what underlies these phenotypes.

Preethi Nalluru, Youth Medical Journal 2021

References

Bacon, E. C., Osuna, S., Courchesne, E., & Pierce, K. (2019). Naturalistic language sampling to characterize the language abilities of 3-year-olds with autism spectrum disorder. Autism, 23(3), 699–712. https://doi.org/10.1177/1362361318766241

Brooks, R., and Meltzoff, A. N. (2008). Infant gaze following and pointing predict accelerated vocabulary growth through two years of age: a longitudinal, growth curve modeling study. J. Child Lang. 35, 207–220. doi: 10.1017/ S030500090700829X

Gernsbacher, M. A., Morson, E. M., & Grace, E. J. (2016). Language Development in Autism. In Neurobiology of Language. Elsevier Inc. https://doi.org/10.1016/B978-0-12-407794-2.00070-5

Kenworthy, L., Wallace, G. L., Powell, K., Anselmo, C., Martin, A., & Black, D. O. (2012). Early language milestones predict later language, but not autism symptoms in higher functioning children with autism spectrum disorders. Research in Autism Spectrum Disorders, 6(3), 1194–1202. https://doi.org/10.1016/j.rasd.2012.03.009

Khundrakpam, B. S., Lewis, J. D., Kostopoulos, P., Carbonell, F., & Evans, A. C. (2017). Cortical thickness abnormalities in autism spectrum disorders through late childhood, adolescence, and adulthood: A large-scale mri study. Cerebral Cortex, 27(3), 1721–1731. https://doi.org/10.1093/cercor/bhx038

Knaus, T. A., Silver, A. M., Lindgren, K. A., Hadjikhani, N., & Tager-Flusberg, H. (2008). fMRI activation during a language task in adolescents with ASD. Journal of the International Neuropsychological Society, 14(6), 967–979. https://doi.org/10.1017/S1355617708081216

Kover, S. T., Edmunds, S. R., & Weismer, S. E. (2016). Brief Report: Ages of Language Milestones as Predictors of Developmental Trajectories in Young Children with Autism Spectrum Disorder. Journal of Autism and Developmental Disorders, 46(7), 2501–2507. https://doi.org/10.1007/s10803-016-2756-y

Mayo, J., Chlebowski, C., Fein, D. A., & Eigsti, I.-M. (2013). Age of first words predicts cognitive ability and adaptive skills in children with ASD. Physiology & Behavior, 176(3), 139–148. https://doi.org/10.1007/s10803-012-1558-0.Age

Mitchell, S. R., Reiss, A. L., Tatusko, D. H., Ikuta, I., Kazmerski, D. B., Botti, J. A. C., Burnette, C. P., & Kates, W. R. (2009). Neuroanatomic alterations and social and communication deficits in monozygotic twins discordant for autism disorder. American Journal of Psychiatry, 166(8), 917–925. https://doi.org/10.1176/appi.ajp.2009.08101538

Osterling, J., & Dawson, G. (1994). Early recognition of children with autism: A study of first birthday home videotapes. Journal of Autism and Developmental Disorders, 24, 247–257.

Patten, E., Belardi, K., Baranek, G. T., Watson, L. R., Labban, J. D., & Oller, D. K. (2014). Vocal patterns in infants with Autism Spectrum Disorder: Canonical babbling status and vocalization frequency. Journal of Autism and Developmental Disorders, 23(1), 1–7. https://doi.org/10.1007/s10803-014-2047-4.Vocal

Ramos-Cabo, S., Vulchanov, V., & Vulchanova, M. (2019). Gesture and language trajectories in early development: An overview from the autism spectrum disorder perspective. Frontiers in Psychology, 10(MAY). https://doi.org/10.3389/fpsyg.2019.01211

Redcay, E. (2008). The superior temporal sulcus performs a common function for social and speech perception: Implications for the emergence of autism. Neuroscience and Biobehavioral Reviews, 32(1), 123–142. https://doi.org/10.1016/j.neubiorev.2007.06.004

Saffin, J. M., & Tohid, H. (2016). Walk like me, talk like me: The connection between mirror neurons and autism spectrum disorder. Neurosciences, 21(2), 108–119. https://doi.org/10.17712/nsj.2016.2.20150472

Senju, A. (2012). Spontaneous theory of mind and its absence in autism spectrum disorders. 18(2), 108–113. https://doi.org/10.1177/1073858410397208.Spontaneous

Sperdin, H. F., & Schaer, M. (2016). Aberrant development of speech processing in young children with autism: New insights from neuroimaging biomarkers. Frontiers in Neuroscience, 10(AUG), 1–15. https://doi.org/10.3389/fnins.2016.00393

Tek, S., Mesite, L., Fein, D., & Naigles, L. (2014). Longitudinal analyses of expressive language development reveal two distinct language profiles among young children with autism spectrum disorders. Journal of Autism and Developmental Disorders, 44(1), 75–89. https://doi.org/10.1007/s10803-013-1853-4

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Warlaumont, A. S., Richards, J. A., Gilkerson, J., & Oller, D. K. (2014). A social feedback loop for speech development and its reduction in autism. 25(7), 1314–1324. https://doi.org/10.1177/0956797614531023.A

Wetherby, A. M., Watt, N., Morgan, L., & Shumway, S. (2007). Social communication profiles of children with autism spectrum disorders late in the second year of life. Journal of Autism and Developmental Disorders, 37(5), 960–975. https://doi.org/10.1007/s10803-006-0237-4

Wetherby, A., Woods, J., Allen, L., Cleary, J., Dickinson, H., & Lord, C. (2004). Early indicators of autism spectrum disor- ders in the second year of life. Journal of Autism and Developmental Disorders, 34(5), 473–493.

Categories
Health and Disease

Overview of Some Advancements in Parkinson’s Disease Treatments

By Melle Hsing

Published 10:29 EST, Sat October 9th, 2021

Parkinson’s disease (PD) remains the second most common neurodegenerative disorder characterized mainly by bodily tremors, muscle rigidity, and postural imbalances. But with the rise of many popular topics regarding medical advancements, PD may be a potential target of some widely discussed therapies. This article introduces and discusses a few of the advancements for Parkinson’s disease treatment, providing insight into its pathophysiology

The development of NXL-112

Dopamine is an important neurotransmitter for regulating movement. In PD, the dopaminergic neurons of the substantia nigra degenerate, leading to increased difficulty in motion. Levodopa (L-DOPA) is the typical drug prescribed to combat PD because it provides synthetic dopamine to the brain. However, when L-DOPA levels peak in the blood, this can lead to motor fluctuations – akin to a surplus in movement. This fluctuation, known as peak-dose dyskinesia (or in broader terms L-DOPA induced dyskinesia [LID]), may not be a serious problem for those with early-stage PD, but given the fact that PD will slowly worsen, increasing L-DOPA dosage to match the worsening of the disease will also exacerbate LID. Other than Amantadine, which is often used to treat LID, researchers from the US biotech company Neurolixis have been working on a new drug: NXL-112.

NXL-112 lowers dopamine levels in serotonin neurons, as L-DOPA can be converted to dopamine and released by these serotonin cells, thereby contributing to LID. While this is what researchers expect NXL-112 to do, it is important that this drug does not inhibit the effectiveness of L-DOPA by overly decreasing net dopamine levels. Neurolixis, a US biotech company, partnered up with their funder, Parkinson’s UK, to conduct a study that tested just that. They found no statistically significant reduction in the effectiveness of L-DOPA for PD patients when NXL-112 was also administered.

Stem cell therapy

Given the side effects of L-DOPA, such as the one discussed above, researchers are seeking alternative methods to treat PD rather than having to take even more medications to combat side effects. This aim has led researchers to ask: how do stem cells fit into the picture?

 Stem cells are special for mainly two reasons. Firstly, embryonic stem cells and stem cells derived from cord blood can be pluripotent, in which they can differentiate into various specialised cells such as nerve cells. Secondly, stem cells seem to have no limit to mitosis, meaning that they can divide an infinite number of times. Given that there are fewer dopaminergic neurons in PD patients, perhaps stem cells can be injected into the substantia nigra such that they can differentiate into new, functional dopaminergic neurons. 

Mesenchymal Stem Cells Debates and Updates

Figure 1: Stained mesenchymal stem cells (“Mesenchymal Stromal, n.d.)

Researchers are particularly hopeful about the use of mesenchymal stem cells sourced from umbilical cord tissue in PD treatments. This type of stem cell is unique in that it does not pose a negative response to the immune system if the patient were immunally incompatible with the donor of the stem cells. Hence, mesenchymal stem cells may be able to help many different patients regardless of immunocompatibility. 

One should note that stem cell therapy does not ultimately cure PD. After some time, Lewy bodies (proteins made of alpha-synuclein whose buildup in dopaminergic neurons is thought to contribute to PD) may accumulate again in these newly made neurons and damage or kill them. However, if it means alleviating the patient’s suffering and improving their life quality, then this treatment may very well be worth pursuing.

GDNF

GDNF, which stands for glial cell line-derived neurotrophic factor, is a protein suggested to promote the production of dopaminergic neurons. Studies conducting GDNF trials have hinted at the possibility of GDNF even slowing down the progression of PD. With a sustained concentration of GDNF in the brain, theoretically, even if Lewy bodies were to build up in dopaminergic neurons, there would be enough GDNF to keep promoting the growth of more dopaminergic neurons to replace damaged ones. However, the current studies available are not extremely clear; hence, more research is needed to come to solid findings. An animal study on rats found that short-term exercise could increase GDNF levels in the spinal cord; hence, exercise may also play a role in encouraging GDNF production in humans. Of course, there would need to be more substantial evidence to justify this, but animal studies can sometimes give insight into how humans may react to exercise.

Conclusion

The treatments discussed above may just be one cornerstone of possible treatments for PD in the coming years, given the rapid advancements in medical research. Other treatments such as gene therapies and deep brain stimulation have also been researched, possibly providing an even wider variety of treatments for the future. While some of these proposed solutions do still have their limitations, they provide significant hope for PD patients who may be struggling to cope with the disease.

Melle Hsing Youth Medical Journal 2021

References

Cona, L. A. (n.d.). Stem cell therapy for Parkinson’s disease in 2021. DVCSTEM Blog. https://dvcstem.com/post/stem-cell-therapy-for-parkinsons

McCullough, M. J., Gyorkos, A. M., & Spitsbergen, J. M. (2013). Short-term exercise increases GDNF protein levels in the spinal cord of young and old rats. Neuroscience, 240, 258–268. https://doi.org/10.1016/j.neuroscience.2013.02.063

[Mesenchymal stromal cells]. (n.d.). Stem Cell. https://www.stemcell.com/mesenchymal-stromal-cells-updates-and-debates

Our research achievements so far. (n.d.). Parkinson’s UK. Retrieved August 24, 2021, from https://www.parkinsons.org.uk/research/our-research-achievements-so-far

Promising drug could treat debilitating movement problems in people with Parkinson’s. (2020, March 1). EurekAlert! https://www.eurekalert.org/news-releases/759442

When will there be a cure for Parkinson’s? (n.d.). Parkinson’s UK. Retrieved August 24, 2021, from https://www.parkinsons.org.uk/research/when-will-there-be-cure-parkinsons

Categories
Neuroscience

An Outlook Into Society and Medicine Through A Neurological Disease

Cause, Symptoms, and Diagnosis

Anti-NMDAR encephalitis is a rare neurological autoimmune disease that can cause severe symptoms [1]. In brief, autoimmune disorders can be simplified as the immune system attacking the body [2]. For this disorder, the immune system has created antibodies against the NMDA receptors, which are responsible for learning, judgment, and autonomic activities like breathing or swallowing. Still, the cause is unknown [3].However, anti-NMDAR encephalitis appears linked to tumors, especially ovarian tumors [4]. In addition, cases appear to occur after a viral infection, especially herpes simplex virus [5]. `

For neurological symptoms, this can include unconscious movement, memory issues, and damage to cognition. However, psychiatric symptoms are more clear from onset. Consequently, anti-NMDAR is often misdiagnosed as a psychiatric disorder. These severe symptoms include paranoia, delusions, and psychosis [1]. Recovery can range from months to years but has improved with the development of immunotherapies [3]. 

Typically, physicians will recognize these symptoms first and then order testing. This involves testing the blood serum or cerebral spinal fluid for NMDAR antibodies [1]. Besides that, additional testing can be done to detect symptoms. This usually includes tumor imaging, an MRI, or an electroencephalogram (EEG) [3]. Still, first-line doctors like emergency physicians or primary care providers often misdiagnose anti-NMDAR encephalitis as a psychiatric disorder because of its symptoms. Its strong prevalence in women, as approximately 80% of patients are female, also causes misdiagnoses. There is no clear marker, so physicians must be familiar with the myriad of symptoms involved in order to identify it [5].

Figure 1. The MRI of a male with anti-NMDA receptor encephalitis, his MRI after treatment, and the MRI of a health volunteer [4].

Treatment and Prognosis

Patients with the best prognosis have typically had a tumor removed, are young, or have a low concentration of antibodies in their blood serum or cerebral spinal fluid. This usually results in substantial improvement. Conversely, patients who did not have a tumor typically have worse outcomes [5]. The length of recovery can range from months to years, depending on severity and treatment. Early diagnosis and treatment is directly correlated with improved outcomes [3]. However, anti-NMDAR encephalitis is frequently misdiagnosed due to the preponderance of severe psychiatric symptoms. This can hinder a patient’s recovery [5]. Other than removing the tumor, patients can receive steroids or immunosuppressants to weaken the antibodies that are attacking the body [1]. After receiving treatment, outcomes are acceptable. The symptoms subside in the order that they occurred, typically beginning with the most severe issues. Still, some patients continue to experience memory and cognition issues. In the worst of cases, anti-NMDAR encephalitis is lethal, killing approximately 6% of patients[4]. 

A Dark History for Women

From Ancient Greece, hysteria has been a common diagnosis for women experiencing psychiatric issues, essentially attributing their issues to their gender. However, some scientists propose that there is a logical explanation for this misdiagnosis. Specifically, that explanation is anti-NMDAR encephalitis. This disease predominantly affects women and also causes severe psychiatric symptoms.

Additionally, the removal of ovarian tumors is one of the most effective treatments for the disease [6]. From antiquity, a treatment for hysteria and other health issues in women has been sterilization by removal of the reproductive organs. In removing the reproductive organs, tumors are also excised. One such operation was created by the surgeon Robert Battey, and he referred to it as the “normal ovariotomy”. Originally, this was to treat menstrual disorders and other symptoms. Later on, it was used to treat psychiatric and neurological disorders in women, often without their consent. Even so, surgeons and their communities accepted this, because the patients generally improved. [7]. 

Additionally, other scientists speculate that anti-NMDAR encephalitis is responsible for historical reports of “demonic possession”.  One of the symptoms are sudden, “jerking” movements of the limbs that are entirely unconscious. In addition, a common psychiatric symptom is paranoid delusions of danger. This appears congruent with descriptions of possession. Once again, because anti-NMDAR encephalitis patients are primarily women, it may have led to the misconception that this gender is weaker and therefore more susceptible to the supernatural or witchcraft [8].

Modern Social Implications

Anti-NMDAR encephalitis is a newly discovered disease, only described in 2007 by Dr. Josep Dalmau at the University of Pennsylvania [9]. Because of its severe symptoms and historical linkage, this led to introspection into the role of women in healthcare. 

Much has changed since Battey’s ovariectomies, but women continue to experience issues in medicine. From the perspective of a patient, some women fail to receive psychiatric treatment, because these issues are considered “normal” for their gender. For anti-NMDAR encephalitis in particular, neurologists voice concerns that their patients cannot receive treatment or will be misdiagnosed with a psychiatric disorder. Some diagnoses include insanity or psychosis, whose treatment still includes electroconvulsive therapy. In essence, patients with those misdiagnoses would receive improper care. Rapid diagnosis and treatment are especially important in recovery, but this is hindered by gender issues [8].

One woman voiced her story in the 2012 novel Brain on Fire: My Month of Madness. The author and career journalist, Susannah Cahalan, contracted anti-NMDAR encephalitis only three years after it was discovered. At the time, her doctor estimated that only ten percent were correctly diagnosed. In her personal stories, Cahalan’s doctors grossly misdiagnosed her, ranging from “parties to much” to bipolar disorder. After a few months and the onset of severe neurological symptoms, she was finally diagnosed with anti-NMDAR encephalitis. Her best-selling novel and subsequent has made anti-NMDAR encephalitis one of the more famous neurological diseases. Now, diagnosis is often faster and treatment has improved [10].

Final Words

Anti-NMDAR encephalitis has an innate link between science, medicine, the media, and society. Specifically, it outlines the path of a disease, from its discovery in science, applications in medicine, coverage by the media, then perception in society. The concern for women and their mental health has not stopped, but it has been ameliorated in the case of anti-NMDAR encephalitis, where patients can get diagnosed quickly enough to have an optimal prognosis. Nonetheless, it is vital that the healthcare industry utilizes the media effectively to advocate for its patients.

References

[1] Anti-NMDAR Encephalitis. Perelman School of Medicine. https://www.med.upenn.edu/autoimmuneneurology/nmdar-encephalitis.html.

[2] Irani, Sarosh and John Radcliffe. NMDAR Antibody Encephalitis. Encephalitis Society. https://www.encephalitis.info/nmdar-antibody-encephalitis.

[3] What is Anti-NMDA Receptor Encephalitis?. The Anti-NMDA Receptor Encephalitis Foundation. https://www.antinmdafoundation.org/the-illness/what-is-anti-nmda-receptor-encephalitis/

[4]  Hughes, Ethan G., et al. (2010). Cellular and Synaptic Mechanisms of Anti-NMDA Receptor Encephalitis. Journal of Neuroscience. 30. https://dx.doi.org/10.1523%2FJNEUROSCI.0167-10.2010 

[5] Chanaka, Amugoda, et al. (2019). Anti-NMDAR Encephalitis: Higher Suspicious Needed for Earlier Diagnosis. Hindawi. https://doi.org/10.1155/2019/7476254 

[6] Pollak, Thomas A. (2013). Hysteria, hysterectomy, and anti-NMDA receptor encephalitis: a modern perspective on an infamous chapter in medicine. British Medical Journal. 346. https://doi.org/10.1136/bmj.f3756 

[7] Komagamine, Tomoko, et al. (2019). Battey’s operation as a treatment for hysteria: a review of a series of cases in the nineteenth century. History of Psychiatry. 55-66. https://doi.org/10.1177/0957154×19877145 

[8] Radecki, Ryan P. (2019). Demonic Possession or Autoantibody-Mediated Encephalitis?. ACEP Now. https://www.acepnow.com/article/demonic-possession-or-autoantibody-mediated-encephalitis/

[9] Dalmau, Josep. (2007). Paraneoplastic anti–N‐methyl‐D ‐aspartate receptor encephalitis associated with ovarian teratoma. Annals of Neurology. 25-36. https://dx.doi.org/10.1002%2Fana.21050 

[10] Cahalan, Susannah. (2012). Brain on Fire: My Month of Madness. Simon and Schuster. 

Aleicia Zhu, Youth Medical Journal 2020