The function of dopamine (DA) in the brain includes the mediation of cognition, emotion and movement, and it is involved in both the production and inhibition of several primary biological drives. Removal of free dopamine from the synaptic cleft is one of the primary mechanisms for regulating dopaminergic tone, with the reuptake of free dopamine from the synaptic cleft mediated by a macromolecular transporter located in the axonal membrane (DAT).

The majority of neuropsychiatric disease and drugs cause compensatory changes in the dopamine transporter before affecting the concentration of the postsynaptic dopaminergic receptors. These striatal transporters are present exclusively on dopamine-producing neurons where they play a key role in the regulation of DA levels in the synaptic cleft. Dopamine transporters are markers of the integrity of presynaptic dopaminergic neurons and as such provide an ideal target for imaging with either SPECT or PET. Figure25.1 below provides an overview of the most important functional imaging targets and some of the more commonly used SPECT and PET tracers (Fusar-Poli et al. 2012).

There is growing evidence to suggest that impulsiveness is caused by dysregulation of brain dopaminergic neurotransmission (Dalley et al. 2008). Areas that are often implicated include the dopaminergic neuronal projections from the midbrain to the ventral striatum (nucleus accumbens). These are associated with the integration of motivational and reward-based processing (Cardinal et al. 2004).

There has been rapid growth in the literature describing the dopaminergic basis of human behaviour, with a parallel increase in tracer development for quantification of dopamine release via D₂/D₃ receptor occupancy imaging.

In a recent publication by Reeves et al. (2012), the association between reduced striatal D₂/D₃ receptor availability and higher levels of impulsivity was explored in 23 healthy volunteers. The authors wanted to evaluate whether a relationship between limbic (ventral) striatal D₂/D₃ receptor availability and the individual components of impulsivity exist. They made use of ¹¹C-raclopride PET imaging in 23 healthy volunteers which was compared to the various components of impulsivity (attention, motor and non-planning), assessed using the Barratt Impulsiveness Scale. After the exclusion of potential dissimulators, a significant association was found between non-planning impulsiveness and limbic D₂/D₃ receptor availability. The authors concluded that non-planning impulsiveness may be associated with individual variation in limbic striatal D₂/D₃ receptor availability and that different facets of impulsivity may have specific neurochemical correlates (Reeves et al. 2012).

In another recent study, Costa et al. (2013) investigated the dopaminergic basis of impulsivity and other ADHD-related traits in healthy individuals by evaluating the association of such traits with striatal dopamine transporter availability. The group imaged 38 healthy males with ¹²³I-FP-CIT SPECT; they measured impulsivity with the Barratt Impulsiveness Scale (BIS) and hyperactivity–impulsivity and inattention with the Adult ADHD Self-Report Scale (ASRS). The authors found that greater dopamine transporter availability was associated with higher impulsivity as measured on BIS but was not associated with ADHD-related traits. This association with BIS was significant even after accounting for individual differences in age and neuroticism. The authors suggested in conclusion that individual differences in the dopamine system may be a neural correlate of trait impulsivity in healthy individuals (Costa et al. 2013).

The serotonergic system is one of the most important and complex neurotransmitter systems in the human brain, with 14 receptors identified to date, many of whose functions remain elusive and many of which play a role in several different processes. Serotonin transmission also plays an important role in several neuropsychiatric conditions and has been strongly implicated in impulsivity, together with the dopaminergic system.

Extensive investigation of the role of serotonin followed the discovery that the metabolite 5-HIAA is often low in the CSF of people with impulsive and aggressive behaviour. The incidence of suicidal acts was also related to the level of 5-hydroxyindoleacetic acid (5HIAA) in the cerebrospinal fluid, where patients with low levels of 5-HIAA (below 15 ng/ml) attempted suicide significantly more often than those with high levels and used more violent means (Asberg et al. 1976) (Fig. 25.2).

In the CNS, 5-HT is synthesized in the raphe nuclei of the human midbrain and brainstem as well as their projection sites. From the raphe nuclei, projections run to the forebrain, reaching nearly all parts of the brain. Tryptophan hydroxylase (TPH) plays an important role in the synthesis of serotonin by synthesizing l-tryptophan to 5-hydroxy-l-tryptophan, which in turn is synthesized by amino acid decarboxylase to serotonin. Serotonin reuptake from the extracellular space and the synaptic cleft is carried out by the SERT, which is an important therapeutic target in the treatment of many psychiatric disorders. The vesicular monoamine transporter type 2 (VMAT2) is a non-serotonin-specific transporter, which also transports other neurotransmitters such as dopamine, norepinephrine and histamine. The enzyme monoamine oxidase A (MAO-A) is in charge of degrading serotonin, and the resulting aldehyde is oxidized by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA).

Paterson and co-workers (2013) reviewed the history and current status of radioligands used for both SPECT and PET imaging of the human serotonin receptors, the serotonin transporter (SERT) and 5-HT synthesis rate. The following table has been taken from their paper and provides a nice summary of the imaging options and studies so far (Paterson et al. 2013) (Table 25.2).

Saulin et al. (2012) published a review, which summarizes the distribution and main functions of the serotonin (5-hydroxytryptamin, 5-HT) receptors as well as that of the serotonin transporter (SERT, 5-HTT), the vesicular monoamine transporter 2, monoamine oxidase type A and 5-HT synthesis in the human brain. They included recent advances in in vivo quantification of these different receptors and enzymes that are part of the serotonergic system using PET. A summary from their publication can be found below (Saulin et al. 2011) (Table 25.3).

Saulin and co-workers (2011) mention the following in their review, which relates to impulsivity.

In 5-HT_1B knockout mice, an increase in impulsive behaviour and defective regulation of impulsivity was observed (Meneses 2007; Meneses and Perez-Garcia 2007).

The 5-HT_1B receptor has been implicated in various psychiatric disorders. Studies have found it to be involved in alcoholism (Hu et al. 2010; Soyka et al. 2004) and substance abuse (Huang et al. 2003; Neumaier et al. 2002) (but see Cigler et al. (2001) for different findings). It has also been implicated in disorders such as attention deficit hyperactivity disorder (ADHD) (Quist et al. 2003) and aggression (Olivier and van Oorschot 2005; Saudou et al. 1994). In studies by Knudsen and co-workers, OCD has been linked to elevated levels of 5-HT_2A binding in the caudate nucleus (Adams et al. 2005), as well as to Tourette’s syndrome which was associated with increased binding in orbitofrontal cortex, anterior cingulate, frontal cortex and other regions of the brain (Haugbøl et al. 2007).

By means of the highly specific radioiodinated 5-HT_2A receptor antagonist 4-amino-N-[1-[3-(4-fluorophenoxy) propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide or ¹²³I-5-I-R91150, Audenaert and co-workers demonstrated with high-resolution SPECT that the 5-HT_2A in deliberate self-harm patients was significantly reduced in the frontal cortex (after correction for age) when compared with healthy controls. They also found that the reduction was more pronounced amongst deliberate self-injury patients (Audenaert et al. 2001).

Rylands et al. also conducted a study in which ¹¹C-MDL100907 was used to measure the availability of 5-HT _2A receptor in males with impulsive aggression. These patients fulfilled the DSM-IV diagnostic criteria of antisocial personality disorder (ASPD) and borderline personality disorder (BPD) and were divided into a high-impulsive aggression (high-IA) and a low-impulsive aggression (low-IA) group. Those with a history of past alcohol and drug dependence, current or past DSM-IV Axis I disorder, current Axis II cluster A personality disorder or use of 3,4-methylenedioxymethamphetamine (ecstasy) were excluded from the study. PET imaging was performed, which demonstrated that 5-HT _2A receptors were lower throughout the brain cortex of highly impulsive individuals. This indicates abnormal postsynaptic mechanisms of serotonin in these impulsive patients (Rylands et al. 2012).

Abnormalities of 5-HT₂ receptors in the brain cortex are viewed as representative of 5-HT_2A receptors in cortex due to the extremely low density and binding of the other two subtypes, 5-HT_2B and 5-HT_2C (Meyer et al. 2008).

In schizophrenia, increased binding was observed in the caudate nucleus (Erritzoe et al. 2008), but decreased levels were found in the dorsolateral prefrontal cortex (dlPFC) and the para-hippocampal gyrus (Burnet et al. 1996). Moreover, the 5-HT_2A polymorphism-1438G/A has been suggested to play a role in OCD (Enoch et al. 1998).

Most prominently in the clinical population (for review, see Daws and Gould (2011)), SERT has been found to play a major role in depression (e.g. Tsao et al. 2006) and bipolar disorder (e.g. Lesch et al. 1995). Other studies suggested SERT to be implicated in OCD (Hesse et al. 2011; Simpson et al. 2003) and substance abuse (Brown et al. 2007), especially MDMA (McCann et al. 2005; Selvaraj et al. 2009). SERT has further been linked to obesity (Erritzoe et al. 2010) and Parkinson’s disease (e.g. Wang et al. 2010).

Changes in 5-HT synthesis have been associated with the treatment of major depression, showing lower 5-HT synthesis rates in patients with major depression (Rosa-Neto et al. 2004). Decrease of tryptophan has also been associated with Parkinson’s disease, especially in the caudate (Kish et al. 2008). Leyton and colleagues found borderline personality disorder to be negatively linked to 5-HT synthesis rates as measured with PET in the medial frontal gyrus, anterior cingulate gyrus, superior temporal gyrus and corpus striatum. They also found reduced synthesis rates in the medial frontal gyrus, anterior cingulate gyrus, temporal gyrus and striatum in subjects scoring high on measures of impulsivity (Leyton et al. 2001).

Drug-free suicide attempters compared with matched controls showed a negative correlation between SERT and impulsiveness with no significant difference demonstrated concerning the regional levels of SERT binding potentials and DAT binding potentials in the two groups. However, a significant regional correlation was seen in the suicide attempters between Marke–Nyman temperament test (which assesses the level of impulsiveness and mental energy) and the SPECT findings. This finding was not evident in the control group and was attributed to an inability of the suicide attempters to regulate their serotonin and dopamine levels in response to external stress (Ryding et al. 2006).

¹²³I − β − CIT, a mixed monoamine transporter tracer which is a potent ligand for both dopamine and serotonin reuptake sites, was used by Lindstrom et al. to evaluate 12 patients (10 men and 2 women) who had previously had a serious suicide attempt and their matched healthy controls. SPECT imaging demonstrated a correlation between SERT and DAT in the suicide attempters which was not evident in the control group indicating that both systems may play a role in impulsivity (Lindström et al. 2004).

The noradrenaline transporter (NAT) is located at the presynaptic terminal of noradrenergic neurons where it plays an integral role in noradrenergic neurotransmission. It regulates the concentration of noradrenaline in the synaptic cleft via a reuptake mechanism. Brain structures known to be rich in norepinephrine (NET) include the locus coeruleus, thalamus, hippocampus and throughout the cerebral cortex, whereas low levels are found in cerebellum and striatum.

Alterations in synaptic noradrenaline levels have been implicated in various neuropsychiatric and neurodegenerative disorders (such as ADHD, anxiety and Alzheimer’s disease. More importantly, NAT is a major therapeutic target for these disorders and provides SPECT and PET with an imaging target to assess drug occupancy levels, amongst other applications (Fig. 25.3).

Most of the initial work on SPECT radiotracers for imaging of the noradrenaline transporter (NAT) has focused on the development of radioiodinated analogues of the noradrenaline reuptake inhibitor, reboxetine. It has lagged behind the tracer development for DAT and SERT somewhat, due to limited availability of suitable radioligands. A few tracers that are selective for NET have recently emerged with several research groups having found the reboxetine derivatives preferable to the nisoxetine series.

Tamagnan and co-workers (2007) worked on the development of SPECT imaging agents for the norepinephrine transporter. They synthesized a series of reboxetine analogues, which was then evaluated for in vitro binding as racemic mixtures. [¹²³I]INER was considered to be the best candidate and was synthesized as the optically pure (S,S) enantiomer. The in vivo binding of [¹²³I]INER was determined by SPECT imaging in an animal model, and the authors found that the tracer’s in vivo specificity, selectivity and kinetics made it a promising agent for SPECT imaging of norepinephrine in vivo (Tamagnan et al. 2007).

Jobson and co-workers (2008) developed a new route for the synthesis of iodinated reboxetine analogues to image the noradrenaline transporter (NAT) with SPECT. The authors prepared 2S,3S- and 2R,3R-iodoreboxetine and performed biological testing against various monoamine transporters, which demonstrated these compounds to be potent and selective for NAT (Jobson et al. 2008).

A specific tracer for quantification of the variation in norepinephrine density will be valuable in gaining insight into the aetiology and pathophysiology of neuropsychiatric disorders such as ADHD and Alzheimer’s. This will especially be of value in identifying therapeutic targets and monitoring treatment response in newly emerging drug treatments, such as atomoxetine. This is the first selective, non-stimulant treatment for ADHD.

Although clinical application may include a primary role in diagnosis, the more promising role of functional imaging seems to be in the fields of drug development, in the evaluation of treatment response and in providing an idea of the severity and prognosis of these conditions.

In addition to the role of functional neuroimaging in the assessment of neural connections involved in impulsivity, several authors have also reported the potential role of molecular imaging in treatment response assessment. By labelling an appropriate tracer with an affinity and selectivity for the molecular target in question to a suitable radioisotope, it is possible to evaluate the kinetics, biodistribution, metabolism and toxicity of particular drugs (Guilloteau and Chalon 2005).

New et al. used ¹⁸F FDG-PET/CT to assess metabolic changes in specific cortical areas in patients with impulsive aggression following treatment with selective serotonin reuptake inhibitors (SSRIs). This group demonstrated increased metabolism in the prefrontal and medial temporal regions (commonly implicated in impulsive aggression) in patients treated with fluoxetine. These patients demonstrated decreased tracer uptake in the aforementioned areas on their baseline scans during their treatment-naive state (New et al. 2004).

Rosa-Neto et al. and Krause and co-workers also used molecular imaging in assessing response to methylphenidate in patients diagnosed with ADHD (Rosa-Neto et al. 2004; Krause et al. 2000). Dose-dependent occupancy of DAT with methylphenidate had been demonstrated by Volkow et al. (1998). Therapeutic doses of this drug have been shown to increase extracellular dopamine concentration. Using ¹¹C-raclopride PET, Rosa-Neto et al. went on to demonstrate a 12 % reduction in the binding potential of striatal dopamine D₂/D₃ receptors during treatment with methylphenidate compared to the baseline pretreatment assessment of adolescents with ADHD. The binding potential assessed with ¹¹C-raclopride PET was found to correlate with the cognitive measures using the TOVA test. They further demonstrated a correlation between the severity of the impulsivity and the magnitude of the binding potential of ¹¹C-raclopride in the striatum of these patients, suggesting a potential role in the evaluation of the prognosis of patients with impulsivity with molecular imaging (Rosa-Neto et al. 2004).

The role of molecular imaging may further be extended to the development of drugs for neuropsychiatric disorders.

This was discussed by Guilloteau and Chalon who explored the potential role of PET and SPECT imaging through in vivo exploration of monoamine transporters. (These are believed to be responsible for the homeostasis of the neurotransmitter pools at the nerve endings.) The authors concluded that in vivo molecular imaging could be used to define the involvement of a specific neurotransmitter and therefore to explain the mechanism of action of drugs through binding site occupancy studies. This therefore makes it possible to evaluate disease evolution and therapeutic effects of treatment and to elucidate the mechanism of action of new drugs (Guilloteau and Chalon 2005).

ADHD is a common and debilitating neuropsychiatric disorder, which frequently starts in childhood and is characterized by age-inappropriate symptoms of hyperactivity, inattentiveness and impulsivity. According to the fourth edition of the Diagnostic and Statistical Manual (DSM-IV), there are three subtypes of ADHD: the predominantly inattentive subtype, the predominantly hyperactive–impulsive subtype and the combined subtype. However, evidence from various neuropsychological studies suggests that “poor inhibitory control is central to ADHD” (Durston 2003).

The understanding of the underlying pathophysiology is complicated by the variety of clinical symptoms with which the condition may present as well as the high incidence of comorbidity. Imaging studies of the past 20 years have shown aberrations in especially the fronto-striatal, parieto-temporal and fronto-cerebellar networks.

Several anatomical studies have shown diffuse volume reductions, which affect the cerebrum and cerebellum. Studies of the basal ganglia have resulted in inconsistent results with some reporting reductions in the right caudate volume and others in the left and no changes noted in the putamen (Castellanos 1996). A meta-analysis by Nakao et al. (2011) has demonstrated that low grey matter in the basal ganglia is the most consistent abnormal finding (Nakao et al. 2011).

The central role of striatal dopamine levels appears undisputed. Hypotheses have linked cognitive impairments to a decrease in DA availability in the prefrontal cortex, while hyperactivity and impulsivity have been linked to a secondary increase in striatal DA (Solanto 2002).

A 2003 review by Sarah Durston provides a comprehensive overview on the anatomical and functional information obtained from various imaging studies prior to 2003, which is conveniently grouped and summarized in table form and which readers are hereby referred to (Durston 2003).

In a recent meta-analysis by Fusar-Poli et al. (2012), the authors evaluated the inconsistent results so far on striatal dopamine receptor density by combining the results of nine nuclear medicine imaging studies, involving either PET or SPECT.

This resulted in a total of 169 ADHD patients with 173 normal controls matched for age, gender and IQ. They extracted striatal-binding potentials (BP) together with clinical, demographic and methodological variables from all publications. However, significant heterogeneity was present and the authors had to use a random-effects model. No publication bias was present and the robustness was proven by sensitivity analysis.

The following studies were included (Table 25.4):