Steve R. Williams

The Effect of Citalopram Pretreatment on Neuronal Responses to Neuropsychological Tasks in Normal Volunteers: An fMRI Study

Changes in serotonin neurotransmission have also been implicated in the etiology and treatment of impulse control disorders, depression, and anxiety. We have investigated the effect of enhancing serotonin function on fundamental brain processes that we have proposed are abnormal in these disorders. In all, 12 male volunteers received citalopram (7.5 mg intravenously) and placebo pretreatment in a single-blind crossover design before undertaking Go/No-go, Loss/No-loss, and covert (aversive) face emotion recognition tasks during functional magnetic resonance imaging (fMRI). Blood oxygenation level dependent responses were analyzed using Statistical Parametric Mapping (SPM2). The tasks activated prefrontal and subcortical regions generally consistent with literature with lateral orbitofrontal cortex (BA47) common to the three tasks. Citalopram pretreatment enhanced the right BA47 responses to the No-go condition, but attenuated this response to aversive faces. Attenuations were seen following citalopram in the medial orbitofrontal (BA11) responses to the No-go and No-loss (ie relative reward compared with Loss) conditions. The right amygdala response to aversive faces was attenuated by citalopram. These results support the involvement of serotonin in modulating basic processes involved in psychiatric disorders but argue for a process-specific, rather than general effect. The technique of combining drug challenge with fMRI (pharmacoMRI) has promise for investigating human psychiatric disorders.

The CREB1-BDNF-NTRK2 Pathway in Depression: Multiple Gene-Cognition-Environment Interactions.

BACKGROUND The neuroplastic pathway, which includes cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor (neurotrophic tyrosine kinase receptor, type 2 [NTRK2]), plays a crucial role in the adaptation of brain to stress, and thus variations of these genes are plausible risk factors for depression. METHODS A population-based sample was recruited, subsets of which were interviewed and underwent functional magnetic resonance imaging. We investigated the association of nine polymorphisms throughout the CREB1-BDNF-NTRK2 pathway with lifetime depression, rumination, current depression severity, negative life events, and sad face emotion processing in a three-level design. RESULTS In the population study, BDNF-rs6265 and CREB1-rs2253206 major alleles were significantly associated with rumination and through rumination with current depression severity. However, childhood adversity increased the risk of lifetime depression in the minor allele carriers of BDNF-rs6265 and CREB1-rs2253206 and in alleles of six other single nucleotide polymorphisms (SNPs). We validated our findings in the interviewed subjects using structural equation modeling. Finally, using functional magnetic resonance imaging, we found that viewing sad faces evoked greater activity in depression-related areas in healthy control subjects possessing the minor alleles of BDNF-rs6265 and CREB1-rs2253206. CONCLUSIONS Genetic variation associated with reduced function in the CREB1-BDNF-NTRK2 pathway has multiple, sometimes opposing, influences on risk mechanisms of depression, but almost all the SNPs studied amplified the effect of childhood adversity. The use of cognitive and neural intermediate phenotypes together with a molecular pathway approach may be critical to understanding how genes influence risk of depression.

Functional magnetic resonance imaging and c-Fos mapping in rats following an anorectic dose of m-chlorophenylpiperazine.

We have used blood-oxygenation-level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) to characterise brain regions responsive to a regulator of appetite. An anorectic dose of the 5-HT(1B/2C) receptor agonist m-chlorophenylpiperazine (mCPP; 3 mg/kg s.c.) was used to compare BOLD contrast fMRI with expression of the c-Fos protein. mCPP was administered to rats, which were then anaesthetised and perfused with fixative 90 min later to allow immunohistochemistry. In a separate experiment, rats were imaged using a T(2)*-weighted gradient echo in a 7 T magnet for 70 min under alpha-chloralose anaesthesia. Both methods detected positive activation in areas of the limbic system: cingulate and orbitofrontal cortices, nucleus accumbens, paraventricular and dorsomedial regions of the hypothalamus. fMRI detected increased signal in the pontine nuclei, the hippocampal formation and olfactory cortex, areas that did not display c-Fos. In addition, BOLD signal was diminished in the ventral tegmental area, preoptic area and the cerebellum-presumably due to decreased neuronal signalling and, therefore, unlikely to display c-Fos. Activity in the limbic system may reflect the appetitive agonist activity of mCPP at the 5-HT(2C) receptor. We conclude that c-Fos provides excellent spatial information but is less useful for detecting inhibited regions, whereas fMRI provides greater temporal resolution. Thus, the two methodologies provide complementary details of brain activity following pharmacological challenge.

Neuronal correlates and serotonergic modulation of behavioural inhibition and reward in healthy and antisocial individuals

Individuals with antisocial personality disorder (ASPD) are impulsive and show impairment in reinforcement processing. There is increasing evidence for a neurobiological basis of psychopathy, which shares some of the characteristics of ASPD, but research on the neuronal correlates of neuropsychological processes in ASPD remains limited. Furthermore, no research has examined the effects of serotonergic manipulation on brain activations in antisocial groups. In this study, 25 male participants with ASPD (mean age 42.1) and 32 male control participants (mean age 30.5; 25 participants providing usable scans) were randomly allocated to receive the 5-HT(2C)-agonist mCPP or placebo. Participants were scanned using functional magnetic resonance imaging (fMRI) during a behavioural inhibition (Go/NoGo) and a reward task. In comparison to healthy controls the ASPD group showed reduced task related activations in the dorsolateral prefrontal cortex (DLPFC) but increased signal in the pre/subgenual anterior cingulate cortex (ACC) in the Go/No-Go task and increased activation in OFC in the reward task. mCPP modulated brain responses in both tasks in the whole group. Interactions between group and drug occured in bilateral OFC, caudate and ventral pallidum during the reward task but no significant interactions were found in the Go/No-Go task. This suggests that ASPD involves altered serotonin modulation of reward, but not motor inhibition pathways. These findings suggest that ASPD involves altered DLPFC, ACC and OFC function. Altered serotonergic modulation of reward pathways seen in the ASPD group raises the possibility that targeting serotonin systems may be therapeutic.

Power Calculations for Multicenter Imaging Studies Controlled by the False Discovery Rate

Magnetic resonance imaging (MRI) is widely used in brain imaging research (neuroimaging) to explore structural and functional changes across dispersed neural networks visible only via multisubject experiments. Multicenter investigations are an effective way to increase recruitment rates. This article describes image‐based power calculations for a two‐group, cross‐sectional design specified by the mean effect size and its standard error, sample size, false discovery rate (FDR), and size of the network (i.e., proportion of image locations) that truly demonstrates an effect. Minimum sample size (for fixed effect size) and the minimum effect size (for fixed sample size) are calculated by specifying the acceptable power threshold. Within‐center variance was estimated in five participating centers by repeat MRI scanning of 12 healthy participants from whom distributions of gray matter were estimated. The effect on outcome measures when varying FDR and the proportion of true positives is presented. Their spatial patterns reflect within‐center variance, which is consistent across centers. Sample sizes 3–6 times larger are needed when detecting effects in subcortical regions compared to the neocortex. Hypothesized multicenter studies of patients with first episode psychosis and control participants were simulated with varying proportions of the cohort recruited at each center. There is little penalty to sample size for recruitment at five centers compared to the center with the lowest variance alone. At 80% power 80 participants per group are required to observe differences in gray matter in high variance regions. Hum Brain Mapp, 2010.

Functional neuroimaging demonstrates that ghrelin inhibits the central nervous system response to ingested lipid

Objective Gut-derived humoural factors activate central nervous system (CNS) mechanisms controlling energy intake and expenditure, and autonomic outflow. Ghrelin is secreted from the stomach and stimulates food intake and gastric emptying, but the relevant mechanisms are poorly understood. Nutrient-activated CNS systems can be studied in humans by physiological/pharmacological MRI (phMRI). This method has been used to examine the CNS responses to exogenous ghrelin. Design phMRI was used to study the CNS responses in healthy people to a ghrelin bolus (0.3 nmol/kg, intravenous) in the post-prandial state, and an intravenous infusion of ghrelin (1.25 pmol/kg/min) alone and after intragastric lipid (dodecanoate, C12) in people who have fasted. Results A ghrelin bolus decreased the blood oxygenation level dependent (BOLD) signal detected by phMRI in feeding-activated areas of the CNS in the post-prandial state. Infusion of ghrelin reversed the effect of C12 in delaying gastric emptying but had no effect on hunger. Intragastric C12 caused strong bilateral activation of a matrix of CNS areas, including the brain stem, hypothalamus and limbic areas which was attenuated by exogenous ghrelin. Ghrelin infusion alone had a small but significant stimulatory effect on CNS BOLD signals. Conclusion Ghrelin inhibits activation of the hypothalamus and brain stem induced by ingested nutrients, suggesting a role in suppression of gut-derived satiety signals in humans.

Assessing the Efficacy of Nano- and Micro-Sized Magnetic Particles as Contrast Agents for MRI Cell Tracking

Iron-oxide based contrast agents play an important role in magnetic resonance imaging (MRI) of labelled cells in vivo. Currently, a wide range of such contrast agents is available with sizes varying from several nanometers up to a few micrometers and consisting of single or multiple magnetic cores. Here, we evaluate the effectiveness of these different particles for labelling and imaging stem cells, using a mouse mesenchymal stem cell line to investigate intracellular uptake, retention and processing of nano- and microsized contrast agents. The effect of intracellular confinement on transverse relaxivity was measured by MRI at 7 T and in compliance with the principles of the ‘3Rs’, the suitability of the contrast agents for MR-based cell tracking in vivo was tested using a chick embryo model. We show that for all particles tested, relaxivity was markedly reduced following cellular internalisation, indicating that contrast agent relaxivity in colloidal suspension does not accurately predict performance in MR-based cell tracking studies. Using a bimodal imaging approach comprising fluorescence and MRI, we demonstrate that labelled MSC remain viable following in vivo transplantation and can be tracked effectively using MRI. Importantly, our data suggest that larger particles might confer advantages for longer-term imaging.

A voxel-based morphometric MRI study in men with borderline personality disorder: preliminary findings

OBJECTIVE There is increasing evidence for subtle changes in brain morphology and function in patients with borderline personality disorder (BPD). Structural brain imaging studies show lower volume in frontal, temporal and parietal brain regions than in healthy controls. The aim of our preliminary study of men with BPD was to investigate structural brain changes and their relationship with a measure of impulsivity. METHODS We examined seven male patients with BPD and six control men using voxel-based morphometry. Analysis of covariance was carried out to assess regionally specific differences in grey and white matter (WM) volumes. Correlations between trait impulsivity as measured using the Impulsiveness-Venturesomeness-Empathy scale and brain volumes were studied. RESULTS Compared with healthy men, men with BPD had similar WM volumes but smaller grey matter (GM) volumes in frontal, temporal and parietal cortices. The latter were negatively correlated with trait impulsivity. CONCLUSIONS Our findings fit with previous reports of smaller regional GM volumes reported in women with BPD, and suggest that in men there may be an association between smaller GM volumes and impulsivity.

5-HT2C antagonism blocks blood oxygen level-dependent pharmacological-challenge magnetic resonance imaging signal in rat brain areas related to feeding

In this study, pharmacological‐challenge magnetic resonance imaging was used to further characterize the central action of serotonin on feeding. In both feeding and pharmacological‐challenge magnetic resonance imaging experiments, we combined 5‐HT1B/2C agonist m‐chlorophenylpiperazine (mCPP) challenge with pre‐treatment with the selective 5‐HT1B and 5‐HT2C receptor antagonists, SB 224289 (2.5 mg/kg) and SB 242084 (2 mg/kg), respectively. Subcutaneous injection of mCPP (3 mg/kg) completely blocked fast‐induced refeeding in freely behaving, non‐anaesthetized male rats, an effect that was not modified by the 5‐HT1B receptor antagonist but was partially reversed by the 5‐HT2C receptor antagonist. mCPP alone induced both positive and negative blood oxygen level‐dependent (BOLD) responses in the brains of anaesthetized rats, including in the limbic system and basal ganglia. Overall, the 5‐HT2C antagonist SB 242084 reversed the effects elicited by mCPP, whereas the 5‐HT1B antagonist SB 224289 had virtually no impact. SB 242084 eliminated BOLD signal in nuclei associated with the limbic system and diminished activation in basal ganglia. In addition, BOLD signal was returned to baseline levels in the cortical regions and cerebellum. These results suggest that mCPP may reduce food intake by acting specifically on brain circuits that are modulated by 5‐HT2C receptors in the rat.

Differential effects of anaesthesia on the phMRI response to acute ketamine challenge

AIMS: Pharmacological-challenge magnetic resonance imaging (phMRI) is powerful new tool enabling researchers to map the central effects of neuroactive drugs in vivo. To employ this technique pre-clinically, head movements and the stress of restraint are usually reduced by maintaining animals under general anaesthesia. However, interactions between the drug of interest and the anaesthetic employed may potentially confound data interpretation. NMDA receptor (NMDAR) antagonists used widely to mimic schizophrenia have recently been shown to interact with the anaesthetic halothane. It may be the case that neural and cerebrovascular responses to NMDAR antagonists are dependent on the types of anaesthetic used. METHODOLOGY: We compared the phMRI response to NMDAR antagonist ketamine in rats maintained under α-chloralose to those under isoflurane anaesthesia. A randomized placebo/vehicle controlled design was used in each of the anaesthetic groups. RESULTS: Changes in the anaesthetic agent resulted in two very different profiles of activity. In the case of α-chloralose, positive activations in cortical and sub-cortical structures reflected a response which was similar to patterns seen in healthy human volunteers and metabolic maps of conscious rats. However, the use of isoflurane completely reversed such effects, causing widespread deactivations in the cortex and hippocampus. CONCLUSION: This study provides initial evidence for a drug-anesthetic interaction between ketamine and isoflurane that is very different from responses to α-chloralose-ketamine.