Transcriptomic and cellular decoding of functional brain connectivity changes reveal regional brain vulnerability to pro- and anti-inflammatory therapies.

BACKGROUND: Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood. METHODS: We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment. RESULTS: Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms. CONCLUSIONS: Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.

A morphometric signature of depressive symptoms in unmedicated patients with mood disorders.

OBJECTIVE: A growing literature indicates that unipolar depression and bipolar depression are associated with alterations in grey matter volume. However, it is unclear to what degree these patterns of morphometric change reflect symptom dimensions. Here, we aimed to predict depressive symptoms and hypomanic symptoms based on patterns of grey matter volume using machine learning. METHOD: We used machine learning methods combined with voxel-based morphometry to predict depressive and self-reported hypomanic symptoms from grey matter volume in a sample of 47 individuals with unmedicated unipolar and bipolar depression. RESULTS: We were able to predict depressive severity from grey matter volume in the anteroventral bilateral insula in both unipolar depression and bipolar depression. Self-reported hypomanic symptoms did not predict grey matter loss with a significant degree of accuracy. DISCUSSION: The results of this study suggest that patterns of grey matter volume alteration in the insula are associated with depressive symptom severity across unipolar and bipolar depression. Studies using other modalities and exploring other brain regions with a larger sample are warranted to identify other systems that may be associated with depressive and hypomanic symptoms across affective disorders.

Chronic exposure to haloperidol and olanzapine leads to common and divergent shape changes in the rat hippocampus in the absence of grey-matter volume loss.

BACKGROUND: One of the most consistently reported brain abnormalities in schizophrenia (SCZ) is decreased volume and shape deformation of the hippocampus. However, the potential contribution of chronic antipsychotic medication exposure to these phenomena remains unclear. METHOD: We examined the effect of chronic exposure (8 weeks) to clinically relevant doses of either haloperidol (HAL) or olanzapine (OLZ) on adult rat hippocampal volume and shape using ex vivo structural MRI with the brain retained inside the cranium to prevent distortions due to dissection, followed by tensor-based morphometry (TBM) and elastic surface-based shape deformation analysis. The volume of the hippocampus was also measured post-mortem from brain tissue sections in each group. RESULTS: Chronic exposure to either HAL or OLZ had no effect on the volume of the hippocampus, even at exploratory thresholds, which was confirmed post-mortem. In contrast, shape deformation analysis revealed that chronic HAL and OLZ exposure lead to both common and divergent shape deformations (q = 0.05, FDR-corrected) in the rat hippocampus. In particular, in the dorsal hippocampus, HAL exposure led to inward shape deformation, whereas OLZ exposure led to outward shape deformation. Interestingly, outward shape deformations that were common to both drugs occurred in the ventral hippocampus. These effects remained significant after controlling for hippocampal volume suggesting true shape changes. CONCLUSIONS: Chronic exposure to either HAL or OLZ leads to both common and divergent effects on rat hippocampal shape in the absence of volume change. The implications of these findings for the clinic are discussed.

White-matter relaxation time and myelin water fraction differences in young adults with autism.

BACKGROUND: Increasing evidence suggests that autism is associated with abnormal white-matter (WM) anatomy and impaired brain 'connectivity'. While myelin plays a critical role in synchronized brain communication, its aetiological role in autistic symptoms has only been indirectly addressed by WM volumetric, relaxometry and diffusion tensor imaging studies. A potentially more specific measure of myelin content, termed myelin water fraction (MWF), could provide improved sensitivity to myelin alteration in autism. METHOD: We performed a cross-sectional imaging study that compared 14 individuals with autism and 14 age- and IQ-matched controls. T 1 relaxation times (T 1), T 2 relaxation times (T 2) and MWF values were compared between autistic subjects, diagnosed using the Autism Diagnostic Interview - Revised (ADI-R), with current symptoms assessed using the Autism Diagnostic Observation Schedule (ADOS) and typical healthy controls. Correlations between T 1, T 2 and MWF values with clinical measures [ADI-R, ADOS, and the Autism Quotient (AQ)] were also assessed. RESULTS: Individuals with autism showed widespread WM T 1 and MWF differences compared to typical controls. Within autistic individuals, worse current social interaction skill as measured by the ADOS was related to reduced MWF although not T 1. No significant differences or correlations with symptoms were observed with respect to T 2. CONCLUSIONS: Autistic individuals have significantly lower global MWF and higher T 1, suggesting widespread alteration in tissue microstructure and biochemistry. Areas of difference, including thalamic projections, cerebellum and cingulum, have previously been implicated in the disorder; however, this is the first study to specifically indicate myelin alteration in these regions.

Alterations in brain structure in adults with anorexia nervosa and the impact of illness duration.

BACKGROUND: Brain structure alterations have been reported in anorexia nervosa, but findings have been inconsistent. This may be due to inadequate sample size, sample heterogeneity or differences in methodology. METHOD: High resolution magnetic resonance images were acquired of 33 adult participants with anorexia nervosa and 33 healthy participants, the largest study sample to date, in order to assess whole-brain volume, ventricular cerebrospinal fluid, white matter and grey matter volume. Voxel-based morphometry was conducted to assess regional grey matter volume. Levels of depression, anxiety, obsessionality and eating disorder-related symptoms were measured and used to explore correlations with brain structure. RESULTS: Participants with anorexia nervosa had smaller brain volumes as well as a global decrease in grey matter volume with ventricular enlargement. Voxel-based morphometry revealed a decrease in grey matter volume spanning across the cerebellum, temporal, frontal and occipital lobes. A correlation was found between grey matter volume loss and duration of illness in the cerebellum and mesencephalon. No correlations were found with clinical measures. CONCLUSIONS: Findings are in accordance with several previous studies on brain structure and match functional studies that have assessed the symptomatology of anorexia nervosa, such as body image distortion and cognitive bias to food. The correlation with duration of illness supports the implication of cerebellar atrophy in the maintenance of low weight and disrupted eating behaviour and illustrates its role in the chronic phase of anorexia nervosa. The lack of other correlations suggests that these findings are not related to the presence of co-morbid disorders.

Multivariate decoding of brain images using ordinal regression.

Neuroimaging data are increasingly being used to predict potential outcomes or groupings, such as clinical severity, drug dose response, and transitional illness states. In these examples, the variable (target) we want to predict is ordinal in nature. Conventional classification schemes assume that the targets are nominal and hence ignore their ranked nature, whereas parametric and/or non-parametric regression models enforce a metric notion of distance between classes. Here, we propose a novel, alternative multivariate approach that overcomes these limitations - whole brain probabilistic ordinal regression using a Gaussian process framework. We applied this technique to two data sets of pharmacological neuroimaging data from healthy volunteers. The first study was designed to investigate the effect of ketamine on brain activity and its subsequent modulation with two compounds - lamotrigine and risperidone. The second study investigates the effect of scopolamine on cerebral blood flow and its modulation using donepezil. We compared ordinal regression to multi-class classification schemes and metric regression. Considering the modulation of ketamine with lamotrigine, we found that ordinal regression significantly outperformed multi-class classification and metric regression in terms of accuracy and mean absolute error. However, for risperidone ordinal regression significantly outperformed metric regression but performed similarly to multi-class classification both in terms of accuracy and mean absolute error. For the scopolamine data set, ordinal regression was found to outperform both multi-class and metric regression techniques considering the regional cerebral blood flow in the anterior cingulate cortex. Ordinal regression was thus the only method that performed well in all cases. Our results indicate the potential of an ordinal regression approach for neuroimaging data while providing a fully probabilistic framework with elegant approaches for model selection.

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.

Using genetic, cognitive and multi-modal neuroimaging data to identify ultra-high-risk and first-episode psychosis at the individual level.

BACKGROUND: Group-level results suggest that relative to healthy controls (HCs), ultra-high-risk (UHR) and first-episode psychosis (FEP) subjects show alterations in neuroanatomy, neurofunction and cognition that may be mediated genetically. It is unclear, however, whether these groups can be differentiated at single-subject level, for instance using the machine learning analysis support vector machine (SVM). Here, we used a multimodal approach to examine the ability of structural magnetic resonance imaging (sMRI), functional MRI (fMRI), diffusion tensor neuroimaging (DTI), genetic and cognitive data to differentiate between UHR, FEP and HC subjects at the single-subject level using SVM. METHOD: Three age- and gender-matched SVM paired comparison groups were created comprising 19, 19 and 15 subject pairs for FEP versus HC, UHR versus HC and FEP versus UHR, respectively. Genetic, sMRI, DTI, fMRI and cognitive data were obtained for each participant and the ability of each to discriminate subjects at the individual level in conjunction with SVM was tested. RESULTS: Successful classification accuracies (p < 0.05) comprised FEP versus HC (genotype, 67.86%; DTI, 65.79%; fMRI, 65.79% and 68.42%; cognitive data, 73.69%), UHR versus HC (sMRI, 68.42%; DTI, 65.79%), and FEP versus UHR (sMRI, 76.67%; fMRI, 73.33%; cognitive data, 66.67%). CONCLUSIONS: The results suggest that FEP subjects are identifiable at the individual level using a range of biological and cognitive measures. Comparatively, only sMRI and DTI allowed discrimination of UHR from HC subjects. For the first time FEP and UHR subjects have been shown to be directly differentiable at the single-subject level using cognitive, sMRI and fMRI data. Preliminarily, the results support clinical development of SVM to help inform identification of FEP and UHR subjects, though future work is needed to provide enhanced levels of accuracy.

A second-order and slice-specific linear shimming technique to improve spinal cord fMRI.

PURPOSE: To develop a second-order and slice-specific linear shimming technique and investigate its efficiency in the mitigation of signal loss and distortions, and the increase of temporal signal-to-noise ratio (tSNR) within the spinal cord during functional Magnetic Resonance Imaging (fMRI) of the human cervical spinal cord. METHODS: All scans were performed on a General Electric Discovery MR750 3 T scanner, using a head, neck and spine coil and a neurovascular array. To improve B0 homogeneity, a field map was acquired, and second-order shims (SOS) were optimized over manually defined regions of interest (ROIs). Signal loss from dephasing by susceptibility-induced gradients was reduced by optimizing slice-specific x-, y- and z-shims to maximize signal within the spinal cord. Spectral-spatial excitation pulses were used in both the slice-specific linear shimming calibration scan and fMRI acquisitions. The shimming technique's efficiency was initially tested on eight healthy volunteers by comparing tSNR between images acquired with the manufacturer's standard linear shimming and with our SOS and xyz-shimming technique. Subsequently, using an increased spatial resolution as needed for fMRI of the spinal cord, tSNR measurements were performed on resting-state fMRI images from 14 healthy participants. RESULTS: Spinal fMRI images acquired with only the standard linear shimming suffered from severe signal loss below the C5 vertebral level. The developed shimming technique compensated for this loss especially at levels C6 and C7, while tSNR was significantly higher at all vertebral levels with SOS and xyz-shimming than without it. CONCLUSION: A comprehensive shimming approach which includes the use of spectral-spatial excitation pulses along with both second-order and slice-specific linear shim optimization reduces regional signal loss and increases tSNR along the c-spine (C3-C7), improving the ability to record functional signals from the human spinal cord.

Differential corticospinal tract degeneration in homozygous 'D90A' SOD-1 ALS and sporadic ALS.

BACKGROUND: The homogeneous genotype and stereotyped phenotype of a unique familial form of amyotrophic lateral sclerosis (ALS) (patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A) superoxide dismutase 1) provides an ideal model for studying genotype/phenotype interactions and pathological features compared with heterogeneous apparently sporadic ALS. The authors aimed to use diffusion tensor tractography to quantify and compare changes in the intracerebral corticospinal tracts of patients with both forms of ALS, building on previous work using whole-brain voxelwise group analysis. METHOD: 21 sporadic ALS patients, seven homD90A patients and 20 healthy controls underwent 1.5 T diffusion tensor MRI. Patients were assessed using 'upper motor neuron burden,' El Escorial and ALSFR-R scales. The intracranial corticospinal tract was assessed using diffusion tensor tractography measures of fractional anisotropy (FA), mean diffusivity, and radial and axial diffusivity obtained from its entire length. RESULTS: Corticospinal tract FA was reduced in sporadic ALS patients compared with both homD90A ALS patients and controls. The diffusion measures in sporadic ALS patients were consistent with anterograde (Wallerian) degeneration of the corticospinal tracts. In sporadic ALS, corticospinal tract FA was related to clinical measures. Despite a similar degree of clinical upper motor neuron dysfunction and disability in homD90A ALS patients compared with sporadic ALS, there were no abnormalities in corticospinal tract diffusion measures compared with controls. CONCLUSIONS: Diffusion tensor tractography has shown axonal degeneration within the intracerebral portion of the corticospinal tract in sporadic ALS patients, but not those with a homogeneous form of familial ALS. This suggests significant genotypic influences on the phenotype of ALS and may provide clues to slower progression of disease in homD90A patients.

Neural correlates of visuospatial working memory in the 'at-risk mental state'.

BACKGROUND: Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia. METHOD: fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object-location paired-associate memory task, with experimental manipulation of mnemonic load. RESULTS: In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS. CONCLUSIONS: Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.

Neural correlates of movement generation in the 'at-risk mental state'.

OBJECTIVE: People with 'prodromal' symptoms have a very high risk of developing psychosis. We examined the neurocognitive basis of this vulnerability by using functional MRI to study subjects with an at-risk mental state (ARMS) while they performed a random movement generation task. METHOD: Cross-sectional comparison of individuals with an ARMS (n = 17), patients with first episode schizophreniform psychosis (n = 10) and healthy volunteers (n = 15). Subjects were studied using functional MRI while they performed a random movement generation paradigm. RESULTS: During random movement generation, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than in the first episode group. CONCLUSION: The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have recently presented with psychosis but less severe.

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans.

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.

A chronic 1 year assessment of MRI contrast agent-labelled neural stem cell transplants in stroke.

Non-invasive identification of transplanted neural stem cells in vivo by pre-labelling with contrast agents may play an important role in the translation of cell therapy to the clinic. Understanding the impact of these labels on the cells' ability to repair is therefore vital. In rats with middle cerebral artery occlusion (MCAo), a model of stroke, the transhemispheric migration of MHP36 cells labelled with the bimodal contrast agent GRID was detected on magnetic resonance images (MRI) up to 4 weeks following transplantation. However, compared to MHP36 cells labelled with the red fluorescent dye PKH26, GRID-labelled transplants did not significantly improve behaviour, and performance was akin to non-treated animals. Likewise, the evolution of anatomical damage as assessed by serial, T(2)-weighted MRI over 1 year indicated that GRID-labelled transplants resulted in a slight increase in lesion size compared to MCAo-only animals, whereas the same, PKH26-labelled cells significantly decreased lesion size by 35%. Although GRID labelling allows the in vivo identification of transplanted cells up to 1 month after transplantation, it is likely that some is gradually degraded inside cells. The translation of cellular imaging therefore does not only require the in vitro assessment of contrast agents on cellular functions, but also requires the chronic, in vivo assessment of the label on the stem cells' ability to repair in preclinical models of neurological disease.

Functional magnetic resonance imaging of synesthesia: activation of V4/V8 by spoken words.

In 'colored-hearing' synesthesia, individuals report color experiences when they hear spoken words. If the synesthetic color experience resembles that of normal color perception, one would predict activation of parts of the visual system specialized for such perception, namely the human 'color center', referred to as either V4 or V8. Using functional magnetic resonance imaging (fMRI), we here locate the region activated by speech in synesthetes to area V4/V8 in the left hemisphere, and demonstrate overlap with V4/V8 activation in normal controls in response to color. No activity was detected in areas V1 or V2, suggesting that activity in primary visual cortex is not necessary for such experience. Control subjects showed no activity in V4/V8 when imagining colors in response to spoken words, despite overtraining on word-color associations similar to those spontaneously reported by synesthetes.

Obstructive sleep apnoea and Alzheimer's disease: In search of shared pathomechanisms.

Alzheimer's disease (AD) is a significant public health concern. The incidence continues to rise, and it is set to be over one million in the UK by 2025. The processes involved in the pathogenesis of AD have been shown to overlap with those found in cognitive decline in patients with Obstructive Sleep Apnoea (OSA). Currently, the standard treatment for OSA is Continuous Positive Airway Pressure. Adherence to treatment can, however, be an issue, especially in patients with dementia. Also, not all patients respond adequately, necessitating the use of additional treatments. Based on the body of data, we here suggest that excessive and prolonged neuronal activity might contribute to genesis and acceleration of both AD and OSA in the absence of appropriately structured sleep. Further, we argue that external factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain, and further promote disease progression. If this hypothesis is proven in future studies, it could have far-reaching clinical translational implications, as well as implications for future treatment strategies in OSA.

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.

Pharmacological MRI of stem cell transplants in the 3-nitropropionic acid-damaged striatum.

Blood oxygen level dependent (BOLD) pharmacological magnetic resonance imaging (phMRI) affords the non-invasive visualization of brain activity resulting from the administration of pharmacological compounds. Once the compound-responsive cells are lost, no change in activity is expected to occur. This principle therefore allows the assessment of neuronal loss or lack of signal transmission. These investigations can provide evidence of pathology in the absence of significant tissue loss and can be highly specific to determine which type of cell has been lost. Conversely, transplantation of cells replacing the lost neurons should restore normal signal transmission. We here demonstrate the application of phMRI to differentiate between rats with 3-nitroproprionic acid (3-NPA)-induced striatal lesions and 3-NPA-lesioned animals with neural stem cell transplants or controls. 3-NPA-induced lesions mainly involve striatal projection neurons that are responsive to dopamine agonists. The D2-agonist bromocriptine acts on these projection cells and loss of these through 3-NPA administration resulted in a significant decrease of locomotor activity and a substantial attenuation of the BOLD-response in the striatum. In contrast, lesioned animals that were grafted with neural stem cells exhibited an activity pattern akin to controls. Hence, grafting of neural stem cells exerts a functionally significant effect on striatal signal transmission that could underpin behavioral recovery.