Neurodevelopmental Disorders Research Paper

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Introduction

The brain’s frontal regions are slow to mature, and they are vulnerable to neurodevelopmental disorders such as autism as well as neurodegenerative disorders of aging such as Parkinson’s and Huntington’s disease. The frontostriatal system involved in neurodevelopmental disorders comprises the dorsolateral prefrontal cortex, the lateral orbitofrontal cortex, the anterior cingulate, the supplementary motor area, and the basal ganglia. These areas are involved in a number of functions, such as executive functions (that is, functions such as self-monitoring, planning, organization, flexibility of thinking, and inhibition), motivation, control of complex behaviors, and sequencing movements. Below we outline the particular frontostriatal areas involved in six different development disorders, how they are characterized clinically, neuropsychologically, and genetically, and how they are best treated. The six disorders are attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), depression, schizophrenia, Tourette’s syndrome (TS), and obsessive–compulsive disorder (OCD).

Attention-Deficit/Hyperactivity Disorder

ADHD is an early-onset behavioral disorder comprising problems with inattention, impulsivity, distractibility, and excessive motor activity. It is classified in the Diagnostic and Statistical Manual of Mental Disorders as three major subtypes: predominantly inattentive (20–30%), predominantly hyperactive (less than 15%), and combined (50–75%). ADHD occurs in approximately 1–10% of school-aged children. Boys are more frequently diagnosed than girls, with ratios ranging from 2:1 to 9:1.

Clinical Features

Diagnosis of ADHD is based on the presence of a sufficient number of symptoms present before the age of 7, and the report that these symptoms impair the child’s functioning in at least two settings (home, school). Other than high levels of distractibility and inattention, children with ADHD tend to be disorganized, struggling to follow routines and to complete tasks. They tend to interrupt others, struggle to follow rules, and are often impulsive. Hyperactive children have difficulty remaining seated and are constantly restless and fidgety. These behaviors wax and wane and are influenced by the environment. Symptoms are typically worse in situations requiring sustained attention or mental effort, or those that are not appealing or novel.

Between 50 and 80% of children with ADHD also meet diagnostic criteria for other disorders, and generally the presence of such a comorbid disorder indicates a more serious problem and worse prognosis. The most common comorbid disorders are other externalizing disorders, such as oppositional defiant disorder and conduct disorder, followed by internalizing disorders, such as mood disorders, anxiety disorders, and specific learning disorders. Language and speech disorders and OCD are also common. While almost half of individuals with TS also have ADHD, the reverse is not the case.

ADHD symptoms usually reduce with maturation but persist to adulthood in 30–50% of cases. ADHD is a major risk factor for later personality and psychiatric disorders, delinquency, substance abuse, driving accidents and speeding violations, and difficulties in adult social relationships, marriage, and employment. Most of these developmental risks are exacerbated by the presence of comorbid aggression/conduct problems.

Treatment

Stimulant medications like methylphenidate and dextroamfetamine are the most commonly used treatment. They have a positive effect for approximately threequarters of children with ADHD at least in the short term. Stimulant medications are primarily dopaminergic (although they also affect noradrenergic and serotonergic systems), and treatment is associated with a reduced risk of later substance abuse. Contrary to popular belief that the effects of stimulant medication are paradoxical because ADHD children appear ‘slowed down,’ normally developing children respond to stimulants in the same way, with improved cognitive function and reduced motor activity.

Antidepressants (tricyclics like imipramine, desipramine; a norepinephrine [noradrenaline] reuptake inhibitor antidepressant, atomoxetine) are alternative treatments if children have intolerable side effects or are unresponsive to stimulants. These particular antidepressants primarily act on norepinephrine transmission.

Education of parents about the disorder, training in managing problem behaviors, learning how to manage stress, and social supports are useful for parents of ADHD children and result in reported improvements in the child’s behavior. Treatment involving medication is better than behavioral treatment alone. Behavior therapy may be a useful adjunct to medication by improving other associated difficulties such as social problems.

Neuropsychology

Executive functioning problems are indicated, with an emphasis on inhibitory deficits and problems with sustaining attention. These individuals typically show slow, variable, and inaccurate responding. They are impaired on tasks requiring inhibition of a response and of distracting stimuli, as well as in thinking flexibly, specifically being able to change response strategies when task demands change (change of set). Planning, word generation, withholding premature responses, working memory, and sustained attention are also deficient. Poor performance on many of these tasks is normalized through stimulant medication. While in the past the inattentive subtype was thought to be characterized more by problems with processing speed and selective attention, it now appears that the underlying neuropsychological deficits are more similar to than different from those with the combined subtype.

Neuroimaging

ADHD is associated with smaller whole-brain volumes, smaller right prefrontal cortex, and structural anomalies in the basal ganglia, cerebellum, and corpus callosum. Functional imaging studies indicate low striatal and frontal activity, particularly on the right, that is partially reversible with stimulant medication. These regions are involved in higher, executive function, such as working memory, rulebased learning, and planning. The right prefrontal cortex is important in editing one’s behavior, spatially focusing attention, resisting distraction, and developing an awareness of self and time. Lesions in the prefrontal cortex cause poor attention regulation, hyperactivity, and impulsivity. The basal ganglia act in switching off automatic responses, in coordination, and in selecting deliberate actions.

Genetics

While environmental factors such as birth complications, maternal alcohol, and tobacco use have been indicated, ADHD has a strong genetic component, with heritability estimates ranging from 61 to 98%. The mode of inheritance, however, is not clear. Like most psychiatric conditions, ADHD is a complex disorder with several genes, each of minor or moderate effect.

Disruption in dopaminergic pathways has been proposed for ADHD, and several dopaminergic genes have been implicated (DRD4, DRD5, DAT1). The dopaminergic system influences motor control, reward, and cognition, and is indicated by the primarily dopaminergic effects of stimulant medication. Dopamine receptors are present in the striatum and dorsolateral prefrontal cortex, areas shown in imaging studies to function abnormally. Problems in the dopaminergic system may also help explain the slow responding, poor timing, and clumsiness in ADHD.

The noradrenergic and serotonergic systems are also implicated, and clearly, multiple neurotransmitters may be involved. The study of the role of neurotransmitters is complicated by the interrelationship between neurotransmitter systems: a change in one results in a change in another. Noradrenergic projections are dense in the frontal cortex and cingulate gyrus, regions that subserve alertness and attentional control. Norepinephrine is implicated in working memory, behavioral inhibition, and attention. Low concentrations of norepinephrine in certain regions of the prefrontal cortex are associated with poor concentration, poor self-control, and greater motor activity. Serotonergic deficiency is associated with impulsivity and aggression, and serotonin is important in mood control, sleep, appetite, memory and learning, and control of attention and locomotion.

Depression

Depression, the ‘common cold’ of psychiatry, has a lifetime risk of between 10 and 20%, with females at twice the risk of males. The mean age of onset of a depressive disorder is between adolescence and the mid-twenties. It is more debilitating than the sadness that everyone sometimes experiences, and different even from grief of bereavement. It may have morbid consequences, with depression being the most common diagnosis in individuals who suicide.

Clinical Features

Major depressive disorder (MDD) is characterized by depressed mood of at least two weeks’ duration (depressed or irritable mood in children/adolescents) or loss of interest or pleasure in all activities. In addition, a number of other symptoms must be present: individuals with MDD often become preoccupied with suicide, plagued by guilt and a sense of worthlessness. They often have difficulty thinking clearly, concentrating, remembering, or making decisions. They may have difficulties with sleeping: they may feel sapped of energy and have trouble sleeping, or instead may want to eat and sleep excessively. They may also have symptoms of psychomotor agitation or retardation (psychomotor symptoms are rare in children/adolescents). MDD can present with psychotic features, usually consistent with depressive themes. It can also, rarely, present with catatonic features (immobility), melancholic features (lack of reactivity to pleasurable stimuli with worsening of symptoms in the morning, psychomotor retardation, and early morning awakening; this is rare in children/adolescents), and atypical features (reactive mood, increased appetite, excessive sleep, leaden paralysis).

Approximately 3–6% may develop a less acute but more chronic dysthymic disorder where symptoms of depressed mood and at least two other symptoms (poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration, or difficulty making decisions and feelings of hopelessness) are present most of the day, more days than not for a period of at least 2 years (1 year in children/adolescents). Bipolar disorder, characterized by episodes of mania (marked by a decreased need for sleep, rapid speech, delusions of grandeur, and engaging in self-destructive activities such as spending sprees and promiscuous sex), typically commences following one or more depressive episodes. It is rarer than unipolar depression, estimated at 1–1.5%.

Depression is comorbid in approximately 60% of cases, with anxiety disorders being the most common comorbidities. Substance abuse, eating disorders, conduct disorders, and ADHD are also often comorbid. Comorbid disorders such as anxiety (but not substance abuse) often precede depression.

Only two-thirds respond to treatment; 15% fail to recover (with the episode lasting for 2 or more years). Among those who respond to treatment one-third will relapse during remission. Of those that recover, 75% will have a recurrent episode. Only 11% ever have a single episode. Those with depression can expect four to six episodes during a lifetime.

Treatment

Cognitive behavior therapy (CBT) and interpersonal therapy (IPT) are the two empirically validated psychotherapies for adolescent and adult depression. CBT focuses on developing a less distorted/negative thinking style and more adaptive coping behaviors, while IPT focuses on improving effective communication. However, severe depression usually requires antidepressant medication. There are added benefits with combined psychotherapy and medication treatment. In very severe treatment-resistant depression, or with severe illness/suicidality, electroconvulsive therapy (ECT) is used, involving induction of brief seizures. It is an efficacious rapid treatment, but benefits need to be maintained with maintenance treatment (e.g., maintenance ECT or antidepressant medication). Transcranial magnetic stimulation, the use of a powerful magnetic field to stimulate brain areas such as the prefrontal cortex, also temporarily ameliorates symptoms.

Antidepressant medications act primarily on serotonin (the serotonergic system plays a role in control of appetite, sleep, memory and learning, control of attention and locomotion, muscle contraction, and endocrine regulation) and norepinephrine. Older tricyclic antidepressants are primarily noradrenergic and especially indicated where psychomotor retardation is prominent, as in the melancholic type. Tricyclics are no more effective than placebo in adolescents, where psychomotor symptoms and melancholic depression are rarely seen. In this group, the newer SSRIs (selective serotonin reuptake inhibitors) are more effective than tricyclics, suggesting that serotonin may be more important in childhood depression. There is recent controversy over the use of SSRIs in children and adolescents, in terms of safety and efficacy. Only fluoxetine (i.e., Prozac/Lovan) was considered to have an acceptable risk–benefit ratio by the Food and Drug Administration, and warning labels have been issued for antidepressants. Lithium remains the standard treatment for bipolar disorder. Some antiepilepsy drugs are also used as mood stabilizers in bipolar disorder.

Neuropsychology

Depressed individuals are slower in cognitive processing and responding. Cognitive deficits have also been observed, such as concentration difficulties and learning and memory problems (especially verbal memory); and reduced executive functioning with an emphasis on flexibility of thinking or shifting attentional set. Individuals with depression are also often impaired in planning, word generation, working memory, and inhibition of irrelevant information. While some difficulties disappear in remission (e.g., verbal fluency), others continue to manifest (e.g., inhibition of irrelevant information). Fewer difficulties are apparent in younger individuals. The neuropsychological difficulties in bipolar disorder are similar, but more severe than in unipolar depression.

Neuroimaging

Structural imaging reveals ventricular enlargement (correlating with cognitive and psychomotor retardation) similar to Alzheimer’s disease, Huntington’s disease, and schizophrenia, together with periventricular white matter lesions, decreased striatal volume, temporal lobe anomalies, and smaller frontal lobe volume. Smaller hippocampus (involved in learning and memory) and enlarged amygdala (involved in emotional functioning) are also reported. Functional imaging studies show lower activity in the anterior cingulate, left dorsolateral prefrontal cortex, amygdala, and striatum. Increased orbitofrontal activity reflects inhibitory processes and rumination. These brain areas mediate the affective aspects (e.g., orbitofrontal cortex, amygdala, hippocampus), psychomotor aspects (e.g., dorsolateral prefrontal cortex), and cognitive/executive function aspects (anterior cingulate and dorsolateral prefrontal cortex).

Genetics

Individuals with major depression are more likely to have relatives suffering from anxiety, depression, and alcohol abuse. There may be overlapping genetic association between mood disorders and alcohol abuse. While relatives of individuals with bipolar disorder are at increased risk of depression, the reverse is not true. Depression has heritability estimates around 40–70%. Environmental risk factors for depression include stressful life events and childhood neglect/abuse, absence of social support, and low maternal support in childhood.

Various genes have been investigated in depression, including those affecting neurotransmitters such as serotonin and norepinephrine and those that control activities of certain hormones, with unclear findings. Some studies find that stress interacts with serotonin transporter genes in predicting depression, while others do not. Neurotoxic effects, possibly from cortisol released during stress, may damage hippocampal cells (part of the limbic system involved in memory and emotion), resulting in depressive symptoms. After a few weeks of antidepressant treatment the hippocampus may regain mass (neurogenesis). Possibly neuroprotective proteins are also implicated. Depression probably involves an interaction of several genes with environmental events.

Tourette’s Syndrome

TS is a severe form of tic disorder, marked by multiple motor tics and one or more vocal tics that are present for at least 1 year. Tics are sudden rapid, recurrent, purposeless movements or vocalizations/utterances. TS is more commonly found in boys than girls (3:1 ratio) and affects less than 1% of the population. Motor tics usually develop before vocal tics, and these symptoms typically progress over time, becoming more severe and complex. Onset is usually during childhood or early adolescence, and is by definition before age 18. Tics typically develop prior to age eight, peak by puberty, and decline substantially thereafter. In some cases symptoms disappear entirely by adulthood.

Clinical Features

Simple motor tics include eye blinking, neck jerking, grimacing, and coughing, whereas simple vocal tics include throat clearing, sniffling, grunting, and barking. Complex tics include licking, head shaking, throwing, biting, jumping, compulsive touching, compulsive copying of another’s actions (echopraxia) or speech (echolalia), obscene gestures (copropraxia), and socially unacceptable utterances (coprolalia). However, coprolalia occurs in less than 15% of cases. Tics are experienced as irresistible but can be suppressed for periods of time, though with an increasing buildup of tension. Most individuals are aware of an urge similar to the urge to sneeze or scratch an itch. Tics constantly change in number, frequency, and severity, and are typically exacerbated by stress or boredom and reduced during concentration.

Tics can cause embarrassment and interfere with social interactions, and can sometimes be quite uncomfortable and painful. Self-injurious behavior such as biting, scratching, cutting, or hitting are also seen in TS. Some individuals with TS have speech dysfluencies that resemble stuttering. The majority of individuals with TS have symptoms of ADHD, OCD, or both, at some time during the course of their condition. There is considerable overlap between TS and OCD, in that in both conditions the repetitive behaviors are considered to be involuntary (although for both there is some degree of voluntary control), tension is experienced if the behavior is inhibited, and relief is reported as the behavior is carried out. TS is also comorbid with problems of poor impulse control and an inability to control anger, learning disorders, and anxiety and depression.

Treatment

Management involves medication, behavior or cognitive therapy, and for a minority of severe cases, surgery (involving for example, making multiple lesions in the cingulum and beneath the head of the caudate nucleus). The main aim of treatment is to achieve a degree of control of tics allowing the individual to function as normally as possible and to relieve tic-related embarrassment or discomfort. Most cases of tic disorders such as TS are mild and are considered not to require medication. Behavioral therapy such as biofeedback, habit reversal (e.g., practicing muscular movements opposite to the tic) and relaxation training (to help relieve stress that aggravates tics) has been suggested to help. Cognitive therapy and supportive psychotherapy are also helpful in avoiding depression and social isolation and improving family support. Habit reversal is superior to supportive psychotherapy in reducing tic severity, but both improve life satisfaction and psychosocial functioning. Most psychotherapeutic interventions (with the exception of habit reversal) have, however, not been systematically evaluated. Often it is the comorbid conditions like ADHD that cause greater impact, and these comorbid disorders are often the reason for seeking help. Medications useful in treating tics target dopaminergic systems by blocking dopamine receptors. Thus antipsychotics (e.g., ‘typicals’ like haloperidol and newer ‘atypicals’ like risperidone) are considered the most effective anti-tic agents, but are often associated with unwanted side effects. Variable efficacy has also been shown for antihypertensives such as clonidine.

Neuropsychology

Increased rates of eye blinking and poor handwriting (similarly found in ADHD) suggest mild impairment in motor control. There is some evidence for difficulties with respect to visuomotor integration (e.g., copying complex designs) and in motor coordination, as well as deficits in eye movement control. Early studies suggested executive function deficits. However, these deficits may be related to the comorbid symptomatology of OCD and ADHD. Studies comparing neuropsychological performance of individuals with TS with and without comorbid ADHD or OCD symptomatology, suggest more extensive impairments in those with comorbid disorders and only mild cognitive deficits in the ‘pure’ form. There is debate that rather than widespread executive deficits, deficits in TS may be more inhibitory in nature, though whether this is so, and precisely which inhibitory processes are involved, requires further investigation.

Neuroimaging

The main brain areas implicated are the basal ganglia (especially the caudate nucleus) and the inferior prefrontal cortex. Caudal volume correlates inversely with tic severity and obsessive–compulsive symptoms. Neuroimaging studies show anomalies of the basal ganglia and activation changes in the ventral striatum, orbitofrontal cortex, and anterior cingulate. The basal ganglia normally gate release of behaviors, with TS probably reflecting excess facilitation of unintended (and inhibition of intended) actions. Tics involve activity of not just motor areas, but also oculomotor, language, limbic, and cognitive/executive areas. During periods of tic suppression, decreased activity is observed in the ventral globus pallidus, putamen, and thalamus, and increased activation in areas involved in the inhibition of unwanted impulses: the prefrontal, parietal, temporal, and cingulate cortical areas. Prior to tic occurrence paralimbic areas are activated (anterior cingulate, insular cortex, supplementary motor area – receiving input from basal ganglia – and parietal cortex) and as the tic commences, sensorimotor activation occurs in the superior parietal cortex and cerebellum. Interestingly, paralimbic and associated areas are implicated not only in tic generation, but also with movements triggered internally by unpleasant sensations such as pain or itching.

Genetics

While environmental factors such as infection, maternal stress, and nausea during the first trimester of pregnancy may influence expression of TS, it also has a strong genetic component. Monozygotic twins have concordance rates of 50–70% (that is, if one identical twin has TS there is a 50–70% probability that the other will also have TS) and dizygotic twins around 10–20%. The disorder’s familial characteristics have been interpreted in terms of autosomal dominant transmission with high but incomplete penetrance and variable expression; thus, not everyone who inherits the genetic vulnerability will show the same severity of symptoms, or even any symptoms at all. Males are more likely than females to show genetic vulnerability to tic expression. However, the exact mode of inheritance is not yet known, and some researchers propose an additive model of gene inheritance where many genes are likely to contribute to the expression of TS. Many chromosomal locations have been proposed – for example, on chromosomes 4, 5, 8, 11, and 17 – likely influencing dopamine receptor subtypes and/or controlling neuronal development. Some forms of OCD may be genetically linked to TS, and a genetic relationship of ADHD to TS has also been proposed.

Obsessive–Compulsive Disorder

OCD is characterized by uncontrolled, recurrent, intrusive thoughts, impulses, and images (obsessions), accompanied by feelings of urgency or catastrophe, leading to repetitive, time-consuming and ritualistic behavior (compulsions), which are an antianxiety attempt to avert fear or distress. The obsessions and compulsions cause marked distress, are time consuming, or interfere with the individual’s normal routine, job, or social activities. There is often variable insight into the reasonableness of the obsessions and compulsions. The disorder is equally common in males and females, and age of onset is typically around or before puberty in males and in the 20s in females. Lifetime prevalence is estimated to be around 2.5%.

Clinical Features

OCD is considered an anxiety disorder that is typically chronic rather than acute. Unlike obsessive–compulsive personality disorder, with its characteristic perfectionism and scrupulosity, where individuals derive pleasure from their obsessions and compulsions, those with OCD feel distress and anxiety. The frequency of common obsessions has been calculated as: fear of contamination (e.g., becoming contaminated by handling money), 45%; pathological doubt (e.g., wondering whether one has left the oven on), 42%; somatic concerns, 36%; need for exactness, symmetry, or evenness, 31%; fear of committing acts of aggression, which unlike in psychopathy are not carried through, 28%; sexual or religious obsessions (e.g., a recurrent pornographic image), 26%. Individuals with obsessions usually attempt to suppress such thoughts or to neutralize them through another thought or action, i.e., compulsions. For compulsions, the figures are: checking (63%), washing or cleaning (50%), counting (36%), need to ask or confess (31%), symmetry and precision until position or number of repetitions are ‘just right’ (28%), and hoarding (18%). Factor analysis suggests the following groupings: aggressive and somatic obsessions with checking compulsions; preoccupations with symmetry and exactness involving counting, ordering, and arranging rituals; fears of contamination or illness with washing or cleaning rituals; sexual and religious obsessions. The last, unlike the others which may change over time, tend to be particularly stable.

Because obsessions are distracting, they may result in inefficient performance in tasks that require concentration. In addition, many individuals may avoid objects or situations related to the content of the obsessions, and for some, performing compulsions may become a major activity leading to severe disruption to occupational functioning and relationships. Disorders commonly comorbid with OCD include depression (67% lifetime rate), simple phobia (22%), social phobia (18%), eating disorder (17%), problems with alcohol (14%), panic disorder (12%) and TS (7%).

Treatment

The tricyclic antidepressant clomipramine, which has serotonergic and noradrenergic action, and the selective serotonin reuptake inhibitors (fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine) are effective treatments. There is controversy over whether clomipramine is more effective than the SSRIs. Behavioral treatments such as exposure and response prevention (this involves gradually learning to tolerate the anxiety associated with not performing the ritual behavior) are effective, compared to control relaxation treatments. Cognitive therapy challenges irrational beliefs and is as effective as exposure treatments. Cognitive behavior treatments are associated with greater long-term gains (despite not entirely eliminating symptoms) than medication treatments, where relapse is highly probable upon stopping medication. Randomized controlled trials are required to clarify whether or not there is any additional benefit of medication and psychological treatment. For patients with severe OCD who do not respond to medication or psychological treatments, psychosurgery (anterior capsulotomy, anterior cingulotomy, subcaudate tractotomy, or limbic leucotomy) is a last resort.

Neuropsychology

Individuals with OCD respond more slowly, and their performance on set shifting, response inhibition, and motor suppression tasks (measures of executive function) correlates negatively with the frequency and intensity of their compulsive behaviors. There is some evidence of selective deficits in pattern recognition and spatial memory, set shifting, and reversal of response set, with largely intact planning and decision processes.

Neuroimaging

Specific brain regions are implicated; the basal ganglia (particularly the caudate and striatum), orbitofrontal cortex, and anterior cingulate, plus perhaps temporal lobe and amygdala, which may provide the emotional features. Caudate volume is reduced and overactivity of the orbitofrontal cortex, anterior cingulate, and right striatum is observed. However, there are many inconsistencies in the literature. These brain areas play an important role in the inhibition of inappropriate responses, for executive functioning, for overriding predominant response patterns, and for error monitoring and detection.

Genetics

OCD has heritability estimates around 27–65%. While the mode of inheritance remains unclear, it is likely to be polygenic with a number of vulnerability genes, including at least chromosomes 4, 5, and 7. Very recent studies indicate significant associations between OCD transmission and a locus on chromosome 9 that may be crucial for controlling the excitatory neurotransmitter glutamate. Genes of the serotonin and dopamine systems (5HTTLPR, 5HT1Db, DRD4) are also implicated in OCD. The relationship between OCD and TS may imply a common genetic background, although the TS genes may not be the only mode of acquisition of OCD. Environmental factors such as pre and perinatal events and infection also play a role in its expression.

Autism Spectrum Disorders

ASDs such as autism and Asperger’s disorder onset within the first 3 years of life. The prevalence of autism and Asperger’s disorder are around 10–12 per 10 000, with Asperger’s disorder possibly more prevalent than autism. Both autism and Asperger’s disorder are more common in boys than girls (4:1), with perhaps a greater preponderance of affected males to females for Asperger’s disorder.

Clinical Features

Autism is defined by impairments in social and communication function, and repetitive and stereotyped behavioral patterns. Areas of social disturbance include poor eye contact, reduced ability to interpret emotional states, failure to develop peer relations, and deficiencies in social-emotional reciprocity (e.g., not participating in social play, impaired awareness of the needs of others). For a diagnosis of autism, a child must, before 3 years of age, exhibit abnormal or delayed functioning in at least one of the following areas of social interaction: social use of language, symbolic play, or imaginative play. Core communication deficiencies include either a delay or total lack of expressive language, as well as a marked impairment in nonverbal behavior. Where individuals develop language, they often have problems in initiating or sustaining conversations. Developmentally inappropriate echolalia (copying another’s speech) and pronoun reversal, reduced prosody and intonation, and impairments in the use of figurative language are also associated with autism. Restricted, repetitive, and stereotyped behaviors manifest as an intense preoccupation with a single subject or activity, adherence to nonfunctional routines or rituals, stereotypies, and motor mannerisms, e.g., hand or finger flapping, and body rocking. Disturbances in sensory modulation may also be observed; for example, under and overreactivity to sensory stimuli.

Treatment

ASDs are lifelong conditions and therefore treatments need to be tailored to the individuals’ particular developmental needs. In general, treatments meet criteria for best practice if they include a combination of educational, behavioral, communication, and social skills training approaches, together with medication if indicated. For example, a comprehensive treatment plan might include: teaching new skills using positive reinforcement; the provision of an individually designed school-based educational program; social skills training tailored to the child’s intellectual and language abilities; and skills training for the parents of children with autism to provide them with appropriate skills to promote their development. Medication may be prescribed to target specific symptoms, e.g., neuroleptic medication or SSRIs to treat anxiety, while lithium and other mood stabilizers may reduce episodes of disruptive, aggressive, and self-injurious behavior.

Neuropsychology

There are three main cognitive theories of autism and Asperger’s disorder: theory-of-mind, the executive dysfunction theory, and the theory of weak central coherence. Deficiencies in theory-of-mind – that is, the ability to understand that other people have unique perspectives and thoughts that are sometimes contextually independent – may be linked to the social-communicative deficits. Weak central coherence, a deficit in the ability to integrate details into a coherent global perception, may be linked to the tendency to be preoccupied with parts of objects and to miss the ‘bigger picture.’ Executive functioning refers to the role of the frontostriatal circuits in coordinating cognitive-motor output so that behavior is well timed, planned, adaptable, appropriate, and relevant. The repetitive, stereotyped, and restricted behaviors may be due, in part, to deficient executive functioning. Movement abnormalities in ASDs, in particular gait (walking) abnormalities, may be underpinned by disruption to neural circuitry involving the basal ganglia and cerebellum.

Neuroimaging

No consistent neuroimaging marker has been identified for ASDs. Structural changes in the brains of individuals with autism include: a slightly increased average brain volume; decreased gray matter volumes in the limbic system (important for social cognition); reduced neuron numbers in the vermis of the cerebellum; and gross structural changes in the cerebellum and the parietal lobes (important for efficient attention). Consistent with the executive functioning and neuromotor impairments associated with ASDs, functional imaging has revealed decreased activation in the highly interconnected cortical and subcortical frontal structures, including lateral and medial premotor cortex, frontal eye fields, caudate, dorsolateral prefrontal cortex, and anterior cingulate, suggesting disruption to multiple frontostriatal circuits.

Genetics

The concordance for autism in monozygotic twins is 60% for autistic disorder and 92% for ASDs. For dizygotic twins the concordance for either diagnosis is up to 10%. If an older sibling has autism, the risk that a subsequent full sibling will have autism is about 5%. Studies of individuals with autism suggest that chromosome 15q11-q13 is a candidate region for genetic risk factors. There is also an increased frequency of the chromosome 4B null allele, and of variant serotonin transporter gene alleles on chromosome 17q11-q12. Autism is associated with defined environmental causes, such as rubella and cytomegalovirus, fetal infections, perinatal brain injury, toxins, and specific genetic abnormalities such as tuberous sclerosis and fragile X syndrome, in less than 10% of cases.

Schizophrenia

Schizophrenia is characterized by psychosis (disturbances in thinking and perception), apathy, withdrawal, and cognitive impairment. Schizophrenia affects emotional reactivity, interpersonal relations, perceptual processes, attention, information processing, and thought. Its psychosocial impact is devastating at an individual, family, and societal level. The prevalence of schizophrenia is between 0.5–1.5%. Recent studies suggest a small, but significantly higher, incidence of schizophrenia among men compared with women when stringent classification criteria are applied. Onset is typically in young adulthood, later in females.

Clinical Features

Individuals experience a combination of ‘positive’ and ‘negative’ symptoms, which interfere with interpersonal relations, work or education, or self-care over (at least) a six-month period. Key ‘positive symptoms’ include: delusions (distortions of thought content), hallucinations (perceptual anomalies), and disorganized thinking, language, and behavior. An example of a delusion might be the belief that someone has inserted a thought into one’s head or broadcast a thought from one’s own mind to others’. Hallucinations are commonly auditory – for example, ‘hearing voices’ that are so intense that they are interpreted as being of external origin. Disorganized thinking, measured clinically by the patients’ verbal output, is often referred to clinically as the single most important feature of schizophrenia. ‘Negative’ symptoms essentially refer to restrictions in the range and intensity of one’s ability to express emotion (affective flattening), a reduced ability to produce fluent thoughts and ideas (alogia), and a reduced ability to form and achieve particular life goals. The negative symptoms of schizophrenia account for the increased suicide rate, estimated at 10% of all those diagnosed with the disorder. The main determinants of quality of life are depression and negative symptoms (not active psychosis).

Depending on the constellation and type of positive and negative symptoms, the disorder may be subtyped as paranoid, disorganized, or catatonic. Individuals may shift between positive and negative symptom types during the progression of the disease – for example, commencing with an exacerbating phase of largely positive symptoms, followed by a plateau phase, where the severity and frequency of positive symptoms stabilize, followed by a remission of hallucinations, delusions, and disorganized behavior with evolution of worsening negative symptoms. Individuals may experience a single psychotic episode followed by more or less total recovery, or suffer repeated psychotic episodes with subtotal recovery, or, more commonly, experience a course progressing to chronic disability.

Treatment

The first line of treatment is pharmacotherapy. While in the past pharmacotherapy was concentrated on controlling positive symptoms using neuroleptic medications that block dopamine D2 receptors, atypical antipsychotic medications (e.g., clozapine) are now more commonly prescribed and are more effective than conventional antipsychotics, as well as yielding a more acceptable side effect profile. Antidepressants and mood stabilizers (e.g., lithium) are commonly used in treatment. Compliant medication use sets the scene for effective psychosocial interventions, including family psychoeducation, social skills training, cognitive-behavior therapy, and substance abuse treatments.

Neuropsychology

Schizophrenia is associated with multiple cognitive deficits, including executive dysfunction (most notably working memory), problems with attention, concentration, psychomotor speed, learning, and memory. Working memory problems and attentional difficulties may underlie the positive and negative symptoms. For example, distortions in perception and thinking may emerge from a difficulty in being able to hold and manipulate cognitive information long enough to reference an actual experience, as compared to emergent associated memory. Similarly, negative symptoms such as a reduced ability to set and execute daily goals may be underpinned by a difficulty in maintaining an initial plan of action. Many of the cognitive deficits associated with schizophrenia manifest during remission, and are therefore considered as core features as opposed to state deficits apparent only during psychotic phases. As for autism, research using retrospective video footage has identified subtle neuromotor features that are apparent prior to clinical onset. Additionally, upper-body bimanual coordination deficits have been systematically documented.

Neuroimaging

Structural and functional brain imaging studies reveal three consistent neuropathological findings: (1) hypofrontality (i.e., decreased neural activity in the frontal regions); (2) enlargement of the lateral ventricles and decreased brain tissue (for example, gray and white matter deficits have consistently been found in the left superior temporal gyrus and the left medial temporal lobe); and (3) reduced hippocampal volume. Impairments in the dorsolateral prefrontal cortex are responsible for core cognitive deficits, most notably working memory. The hypometabolism of the dorsolateral prefrontal cortex and anterior cingulate are linked to negative symptom severity, while hypermetabolism of the temporolimbic cortex has been linked to positive symptomatology. Abnormalities have also been reported in neuron density, number, and size in the nucleus accumbens, substantia nigra, thalamus, locus coeruleus, pedunculopontine nucleus, basal ganglia, thalamus, and corpus callosum. The highly salient clinical feature of disorganized thinking is thought to be underpinned by a neuronal disconnectivity between the multiple neural sites identified in schizophrenia.

Genetics

Schizophrenia is highly heritable. The monozygotic cotwin of an affected individual has an estimated risk of 60–84%, whereas that of a dizygotic co-twin is around 14%. There is an 8% risk if a sibling has the disorder, and 12% if one parent and 40% if both parents are sufferers. There are likely to be multiple susceptibility genes, each with small effects, or several such genes, each with moderate effects. Linkage analysis has identified 5q, 6p, 8p, 13q, 15q14, and 22q as promising genetic susceptibility regions. Chromosomes 3, 9, and 20 have also been implicated. The location of a schizophrenia susceptibility locus at chromosome 22q11 has been suggested by recent genome-wide linkage studies. Approximately 20–30% of individuals with 22q11 microdeletions develop schizophrenia or a related psychiatric condition (e.g., schizoaffective disorder).

Conclusion

There are many similarities across the neurodevelopmental disorders, in terms of high rates of comorbidity and the fact that the mode of inheritance is typically unclear, usually with a number of genes implicated. The neuropsychology deficits and implicated brain areas overlap, and how each disorder manifests may depend on how the frontostriatal system is compromised as a result of both genetic predisposition and environmental factors.

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