Paul Shotbolt

Neuroimaging Auditory Hallucinations in Schizophrenia: From Neuroanatomy to Neurochemistry and Beyond

Despite more than 2 decades of neuroimaging investigations, there is currently insufficient evidence to fully understand the neurobiological substrate of auditory hallucinations (AH). However, some progress has been made with imaging studies in patients with AH consistently reporting altered structure and function in speech and language, sensory, and nonsensory regions. This report provides an update of neuroimaging studies of AH with a particular emphasis on more recent anatomical, physiological, and neurochemical imaging studies. Specifically, we provide (1) a review of findings in schizophrenia and nonschizophrenia voice hearers, (2) a discussion regarding key issues that have interfered with progress, and (3) practical recommendations for future studies.

Connectivity-Based Functional Analysis of Dopamine Release in the Striatum Using Diffusion-Weighted MRI and Positron Emission Tomography

The striatum acts in conjunction with the cortex to control and execute functions that are impaired by abnormal dopamine neurotransmission in disorders such as Parkinsons and schizophrenia. To date, in vivo quantification of striatal dopamine has been restricted to structure-based striatal subdivisions. Here, we present a multimodal imaging approach that quantifies the endogenous dopamine release following the administration of d-amphetamine in the functional subdivisions of the striatum of healthy humans with [(11)C]PHNO and [(11)C]Raclopride positron emission tomography ligands. Using connectivity-based (CB) parcellation, we subdivided the striatum into functional subregions based on striato-cortical anatomical connectivity information derived from diffusion magnetic resonance imaging (MRI) and probabilistic tractography. Our parcellation showed that the functional organization of the striatum was spatially coherent across individuals, congruent with primate data and previous diffusion MRI studies, with distinctive and overlapping networks. d-amphetamine induced the highest dopamine release in the limbic followed by the sensory, motor, and executive areas. The data suggest that the relative regional proportions of D2-like receptors are unlikely to be responsible for this regional dopamine release pattern. Notably, the homogeneity of dopamine release was significantly higher within the CB functional subdivisions in comparison with the structural subdivisions. These results support an association between local levels of dopamine release and cortical connectivity fingerprints.

Dopaminergic Function in the Psychosis Spectrum: An [18F]-DOPA Imaging Study in Healthy Individuals With Auditory Hallucinations

BACKGROUND The psychosis phenotype appears to exist in the population as a continuum, but it is not clear if subclinical psychotic symptoms and psychotic disorders share the same neurobiology. We investigated whether the dopaminergic dysfunction seen in psychotic disorders is also present in healthy, well-functioning people with hallucinations. METHODS We compared dopamine synthesis capacity (using 6-[(18)F]fluoro-L-DOPA [[(18)F]-DOPA] positron emission tomography imaging) in 16 healthy individuals with frequent persistent auditory verbal hallucinations (hallucinating group) with that in 16 matched controls. RESULTS There was no significant difference in dopamine synthesis capacity in the striatum, or its functional subdivisions, between groups and no relationship between subclinical psychotic symptom severity or schizotypal traits and dopamine synthesis capacity in the hallucinating group. CONCLUSIONS Altered dopamine synthesis capacity is unlikely to underlie subclinical hallucinations, suggesting that although there may be a phenomenological psychosis continuum, there are distinctions at the neurobiological level.

Striatal dopamine synthesis capacity in twins discordant for schizophrenia

BACKGROUND Elevated striatal dopamine synthesis capacity is thought to be fundamental to the pathophysiology of schizophrenia and has also been reported in people at risk of psychosis. It is therefore unclear if striatal hyperdopaminergia is a vulnerability marker for schizophrenia, or a state feature related to the psychosis itself. Relatives of patients with schizophrenia are themselves at increased risk of developing the condition. In this study we examined striatal dopamine synthesis capacity in both members of twin pairs discordant for schizophrenia. METHOD In vivo striatal dopamine synthesis capacity was examined using fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scans in seven twin pairs discordant for schizophrenia and in a control sample of 10 healthy control twin pairs. RESULTS Striatal 18F-DOPA uptake was not elevated in the unaffected co-twins of patients with schizophrenia (p=0.65) or indeed in the twins with schizophrenia (p=0.89) compared to the control group. Levels of psychotic symptoms were low in the patients with schizophrenia who were in general stable [mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total=56.8 (25.5)] whereas the unaffected co-twins were largely asymptomatic. CONCLUSIONS Striatal dopamine synthesis capacity is not elevated in symptom-free individuals at genetic risk of schizophrenia, or in well-treated stable patients with chronic schizophrenia. These findings suggest that striatal hyperdopaminergia is not a vulnerability marker for schizophrenia.

Nature or Nurture? Determining the Heritability of Human Striatal Dopamine Function: an (18F)-DOPA PET Study

Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.

The Enduring Centrality of Dopamine in the Pathophysiology of Schizophrenia: In Vivo Evidence from the Prodrome to the First Psychotic Episode

Abstract Dopamine has been thought to be central to the pathophysiology of schizophrenia for the last four decades. However, the last decade or so has seen a considerable advance in understanding of dopamine’s role in the neurobiology of schizophrenia. This has been informed by advances in neuroimaging, preclinical models, and the study of the prodrome to schizophrenia. Studies using these approaches have identified that the major locus of dopaminergic dysfunction is presynaptic, characterized by elevated dopamine synthesis and release capacity. Moreover, this is seen in the prodrome to the illness, is linked to the symptoms, and increases with the onset of frank symptoms. It has also become clear that there is no marked alteration in dopamine transporter or D2/3 receptor availability in schizophrenia in general, and, similarly, there do not seem to be D2/3 receptor alterations in people at high clinical risk of psychosis. These findings highlight the enduring role of dopamine in the onset of schizophrenia. They suggest that presynaptic dopamine dysregulation underlies the onset of psychosis and are in line with an integrative model accounting for many of the genetic and environmental risk factors for schizophrenia.

Does human presynaptic striatal dopamine function predict social conformity

Socially desirable responding (SDR) is a personality trait which reflects either a tendency to present oneself in an overly positive manner to others, consistent with social conformity (impression management (IM)), or the tendency to view one’s own behaviour in an overly positive light (self-deceptive enhancement (SDE)). Neurochemical imaging studies report an inverse relationship between SDR and dorsal striatal dopamine D2/3 receptor availability. This may reflect an association between SDR and D2/3 receptor expression, synaptic dopamine levels or a combination of the two. In this study, we used a [18F]-DOPA positron emission tomography (PET) image database to investigate whether SDR is associated with presynaptic dopamine function. Striatal [18F]-DOPA uptake, ( k i cer , min-1), was determined in two independent healthy participant cohorts (n=27 and 19), by Patlak analysis using a cerebellar reference region. SDR was assessed using the revised Eysenck Personality Questionnaire (EPQ-R) Lie scale, and IM and SDE were measured using the Paulhus Deception Scales. No significant associations were detected between Lie, SDE or IM scores and striatal [18F]-DOPA k i cer . These results indicate that presynaptic striatal dopamine function is not associated with social conformity and suggests that social conformity may be associated with striatal D2/3 receptor expression rather than with synaptic dopamine levels.

MR-DTI and PET multimodal imaging of dopamine release within subdivisions of basal ganglia

The basal ganglia is a group of anatomical nuclei, functionally organised into limbic, associative and sensorimotor regions, which plays a central role in dopamine related neurological and psychiatric disorders. In this study, we combine two imaging modalities to enable the measurement of dopamine release in functionally related subdivisions of the basal ganglia. [11C]−(+)-PHNO Positron Emission Tomography (PET) measurements in the living human brain pre- and post-administration of amphetamine allow for the estimation of regional dopamine release. Combined Magnetic Resonance Diffusion Tensor Imaging (MR-DTI) data allows for the definition of functional territories of the basal ganglia from connectivity information. The results suggest that there is a difference in dopamine release among the connectivity derived functional subdivisions. Dopamine release is highest in the limbic area followed by the sensorimotor and then the associative area with this pattern reflected in both striatum and pallidum.

CHARACTERISTICS OF FUNCTIONAL AND ORGANIC STROKE MIMICS

Aim To establish whether the groups of patients with conditions that mimic Stroke display certain characteristics which differentiate them from patients with true Stroke. Methods All admissions to Kings College Hospitals Hyper–Acute Stroke Unit (HASU) over 12 months were reviewed using SINAP data. Subgroups of functional stroke mimics (FSM) and medical mimics (MM) were identified through consensus between experts. Statistical analysis comparing these subgroups to Stroke admissions was performed using Chi2, Kruskal–Wallis and Mann–Whitney methods. Results FSM patients (N=98) were younger (mean age 49, p<0.001) and mostly females (63.27%, p=0.003). They had the shortest stay on HASU and were more likely to have had MRI during admission. Compared to MM (N=198), FSM were more likely to have had history of Asthma, Back Pain, Migraine or Depression (p=0.001). FSM presented later compared to Strokes (N=904) (latency FSM 4.57 hrs vs. Stroke 2.17 hrs, p<0.001) and were less likely to present with cortical features (Visual disturbances, Dysphasia or Neglect, p<0.001) or facial weakness or numbness. MM were much more likely to present with altered consciousness (MM 15.34% vs. FSM 4.08% vs. Stroke 1.99%, p<0.001). Conclusion Both functional and medical stroke mimics appear to have distinct features that could aid the diagnostic process.

A combined diffusion tensor imaging (DTI) and [11C]-(+)-PHNO positron emission tomography (PET) study to quantify dopamine D3/D2 receptors in pallidum

Purpose: Pallidum, is a major component of the basal ganglia and has an important role in reward, addiction and movement disorders. Anatomically, pallidum is segregated into globus pallidus external (GPe), globus pallidus internal (GPi), and ventral pallidum (VP). Post-mortem and in-vivo studies suggest that there is a heterogeneous distribution of the dopamine D3 receptors (D3R) in pallidum. Post-mortem, the highest concentration is in the VP and GPi [1–2]. In-vivo, in [C]-(+)-PHNO PET scans, we observed the highest signal in VP and anterior segments of the GP. This study aimed to quantify the D3R in-vivo in the pallidum using [C]-(+)-PHNO PET, structural MRI and DTI to distinguish its GPi/GPe subdivisions that are not easily differentiated in conventional T1-weighted (T1w) or T2-weighted (T2w) MRI.