Paul G. Mullins

Use of tissue water as a concentration reference for proton spectroscopic imaging

A strategy for using tissue water as a concentration standard in 1H magnetic resonance spectroscopic imaging studies on the brain is presented, and the potential errors that may arise when the method is used are examined. The sensitivity of the method to errors in estimates of the different water compartment relaxation times is shown to be small at short echo times (TEs). Using data from healthy human subjects, it is shown that different image segmentation approaches that are commonly used to account for partial volume effects (SPM2, FSLs FAST, and K‐means) lead to different estimates of metabolite levels, particularly in gray matter (GM), owing primarily to variability in the estimates of the cerebrospinal fluid (CSF) fraction. While consistency does not necessarily validate a method, a multispectral segmentation approach using FAST yielded the lowest intersubject variability in the estimates of GM metabolites. The mean GM and white matter (WM) levels of N‐acetyl groups (NAc, primarily N‐acetylaspartate), choline (Ch), and creatine (Cr) obtained in these subjects using the described method with FAST multispectral segmentation are reported: GM [NAc] = 17.16 ± 1.19 mM; WM [NAc] = 14.26 ± 1.38 mM; GM [Ch] = 3.27 ± 0.47 mM; WM [Ch] = 2.65 ± 0.25 mM; GM [Cr] = 13.98 ± 1.20 mM; and WM [Cr] = 7.10 ± 0.67 mM. Magn Reson Med, 2006.

Closed-head minimal traumatic brain injury produces long-term cognitive deficits in mice

Victims of minimal traumatic brain injury (mTBI) do not show clear morphological brain defects, but frequently suffer lasting cognitive deficits, emotional difficulties and behavioral disturbances. In the present study we adopted a non-invasive closed-head weight-drop mouse model to produce mTBI. We examined the effects of 20, 25, or 30 g weight drop 7, 30, 60 and 90 days following injury on mices ability to perform the Morris water maze. The mice suffered profound long-lasting learning and memory deficits that were force- and time-dependent. Although the injured mice could acquire the task, they could not improve their initial escape latency by more than 50%, while normal mice improved by up to 450% (P<0.001). In order to directly compare the learning ability of individual mice following our mTBI we have devised a new measure which we term learning rate. We define learning rate as the rate the mouse improved its own performance in consecutive trials in a given experimental day. The learning rate of control mice increased linearly throughout the testing period with a slope of approximately 0.9. Injured mice that sustained 20 and 25 g weight drop could also improve their learning rate linearly but with a slope of only 0.2. Mice who sustained 30 g weight drop could not improve their learning rate linearly and reached a plateau after the third experimental learning day. These results indicate that the severity of injury may correlate with the degree of integration of the learning task. These cognitive deficits occurred without any other clear neurological damage, no evident brain edema, no notable damage to the blood-brain barrier and no early anatomical changes to the brain (observed by magnetic resonance imaging imaging). These results demonstrate that persistent deficits of cognitive learning abilities in mice, similar to those observed in human post-concussive syndrome, can follow mTBI without any anatomical damage to the brain and its surrounding tissue.

The salience network is responsible for switching between the default mode network and the central executive network: Replication from DCM

With the advent of new analysis methods in neuroimaging that involve independent component analysis (ICA) and dynamic causal modelling (DCM), investigations have focused on measuring both the activity and connectivity of specific brain networks. In this study we combined DCM with spatial ICA to investigate network switching in the brain. Using time courses determined by ICA in our dynamic causal models, we focused on the dynamics of switching between the default mode network (DMN), the network which is active when the brain is not engaging in a specific task, and the central executive network (CEN), which is active when the brain is engaging in a task requiring attention. Previous work using Granger causality methods has shown that regions of the brain which respond to the degree of subjective salience of a stimulus, the salience network, are responsible for switching between the DMN and the CEN (Sridharan et al., 2008). In this work we apply DCM to ICA time courses representing these networks in resting state data. In order to test the repeatability of our work we applied this to two independent datasets. This work confirms that the salience network drives the switching between default mode and central executive networks and that our novel technique is repeatable.

1H-MRS at 4 Tesla in minimally treated early schizophrenia

We investigated glutamate-related neuronal dysfunction in the anterior cingulate (AC) early in schizophrenia before and after antipsychotic treatment. A total of 14 minimally treated schizophrenia patients and 10 healthy subjects were studied with single-voxel proton magnetic resonance spectroscopy (1H-MRS) of the AC, frontal white matter and thalamus at 4 T. Concentrations of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln) and Gln/Glu ratios were determined and corrected for the partial tissue volume. Patients were treated with antipsychotic medication following a specific algorithm and 1H-MRS was repeated after 1, 6 and 12 months. There were group × region interactions for baseline NAA (P=0.074) and Gln/Glu (P=0.028): schizophrenia subjects had lower NAA (P=0.045) and higher Gln/Glu (P=0.006) in the AC before treatment. In addition, AC Gln/Glu was inversely related to AC NAA in the schizophrenia (P=0.0009) but not in the control group (P=0.92). Following antipsychotic treatment, there were no further changes in NAA, Gln/Glu or any of the other metabolites in any of the regions studied. We conclude that early in the illness, schizophrenia patients already show abnormalities in glutamatergic metabolism and reductions in NAA consistent with glutamate-related excitotoxicity.

Proton Echo-Planar Spectroscopic Imaging of J-Coupled Resonances in Human Brain at 3 and 4 Tesla

In this multicenter study, 2D spatial mapping of J‐coupled resonances at 3T and 4T was performed using short‐TE (15 ms) proton echo‐planar spectroscopic imaging (PEPSI). Water‐suppressed (WS) data were acquired in 8.5 min with 1‐cm3 spatial resolution from a supraventricular axial slice. Optimized outer volume suppression (OVS) enabled mapping in close proximity to peripheral scalp regions. Constrained spectral fitting in reference to a non‐WS (NWS) scan was performed with LCModel using correction for relaxation attenuation and partial‐volume effects. The concentrations of total choline (tCho), creatine + phosphocreatine (Cr+PCr), glutamate (Glu), glutamate + glutamine (Glu+Gln), myo‐inositol (Ins), NAA, NAA+NAAG, and two macromolecular resonances at 0.9 and 2.0 ppm were mapped with mean Cramer‐Rao lower bounds (CRLBs) between 6% and 18% and ∼150‐cm3 sensitive volumes. Aspartate, GABA, glutamine (Gln), glutathione (GSH), phosphoethanolamine (PE), and macromolecules (MMs) at 1.2 ppm were also mapped, although with larger mean CRLBs between 30% and 44%. The CRLBs at 4T were 19% lower on average as compared to 3T, consistent with a higher signal‐to‐noise ratio (SNR) and increased spectral resolution. Metabolite concentrations were in the ranges reported in previous studies. Glu concentration was significantly higher in gray matter (GM) compared to white matter (WM), as anticipated. The short acquisition time makes this methodology suitable for clinical studies. Magn Reson Med, 2007.

Habituation and sensitization to heat and cold pain in women with fibromyalgia and healthy controls

Abstract The purpose of this study was to examine differences in habituation to heat and cold pain in women with fibromyalgia (FM; n = 33) and in women who were healthy controls (HC; n = 44). Quantitative sensory testing (QST) was used to assess pain thresholds during five consecutive trials of ascending heat and descending cold stimulation. Anxiety, depression, fatigue, and pain during the previous week were assessed using self‐report measures. The overall hypotheses were that there would be differences between groups in pain thresholds and in the rate of habituation to heat and cold pain stimuli. Multilevel modeling was used to test the hypotheses. There were large overall differences in pain thresholds, with the FM group showing greater sensitivity to heat and cold pain stimuli compared with the HC group. While habituation occurred in both of the groups for heat pain, the HC group had stronger habituation across trials than the FM group. Conversely, while the HC group habituated to cold pain stimuli, the FM group showed sensitization and had decreased cold pain thresholds across trials (they felt cold pain at higher temperatures). In addition, anxiety, depression, fatigue, and pain were related to decreased heat and cold pain thresholds in the overall sample. However, when group was controlled, none of these variables were related to thresholds or rates of habituation or sensitization. The differences between women with FM and healthy women in habituation and sensitization may have important implications for the etiology, diagnosis, and treatment of FM and other chronic pain conditions.

Comparative reliability of proton spectroscopy techniques designed to improve detection of J-coupled metabolites.

Improved detection of J‐coupled neurometabolites through the use of modified proton magnetic resonance spectroscopy (1H‐MRS) techniques has recently been reported. TE‐averaged point‐resolved spectroscopy (PRESS) uses the J modulation effects by averaging FIDs with differing echo times to improve detection of glutamate, while standard PRESS detection of glutamate can be improved by using an appropriate single echo determined from J‐modulation simulations. In the present study, the reliabilities of TE‐averaged PRESS, standard PRESS with TE = 40 ms, and standard PRESS with TE = 30 ms in detecting metabolite levels in the cingulate gyrus of the human brain at 3T were compared in six subjects. TE‐averaged PRESS measures showed a mean variability of 9% for N‐acetyl aspartate, choline, and creatine, compared with < 4% for the 30‐ and 40‐ms PRESS techniques. The coefficients of variation for glutamate were 10%, 7%, and 5% for TE‐averaged, 30‐ms, and 40‐ms PRESS, respectively. PRESS with a TE of 40 ms also demonstrated improved reliability for GABA and glutamine concentrations. These results show that with the appropriate selection of echo time standard PRESS can be a reliable 1H‐MRS technique for the measurement of J‐coupled neurometabolites in the human brain and, moreover, compares favorably with at least one J‐edited technique. Magn Reson Med 60:964–969, 2008.

Selective Blockade of the mGluR1 Receptor Reduces Traumatic Neuronal Injury in Vitro and Improves Outcome after Brain Trauma

The effects of selective blockade of group I metabotropic glutamate receptor subtype 1 (mGluR1) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. The selective mGluR1 antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), and (S)-(+)-alpha-amino-4-carboxy-2-methylbezeneacetic acid (LY367385) provided significant neuroprotection in rat cortical neuronal cultures subjected to mechanical injury, in both pretreatment or posttreatment paradigms. Administration of the antagonists also attenuated glutamate-induced neuronal cell death in the cultures. Coapplication of these antagonists with the N-methyl-d-aspartate (NMDA) receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) had additive neuroprotective effects in glutamate injured cultures. Intracerebroventricular administration of AIDA to rats markedly improved recovery from motor dysfunction after lateral fluid percussion induced traumatic brain injury (TBI). Treatment with mGluR1 antagonists also significantly reduced lesion volumes in rats after TBI, as evaluated by MRI. It appears that these compounds mediate their neuroprotective effect through an mGluR1 antagonist action, as demonstrated by inhibition of agonist induced phosphoinositide hydrolysis in our in vitro system. Moreover, AIDA, CPCCOEt, and LY367385, at concentrations shown to be neuroprotective, had no significant effects on the steady state NMDA evoked whole cell current. Taken together, these data suggest that modulation of mGluR1 activity may have substantial therapeutic potential in brain injury.

A novel technique to study the brain's response to pain: Proton magnetic resonance spectroscopy

Glutamate, a major excitatory neurotransmitter, has been implicated as an important mediator in the neurotransmission, potentiation, and negative affect associated with pain. We present results showing that a painful stimulus elicits a dynamic increase in glutamate (9.3% from baseline) concentrations in the anterior cingulate cortex, detectable using proton Magnetic Resonance Spectroscopy ((1)H-MRS). Increases in glutamine levels were also seen, which correlate strongly with the subjective level of pain experienced by participants (r(2) = 0.58, P < 0.01). These novel findings are the first time a dynamic change in glutamate and glutamine levels from baseline in response to an external stimuli has been measured in a single proton MRS scanning session. As such, this report demonstrates the efficacy of (1)H-MRS as a non-invasive tool for the study of neural responses to pain in vivo. The paradigm used in this study demonstrates that dynamic glutamate/glutamine changes due to stimulation are measurable by proton MRS, and could provide a means of testing novel pharmaceutical agents and other treatments for chronic pain.

Small Shifts in Craniotomy Position in the Lateral Fluid Percussion Injury Model Are Associated with Differential Lesion Development

Previous studies have shown that location and direction of injury may affect outcome in experimental models of traumatic brain injury. Significant variability in outcome data has also been noted in studies using the lateral fluid percussion brain injury model (FPI) in rats. In recent studies from our laboratory, we observed considerable variability in localization and severity of tissue damage as a function of small changes in craniotomy position. To further address this issue, we examined the relationship between craniotomy position and brain lesion size/location in rats subjected to moderate FPI (2.28 +/- 0.18 atmospheres). With placement of a 5-mm craniotomy adjacent to the sagittal suture, there was both ipsilateral and contralateral damage as detected at 3 weeks posttrauma using T2-weighted magnetic resonance imaging (MRI). The MRI lesions were generally restricted to the hippocampus and subcortical layers. Shifting of the craniotomy site laterally was associated with increased ipsilateral tissue damage and a greater cortical component that correlated with distance from the sagittal suture. In contrast, the contralateral MRI lesion did not change significantly in size or location unless the center of the craniotomy was placed more than 3.5 mm from the sagittal suture, under which condition contralateral damage could no longer be detected. Ipsilateral tissue damage as determined from the MRI scans was linearly correlated to motor outcome but not with cognitive outcome as assessed by the Morris Water Maze. We conclude that craniotomy position is critical in determining extent and location of tissue injury produced during the lateral FPI model in rats. Addressing such potential variability is essential for studies that address either injury mechanisms or therapeutic treatments.