What are the main characteristics of neurodevelopmental disorders? - Chapter 8

Neurodevelopmental disorders is an umbrella term that is used to describe those conditions that manifest early in life and are characterised by delay or impairment in functions that are associated with the biological maturation of the central nervous system (CNS). Neurodevelopmental disorders comprise a diverse range of conditions, including attention deficit hyperactivity disorder (ADHD), tic disorders such as Tourette syndrome (TS), autism spectrum disorder (ASD), specific language impairment (SLI), developmental coordination disorder (DCD), learning disability (LD), and dyslexia. Neurodevelopmental disorders are life-long conditions, although symptoms may vary over time and even be absent for brief periods of time. Neurodevelopmental disorders are likely to have a strong genetic influence, tend to occur in families with a history of similar or associated disorders. In addition, neurodevelopmental disorders are more common in men than women. Traditionally, neurodevelopmental disorders were considered to result from obstetric complications or birth injury. To date, they are viewed as disorders that reflect the endpoint of a process that starts with a relatively non-specific, genetically influenced disruption to early brain development. It is unlikely that neurodevelopmental disorders result from a single mutant gene. Rather, it is suggested that multiple genes of small effect interact with environmental factors in order to exert probabilistic instead of deterministic effects on later-developing neural systems.

The remainder of this chapter focuses on the aetiology, neuropathological and neuropsychological correlates, functional outcomes, and interventions for four specific conditions that fall under the umbrella term neurodevelopmental disorders: (1) ADHD; (2) TS; (3) ASD; and (4) SLI. These serve as prototypic examples of neurodevelopmental disorders in general. 

What are the characteristics of Attention Deficit Hyperactivity Disorder?

Epidemiology

Attention Deficit Hyperactivity Disorder (ADHD) is defined in the DSM-5 as a persistent pattern of inattention and/or hyperactivity - impulsivity that interferes with daily functioning and is inconsistent with developmental expectations. ADHD is the most common neurodevelopmental disorder with an estimated prevalence of 5-10% of all children worldwide. The symptoms have to be present before age 12. In addition, symptoms must occur across two or more settings (for example: school and at home) and impair the quality of academic, social, or occupational activities. Symptoms often persist into adulthood, although the expression of these symptoms may change over time. For example, short play sequences (<3 minutes) in preschool may change to brief activities (< 10 minutes) in primary school, which in turn may change to persistence less than peers in adolescence, which may change to details not completed in adulthood.

A core feature of ADHD is difficulties in group settings. In addition, during the early school years, learning difficulties become evident, in particular language problems. Core symptoms of ADHD, including inattention, motor restlessness, and executive dysfunction, are likely to play an important role in the underachievement of children with ADHD. Working memory (the capacity to acquire, manipulate, and retain novel information) is strongly associated with academic achievement, and this skill is known to be impaired in children with ADHD. These learning difficulties are often sufficiently severe to require the need to access post-school study and training. In fact, children with ADHD are four to five times more likely to require special educational services in comparison to children without ADHD. Although children with ADHD form a heterogeneous group, they do share features of poor behavioural and emotional self-regulation which is reflected in labile mood, increased irritability, high activity levels, restless and impulsive behaviour, reduced task persistence, oppositionality, aggression, and rule breaking. These problems often emerge early and increase over childhood. They are associated with an elevated risk for accidental injury and self-harm. 

Classification and diagnosis

ADHD is divided into three types: inattentive, hyperactivity/impulsivity, and combined. The first type, inattention, manifests itself as difficulty sustaining focus, disorganisation, and a lack of persistence that cannot be explained by oppositionality or lack of comprehension. Children with this type of ADHD typically exhibit educational underachievement, but do not have other psychiatric comorbidities apart from an elevated risk for anxiety disorders. Hyperactivity refers to excessive motor activity (in young children), restlessness and fidgeting (in older children and adults). Impulsivity refers to acting without thinking and lack of regard for negative consequences or danger, as well as social intrusiveness. Both the hyperactive/impulsive and combined type are associated with high comorbidity rates, both with other neurodevelopmental disorders and other psychiatric disorders such as oppositional defiant and conduct disorder and anxiety. 

The diagnosis of ADHD is thought to be quite controversial. ADHD is diagnosed on the basis of behaviour. To date, no definitive biomarkers for ADHD have been identified, hence the diagnosis is essentially a behavioural one. There is an ongoing debate in the literature whether a pure disorder of ADHD exists, and if it does, whether the different subtypes share the same causality. In addition, early identification of ADHD is problematic, because short attention span and impulsive and hyperactive behaviour is ubiquitous in preschool-aged children. Yet, by the age of four years, behaviour meeting criteria for a diagnosis of ADHD is likely to persist into school age. 

Comorbidity

ADHD has a high rate of comorbidity, particularly in boys. ADHD often occurs in the presence of other neurodevelopmental or psychiatric disorders, including learning disability (LD), anxiety disorders, motor coordination deficits, oppositional defiant disorder (ODD), and conduct disorder (CD). When both ADHD and ODD are present, ADHD typically precedes ODD. The reverse is very uncommon.

Due to the high comorbidity of ADHD with intellectual disability (IQ) it is difficult to estimate IQ in ADHD samples. In fact, the DSM-4 specifically excluded a diagnosis of ADHD if the symptoms were better explained by ID. Although this exclusionary criterion has been removed in the DSM-5, it does specify that ADHD in children with an intellectual disability must include symptoms of inattention and hyperactivity that are excessive for their mental age. 

Aetiology

The aetiology of ADHD is complex. It is thought to reflect both genetic and environmental factors, as well as their interplay. Several candidate genes have been identified, including the dopamine receptor genes (DRD4, DRD5), the dopamine transporter gene (DAT1), and some genes involved in serotonin transmission (SLC6A4, HTR1B). Similarly, several environmental factors are considered to influence the ADHD phenotype, including: foetal exposure to maternal stress, alcohol, nicotine, and other drugs, low birth weight, preterm birth, and obstetric complications. Post-natal risk factors that have been identified are: post-natal depression, exposure to lead or other neurotoxins, food additives, and psychosocial adversity. Although parenting practices are probably not causal, specific parenting styles (incorporating warm and authoritative parenting) may decrease symptoms in ADHD, while punitive parenting styles may increase symptoms.

Neuropsychological findings

Central to the pathophysiology of ADHD are dysregulation of the frontal, subcortical, or cerebellar catecholaminergic circuitry and abnormalities in the dopamine transporter system. Neuroimaging studies have identified reduced whole-brain volumes as well as reductions of approximately 5% in regional volume in the frontal lobes, subcortical brain regions, corpus callosum, and the cerebellum. In addition, functional imaging studies in ADHD revealed reduced activation during response inhibition tasks as well as greater variability in resting-state functional magnetic resonance imaging (R-fMR) metrics in brain regions similar to those showing reduction in volume, including the prefrontal cortex, anterior cingulate, striatum, and cerebellum. 

Treatment

The strongest evidence for efficacy in reducing ADHD symptoms is found for stimulant medication, at least in the short term. Psycho-education, parent training, and intensive behaviour therapy are subsequent effective interventions for ADHD after (or in combination with) stimulant medication; these appear to be particularly effective for treating comorbid symptoms of oppositional behaviour and anxiety, as well as for dealing with family conflicts. Tools and adaptions that may be helpful in the school setting are: smaller class sizes, a reduction in classroom distractions, teacher education, modified teacher approaches, and academic schedules with increased opportunity for physical activity. There is less evidence for the efficacy of social skills training or family therapy, although these interventions are potentially helpful for reducing comorbid problems.

What are the characteristics of Tourette Syndrome?

Tourette syndrome (TS) is a neurodevelopmental disorder that is characterised by the presence of tics. A tic is a sudden, involuntary, repetitive stereotypic movement (for example: eye blinks, head jerks, facial grimaces) or utterance (for example: throat clearing, complex vocalisations, coprolalia), that mimics some aspect of normal behaviour but occurs out of context and with no environmental precipitant.

Epidemiology

TS is the most severe childhood-onset tic disorder and has an estimated prevalence ranging from 1 to 10 per 10,000 children. TS occurs more in boys than in girls (ratio 4.3:1). The earlier tics occur, the more likely that there is a family history involving TS. Symptoms usually manifest between five and seven years of age and are initially spasmodic. Over time (typically between 9 and 12 years), the symptoms become more severe and persistent, causing a high level of distress to both the child and family. Further, motor tics usually appear before vocal tics, who typically appear one or two years later. The ability to suppress tics tends to improve with age, although sufferers report that this effort often impairs concentration (at school) and increases subjective distress and reduces fatigue. Moreover, paradoxically, fatigue and stress tend to increase symptoms, while relaxation, concentration, and physical exercise tend to decline symptoms. The diagnosis TS is given, according to the DSM-5, when both motor and one or more vocal tics are present at some time points. In addition, the tics must persist over a 12-month period and manifest prior to 18 years. In the majority of children with TS, approximately 80%, tics decline in late adolescence. 

Little is known about the pathogenesis of TS. Several twin studies indicate genetic influences. Yet, the search for specific candidate genes for TS is still in its infancy. Not surprisingly, environmental influences are also likely to contribute. For example, many individuals with TS experience(d) premorbid stress and adverse perinatal events. 

Neuropsychological findings

The tics arise from disruptions to the frontal-striatal-thalamocortical circuits that usually subserve self-regulatory capacities, such that the capacity to control sensory urges and motor behaviours is impaired. To put it differently, the tics arise from disruption to the neural circuits that link the prefrontal cortex to the basal ganglia, cerebellum, and back. Dopamine receptors, in particular, are thought to be over-sensitive in TS. Th direct pathway of the cortex to the subthalamic nucleus appears to be a 'hyperactive pathway', in which there is increased activity. Vice versa, the indirect pathway from cortex to subthalamic nucleus (via striatum caudata and putamen, and globus pallidus externa) appears to show a reduced firing rate.

Neuroimaging studies have identified several neuroanatomical differences in children with TS compared to healthy controls, including abnormal thinning of the sensorimotor and premotor cortices, reduced bilateral caudate volumes, and a 50% reduction in the number and density of GABA-ergic cells in basal ganglia. To compensate, increased volumes have been found in the prefrontal cortex and increased activation in the fronto-striatal circuitry in children who suppress tics and showed fewer symptoms in adulthood. 

Comorbidity

TS is known to have a high rate of comorbidity. TS and ADHD occur is approximately 30-50% of all cases and are associated with poorer outcomes than either condition in isolation. Typically, ADHD precedes the emergence of TS. Another comorbid condition is OCD, occurring in approximately one third to half of the children with TS. Some children (estimated prevalence: 22.3%) present a triad of TS, ADHD, and OCD. Estimates of the prevalence of TS and comorbid conditions are given below. 

• TS only: 40.2%.
• TS + ADHD: 20.3%.
• TS + OCD: 17.3%.
• TS + ADHD + OCD: 22.2.

Functional outcomes

The literature is inconsistent regarding IQ in children with TS. Several studies found than children with TS, in particular those without comorbid conditions, had higher than expected IQ scores. However, sampling issues may have contributed to these findings. For example, one of these studies used unmedicated children only, which may suggest that these children only suffered from a mild form of TS and hence not accurately represent the TS population. Other studies, in particular those with comorbid conditions, found lower IQ scores. However, a nuance should be included here. TS and ADHD was found to yield lower IQ scores, while TS and OCD was found to yield higher IQ scores compared to other TS subgroups. Similarly, memory deficits were apparent in TS and ADHD, but not in TS and OCD. To conclude, neuropsychological profiles are very diverse and depend (among others) on specific comorbidities. 

Children with TS often experience learning difficulties and are more likely to attain special education, in particular if they have comorbid ADHD. Commonly identified difficulties are found in numeracy, sustained attention, writing, and timed activities. Children with TS, regardless of the presence of comorbidities, report lower levels of quality of life. They experience high levels of bullying. Peers often rate them more negatively and perceive them as withdrawn and aggressive. Parents of children with TS often report high levels of distress and emphasise the impact it has on the family. As was said before, tics frequently disappear in late adulthood. Yet, the emotional and social consequences of childhood tics may persist into adulthood.

Treatment

Although only few studies have studied the long-term effects of pharmacological and behavioural interventions, there is consensus that psycho-education should be the first aim. Prior to deciding on a specific intervention, a careful assessment for comorbidities in addition to TS must take place. Other interventions that have shown to have some success are habit reversal therapy and other behavioural approaches (CBT), in particular when they are adapted specifically for TS.

What are the characteristics of Autism Spectrum Disorder?

Epidemiology

Autism Spectrum Disorder (ASD) refers to a heterogeneous spectrum that is characterised by persistent deficits in social communication and reciprocal social interaction (impaired use of non-verbal behaviours, failure to develop peer friendships, little seeking of shared enjoyment of activities, restricted socio-emotional reciprocity), as well as unusual and preoccupying interests (obsessions), rigid adherence to non-functional routines, stereotypic movements, and sensory disturbances. ASD is prevalent in approximately 1-2% of the general population. The increased prevalence of the past decades is likely to be artificial and caused by increased community awareness and changes in diagnostic criteria. ASD is consistently found to occur more in boys than in girls with a ratio of 4:1. 

Diagnosis

In earlier editions of the DSM, autism was diagnosed using a subtype approach, distinguishing: Asperger's syndrome, pervasive developmental disorder, and autism spectrum disorder. To date, in the DSM-5, they use an all-encompassing classification, arguing that a spectrum approach is more clinically meaningful, because it better reflects the phenotypic heterogeneity of the disorder. For a DSM-5 diagnosis of ASD, the symptoms as described in the above paragraph must be evident in early life, not better explained by an intellectual disability, and result in significant functional impairment.

Aetiology

The aetiology of ASD is not fully understood yet, but twin studies showed that there is a strong genetic contribution involved. Chromosomal abnormalities have been identified in ASD with most consistent evidence for involvement of chromosomes 2q, 7q, and 11q12-13. Yet, findings are far from definitive.

Comorbidity 

ASD is a frequently occurring comorbidity in medical conditions, including: fragile X, phenylketonuria, neurofibromatosis, tuberous sclerosis, congenital rubella, seizure disorders, and Down's syndrome. There is also a high comorbidity rate of ASD and ADHD.

Neuropsychological findings

Accurate identification of the underlying pathogenesis of ASD is difficult due to a number of methodological issues. However, there is emerging consensus that there is an overgrowth phenomenon in the CNS with regional specificity. It is the time course of brain development rather than the final product that is most disturbed in autism. More specifically, brain size is normal at birth, then undergoes precocious growth in the early post-natal period (at this time, the first symptoms also emerge). Young children show increases of 5-10% in both grey and white matter in frontal, temporal, and parietal brain regions, the amygdala, and -in particular- in frontal and temporal cortices. During middle childhood, a deceleration in age-related growth is noted with a possible premature neurodegeneration from adolescence. Further, fMRI studies have shown aberrant and reduced connectivity within the cortex and between cortical and subcortical neural systems. 

Due to the heterogeneity of ASD, it is difficult to formulate a neuropsychological profile. Usually, there is a discrepancy between verbal IQ and performance IQ with performance IQ being higher. A core feature of ASD is delayed and/or abnormal language. In fact, concern about language development is often the precipitant for parents to seek help for their child. Other core problems of ASD are related to central coherence (the ability to derive overall meaning from bits of environmental information), social cognition (the ability to identify and interpret socially salient information), and theory of mind (the ability to mentalise and emphasise with the internal states of others). In line with this is the identification of impaired reading comprehension, often in the context of intact reading accuracy. Other academic difficulties in ASD (for instance in maths, writing, and spelling) may occur, but these are currently not well characterised.

Treatment

Early diagnosis is crucial for effective treatment of ASD. Yet, this is often problematic. Parents are often the first to notice abnormalities in their child. Yet, many report being reassured initially by family, paediatricians, and childcare workers. As a consequence, many children with milder forms of ASD are not identified until they attend school or even later. The challenge of (early) diagnosis is also complicated by the fact that symptoms vary or change over time. To date, there is no evidence-based 'cure' of ASD, but early, intensive intervention has been shown to improve the negative impact of ASD symptoms on the child and to reduce family stress. The greatest efficacy is found for multimodal treatment approaches, incorporating family psycho-education, parenting skills and individual behaviour modification programmes based on applied behaviour analysis (ABA) as well as appropriate, supportive educational placement. Treatment goals focus, among others, on trying to 'normalise' cognition, communication, and socialisation and to decrease maladaptive autism-specific behaviours such as rituals and rigidity as much as possible. Considering the heterogeneity of cognitive profiles in ASD, neuropsychological assessment should be a key component of any management and intervention plan. 

What are the characteristics of Specific Language Impairment?

Epidemiology

Specific Language Impairment (SLI) is characterised by a failure to acquire language normally. SLI has an estimated prevalence rate ranging from 3% to 8% with boys more often affected than girls. In the DSM-5, SLI is proposed as a single category of Language Disorder, requiring a delay (skills below those expected for age, but otherwise not quantified) in the acquisition and use of language across modalities (oral, written) due to deficits in either comprehension or expression. To meet the criteria for SLI, the delay must appear early in life and cause functional impairment in communication, social participation, and academic achievement. In addition, the language difficulties cannot be attributed to environmental deprivation, intellectual disability, a speech-motor or hearing defect, or another disorder such as selective mutism, acquired epileptic aphasia or ASD. In other words, SLI occurs in the context of otherwise 'normal' development. 

Aetiology

It is likely that SLI has a strong genetic component. Twin studies suggest high heritability with evidence pointing towards the FOXP2 gene, in particular paternal deletions, in the aetiology of developmental verbal dyspraxia, which is a specific form of SLI. Recently, a review study has identified various other candidate genes, including CNTNAP2 and CMIP of chromosome 16q as important genes in SLI. Environmental factors are likely to play an influential role as well, although these are probably not causal in themselves. Examples of influential environmental factors are: impoverished home language environment, perinatal adversity, low SWS, low maternal education, a positive family history, and a bilingual language environment.

Neuropathology

Neuroimaging studies have identified a number of abnormalities in SLI, including neuronal migration disorders, abnormalities in the corpus callosum, anomalous cerebral lateralisation, and increased grey matter volume in the left inferior frontal cortex, as well as decreased grey matter volume in the right caudate nucleus and bilateral superior temporal cortex. In addition, the planum temporale (Wernicke's area) and the pars triangularis (Broca's area) are smaller on the left than the right hemisphere, whereas the reverse is true for normally developing children. 

Neuropsychological findings

A discrepancy is found between verbal IQ and performance IQ. Typically in children with SLI, verbal IQ falls in the borderline range, while performance IQ falls within the low average to average range, but still below that of healthy controls. Although there is a high degree of overlap in the language profiles of ASD and SLI, distinct cognitive profiles in these two conditions can be identified. More specifically, children with SLI show a relative absence of the idiosyncratic language and pragmatic deficits that is evident in children with ASD. Further, children with SLI can be discriminated from normally developing peers by their auditory perception, phonological short-term auditory memory, and working memory deficits. In addition, children with SLI exhibit deficits in both fine and gross motor skills. They also exhibit slowed processing speed. 

Functional outcomes

SLI is strongly associated with learning difficulties, in particular concerning language and literacy skills. Children with SLI are often viewed as inattentive or lazy in the classroom setting. This negative misconception may increase the risk for low self-esteem and an expectation of academic failure.

Treatment

A primary role in the assessment and treatment of children with SLI is provided by speech pathologists. However, considering the evidence described above for more overall information processing deficits, a comprehensive neuropsychological assessment is needed to identify specific strengths and weaknesses of children and to guide treatment planning and educational placement. In doing so, one must carefully consider the possible negative impact of receptive language deficits on comprehension of instructions on both verbal and non-verbal tasks. Finally, there is some evidence that parent-led interventions with clinician support may be as effective as clinician-led interventions. In addition, they have the advantage of being cost effective and encouraging generalisation of language gains into everyday life.