Test-retest reliability of the BOLD pharmacological MRI response to ketamine in healthy volunteers.

The pharmacological MRI (phMRI) technique is being increasingly used in both pre-clinical and clinical models to investigate pharmacological effects on task-free brain function. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, induces a strong phMRI response and represents a promising pharmacological model to investigate the role of glutamatergic abnormalities in psychiatric symptomatology. The aim of this study was to assess whether the brain response to ketamine is reliable in order to validate ketamine phMRI as a mechanistic marker of glutamatergic dysfunction and to determine its utility in repeated measures designs to detect the modulatory effect of other drugs. Thus we assessed the test-retest reliability of the brain response to ketamine in healthy volunteers and identified an optimal modelling approach with reliability as our selection criterion. PhMRI data were collected from 10 healthy male participants, at rest, on two separate occasions. Subanaesthetic doses of I.V. ketamine infusion (target plasma levels 50 ng/mL and 75 ng/mL) were administered in both sessions. Test-retest reliability of the ketamine phMRI response was assessed voxel-wise and on pre-defined ROIs for a range of temporal design matrices including different combinations of nuisance regressors designed to model shape variance, linear drift and head motion. Effect sizes are also reported. All models showed a significant and widespread response to low-dose ketamine in predicted cerebral networks and as expected, increasing the number of model parameters improved model fit. Reliability of the predefined ROIs differed between the different models assessed. Using reliability as the selection criterion, a model capturing subject motion and linear drift performed the best across two sessions. The anatomical distribution of effects for all models was consistent with results of previous imaging studies in humans with BOLD signal increases in regions including midline cingulate and supracingulate cortex, thalamus, insula, anterior temporal lobe and ventrolateral prefrontal structures, and BOLD signal decreases in the subgenual cingulate cortex. This study represents the first investigation of the test-retest reliability of the BOLD phMRI response to acute ketamine challenge. All models tested were effective at describing the ketamine response although the design matrix associated with the highest reliability may represent a robust and well-characterised ketamine phMRI assay more suitable for repeated-measures designs. This ketamine assay is applicable as a model of neurotransmitter dysfunction suitable as a pharmacodynamic imaging tool to test and validate modulatory interventions, as a model of NMDA hypofunction in psychiatric disorders, and may be adapted to understand potential antidepressant and analgesic effects of NMDAR antagonists.

Quantifying the attenuation of the ketamine pharmacological magnetic resonance imaging response in humans: a validation using antipsychotic and glutamatergic agents.

Ketamine acts as an N-methyl-D-aspartate receptor antagonist and evokes psychotomimetic symptoms resembling schizophrenia in healthy humans. Imaging markers of acute ketamine challenge have the potential to provide a powerful assay of novel therapies for psychiatric illness, although to date this assay has not been fully validated in humans. Pharmacological magnetic resonance imaging (phMRI) was conducted in a randomized, placebo-controlled crossover design in healthy volunteers. The study comprised a control and three ketamine infusion sessions, two of which included pretreatment with lamotrigine or risperidone, compounds hypothesized to reduce ketamine-induced glutamate release. The modulation of the ketamine phMRI response was investigated using univariate analysis of prespecified regions and a novel application of multivariate analysis across the whole-brain response. Lamotrigine and risperidone resulted in widespread attenuation of the ketamine-induced increases in signal, including the frontal and thalamic regions. A contrasting effect across both pretreatments was observed only in the subgenual prefrontal cortex, in which ketamine produced a reduction in signal. Multivariate techniques proved successful in both classifying ketamine from placebo (100%) and identifying the probability of scans belonging to the ketamine class (ketamine pretreated with placebo: 0.89). Following pretreatment, these predictive probabilities were reduced to 0.58 and 0.49 for lamotrigine and risperidone, respectively. We have provided clear demonstration of a ketamine phMRI response and its attenuation with both lamotrigine and risperidone. The analytical methodology used could be readily applied to investigate the mechanistic action of novel compounds relevant for psychiatric disorders such as schizophrenia and depression.

An fMRI study of prefrontal dysfunction and symptomatic recovery in schizophrenia.

OBJECTIVE: Prefrontal cortical dysfunction has been implicated in the pathophysiology of schizophrenia but it is unclear to what extent these are related to changes in symptomatology as well as task demand. METHOD: We examined the neural correlates of symptom change and task demand during a longitudinal functional magnetic resonance imaging (fMRI) study using a verbal fluency task with differential task demands in patients with schizophrenia and matched healthy control subjects. The fMRI data were acquired using clustered acquisition technique, enabling ongoing monitoring of behavioural responses, in the patient group on two occasions separated by 6-8 weeks, and the control group at baseline. RESULTS: Positive psychotic symptoms were significantly reduced over the 6-8-week duration of the study. This change was associated with increased activation within the left middle frontal gyrus and decreased activation of the left precuneus. An interaction between symptom change and task demand was evident in the activation of the left middle frontal gyrus. The decrease in positive symptoms was associated with normalisation of activation in the dorsolateral prefrontal cortex and a decrease in parietal activation during the verbal fluency task. CONCLUSION: The data supports the role of dysfunctional prefronto-parietal relationships in the genesis of positive psychotic symptoms.

Delineation between different components of chronic pain using dimension reduction - an ASL fMRI study in hand osteoarthritis.

BACKGROUND: Traditional psychometric measures aimed at characterizing the pain experience often show considerable overlap, due to interlinked affective and modulatory processes under central nervous system control. Neuroimaging studies have been employed to investigate this complexity of pain processing, in an attempt to provide a quantifiable, adjunctive description of pain perception. In this exploratory study, we examine psychometric and neuroimaging data from 38 patients with painful osteoarthritis of the carpometacarpal joint. We had two aims: first, to utilize principal component analysis (PCA) as a dimension reduction strategy across multiple self-reported endpoints of pain, cognitive and affective functioning; second, to investigate the relationship between identified dimensions and regional cerebral blood flow (rCBF) as an indirect measure of brain activity underpinning their ongoing pain experiences. METHODS: Psychometric data were collected using validated questionnaires. Quantitative estimates of rCBF were acquired using pseudo-continuous arterial spin-labelled functional magnetic resonance imaging. RESULTS: Two principal components were identified that accounted for 73% of data variance; one related to pain scores and a second to psychological traits. Voxel-wise multiple regression analysis revealed a significant negative association between the 'pain score' component and rCBF to a right temporal lobe cluster, including the amygdala and the parahippocampal cortex. CONCLUSION: We suggest this association may represent a coping mechanism that aims to reduce fear-related pain-anxiety. Further investigation of central brain processing mechanisms in osteoarthritis-related pain may offer insights into more effective therapeutic strategies. SIGNIFICANCE: This study demonstrates that dimension reduction using PCA allows insight into pain perception and its affective components in relation to brain activation patterns in patients with painful hand osteoarthritis.

Investigating virtual reality navigation in amnestic mild cognitive impairment using fMRI.

Spatial navigation requires a well-established network of brain regions, including the hippocampus, caudate nucleus, and retrosplenial cortex. Amnestic Mild Cognitive Impairment (aMCI) is a condition with predominantly memory impairment, conferring a high predictive risk factor for dementia. aMCI is associated with hippocampal atrophy and subtle deficits in spatial navigation. We present the first use of a functional Magnetic Resonance Imaging (fMRI) navigation task in aMCI, using a virtual reality analog of the Radial Arm Maze. Compared with controls, aMCI patients showed reduced activity in the hippocampus bilaterally, retrosplenial cortex, and left dorsolateral prefrontal cortex. Reduced activation in key areas for successful navigation, as well as additional regions, was found alongside relatively normal task performance. Results also revealed increased activity in the right dorsolateral prefrontal cortex in aMCI patients, which may reflect compensation for reduced activations elsewhere. These data support suggestions that fMRI spatial navigation tasks may be useful for staging of progression in MCI.

Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied in relation to the glutamate hypothesis of schizophrenia and increases dissociation, positive and negative symptom ratings. Ketamine effects brain function through changes in brain activity; these activity patterns can be modulated by pre-treatment of compounds known to attenuate the effects of ketamine on glutamate release. Ketamine also has marked effects on brain connectivity; we predicted that these changes would also be modulated by compounds known to attenuate glutamate release. Here, we perform task-free pharmacological magnetic resonance imaging (phMRI) to investigate the functional connectivity effects of ketamine in the brain and the potential modulation of these effects by pre-treatment of the compounds lamotrigine and risperidone, compounds hypothesised to differentially modulate glutamate release. Connectivity patterns were assessed by combining windowing, graph theory and multivariate Gaussian process classification. We demonstrate that ketamine has a robust effect on the functional connectivity of the human brain compared to saline (87.5 % accuracy). Ketamine produced a shift from a cortically centred, to a subcortically centred pattern of connections. This effect is strongly modulated by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based on the differential effect of these compounds on ketamine response, we suggest the observed connectivity effects are primarily due to NMDAR blockade rather than downstream glutamatergic effects. The connectivity changes contrast with amplitude of response for which no differential effect between pre-treatments was detected, highlighting the necessity of these techniques in forming an informed view of the mechanistic effects of pharmacological compounds in the human brain.

Alterations in working memory networks in amnestic mild cognitive impairment.

Patients with amnestic mild cognitive impairment (aMCI) show preserved or mildly impaired working memory, despite their deficits in episodic memory. We aimed to identify performance and/or neural differences between aMCI patients and matched controls on a standard working memory fMRI task. Neuropsychological assessment demonstrated aMCI impairments in verbal and visual episodic long-term memory, with intact IQ and executive function. Participants completed a standard three-level N-back task where patients were unimpaired. Functional activations in the control group were found in expected areas, including the inferior parietal lobule and dorsolateral prefrontal cortex. Group differences were found in the insula and lingual gyrus and, in a region of interest analysis, in the hippocampus. In all cases, these were caused by an absence of task-related deactivations in the aMCI group. The results are consistent with reports of failure in task-related deacivations in aMCI and could be early indications of pathology.

An evoked auditory response fMRI study of the effects of rTMS on putative AVH pathways in healthy volunteers.

BACKGROUND: Auditory verbal hallucinations (AVH) are the most prevalent symptom in schizophrenia. They are associated with increased activation within the temporoparietal cortices and are refractory to pharmacological and psychological treatment in approximately 25% of patients. Low frequency repetitive transcranial magnetic stimulation (rTMS) over the temporoparietal cortex has been demonstrated to be effective in reducing AVH in some patients, although results have varied. The cortical mechanism by which rTMS exerts its effects remain unknown, although data from the motor system is suggestive of a local cortical inhibitory effect. We explored neuroimaging differences in healthy volunteers between application of a clinically utilized rTMS protocol and a sham rTMS equivalent when undertaking a prosodic auditory task. METHOD: Single-blind placebo controlled fMRI study of 24 healthy volunteers undertaking an auditory temporoparietal activation task, who received either right temporoparietal rTMS or sham RTMS. RESULTS: The main effect of group was bilateral inferior parietal deactivation following real rTMS. An interaction of group and task type showed deactivation during real rTMS in the right superior temporal gyrus (STG), left thalamus, left postcentral gyrus and cerebellum. However, the left parietal lobe showed an increase in activation following right sided real rTMS, but this increase was specific to a non-linguistic, tone-sequence task. CONCLUSION: rTMS does cause local inhibitory effects, not only in the underlying region of application, but also in functionally connected cortical regions. However, there is also a related, task dependent, increase in activation within selected cortical areas in the contralateral hemisphere; these are likely to reflect compensatory mechanisms, and such cortical activation may in some cases contribute to, or retard, some of the therapeutic effects seen with rTMS.

Prosodic discrimination in patients with schizophrenia.

Fifteen patients with prominent positive symptoms of schizophrenia and 15 normal controls performed verbal prosodic and pure musical discrimination tasks, with changes in pitch and timing parameters. The patients' performance was comparable to that of controls on the discrimination of terminal pitch changes, but significantly poorer on the more difficult internal pitch discrimination. The latter deficit was positively correlated with the severity of their positive symptoms. The results suggest that patients have a deficit in processing fundamental aspects of prosody, which is associated with the presence of positive symptoms.