Krisztina L. Malisza

Evaluation of spatial working memory function in children and adults with fetal alcohol spectrum disorders: a functional magnetic resonance imaging study.

Magnetic resonance imaging (MRI) and functional MRI studies involving n-back spatial working memory (WM) tasks were conducted in adults and children with Fetal Alcohol Spectrum Disorders (FASD), and in age- and sex-matched controls. FMRI experiments demonstrated consistent activations in regions of the brain associated with working memory. Children with FASD displayed greater inferior-middle frontal lobe activity, while greater superior frontal and parietal lobe activity was observed in controls. Control children also showed an overall increase in frontal lobe activity with increasing task difficulty, while children with FASD showed decreased activity. FASD adults demonstrated less functional brain activity overall, but greater inferior-middle frontal lobe activity during the simpler tasks, relative to controls. Control adults demonstrated greater inferior frontal activity with increasing task difficulty, while this pattern was not consistently observed in FASD adults. All four groups showed increasing activity with increases in task difficulty in the parietal and frontal regions at more superior slice levels. The results suggest impairment in spatial working memory in those with FASD that does not improve with age, and that fMRI may be useful in evaluation of brain function in these individuals.

Functional magnetic resonance imaging in rats subjected to intense electrical and noxious chemical stimulation of the forepaw.

&NA; We examined whether cerebral activation to two different intense and painful stimuli could be detected using functional magnetic resonance imaging (fMRI) in &agr;‐chloralose anesthetized rats. Experiments were performed using a 9.4 T magnet and a surface coil centered over the forebrain. A set of gradient echo images were acquired and analyzed using our software based on fuzzy cluster analysis (EvIdent™). Following the injection of 50 &mgr;l of formalin (5%) into the forepaw we observed a regional increase in signal intensity in the MR images in all animals. Anterior cingulate cortex, frontal cortex and sensory‐motor cortex were some of the regions that activated frequently and often bilaterally. Surprisingly, activation appeared sequentially, often occurring first in either the right or the left hemisphere with a separation of seconds to minutes between peak activations. Morphine pre‐treatment (1 mg/kg, i.v.) delayed and/or reduced the intensity of the activation resulting in a decrease in the overall response. Following episodes of intense electrical stimulation, produced by two brief stimulations (15 V, 0.3 ms, 3 Hz) of the forepaw, activation was observed consistently in the sensory‐motor cortex contralateral to the stimulation. Activation also occurred frequently in the anterior cingulate cortex, ipsilateral sensory‐motor cortex and frontal cortical regions. All these regions of activation were markedly reduced during nitrous oxide inhalation. Treatment with morphine resulted in an inhibition of the activation response to electrical stimulation in most regions except for sensory‐motor cortex. Thus, electrical and chemical noxious stimuli activated regions that are known to be involved in the central processing of pain and morphine modified the activation observed. fMRI combined with appropriate exploratory data analysis tools could provide an effective new tool with which to study novel analgesics and their effects on the CNS processing of pain in animal models.

Mapping of neuronal function in the healthy and injured human spinal cord with spinal fMRI.

Functional magnetic resonance imaging of the human spinal cord is carried out with a graded thermal stimulus in order to establish the relationship between signal changes and neural activity. Studies of the lumbar spinal cord in 15 healthy subjects with 10 degrees C stimulation of the skin overlying the calf demonstrate a pattern of activity that matches the neuronal anatomy of the spinal cord. This pattern shows primarily dorsal horn activity, with expected components of motor reflex activity as well. Moreover, a later response shifting to noxious cold over time is also demonstrated with a shift to more dorsal horn activity. Signal intensity changes detected at different degrees of thermal stimulation have a biphasic nature, with much larger signal changes below 15 degrees C as the stimulus becomes noxious, and agree well with electrophysiological results reported in the literature. These findings demonstrate a strong correspondence between Spinal fMRI results and neural activity in the human spinal cord. Spinal fMRI is also applied to studies of the injured spinal cord, below the site of injury. Results consistently demonstrate activity in the spinal cord even when the subjects cannot feel the stimulus being applied. Signal intensity changes demonstrate the same stimulus-response pattern as that in noninjured subjects, but the areas of activity in the spinal gray matter are notably altered. In subjects with complete injuries, activity is absent ipsilateral to the thermal stimulation, but appears to be enhanced on the contralateral side. These findings demonstrate the reliability of Spinal fMRI and its clinical potential.

Striatal Function in Generalized Social Phobia: A Functional Magnetic Resonance Imaging Study

BACKGROUND Although evidence suggests the involvement of the amygdala in generalized social phobia (GSP), few studies have examined other neural regions. Clinical, preclinical, and dopamine receptor imaging studies demonstrating altered dopaminergic functioning in GSP suggest an association with striatal dysfunction. This is the first functional magnetic resonance imaging (fMRI) study to use a cognitive task known to involve the striatum to examine the neural correlates of GSP. We examined whether subjects with GSP had differential activation in striatal regions compared with healthy control subjects while engaged in a cognitive task that has been shown to activate striatal regions reliably. METHODS Ten adult, unmedicated subjects with a primary DSM-IV diagnosis of GSP and 10 age-, gender-, and education-matched healthy comparison subjects underwent fMRI while performing the implicit sequence learning task. RESULTS The GSP and healthy comparison subjects did not differ significantly on the behavioral performance of the task. Subjects with GSP, however, had significantly reduced neural activation related to implicit learning compared with healthy comparison subjects in the left caudate head, left inferior parietal lobe, and bilateral insula. CONCLUSIONS These findings support the hypothesis that GSP is associated with striatal dysfunction and further the neurobiological understanding of this complex anxiety disorder.

Extravascular proton-density changes as a non-BOLD component of contrast in fMRI of the human spinal cord.

The fractional signal intensity change (ΔS/S) observed during activation in T2‐weighted fMRI of the spinal cord has previously been shown to depend linearly on the echo time (TE) but to have a positive value of roughly 2.5% extrapolated to zero TE. In this study we investigated the origin of this finding by measuring the ΔS/S in spinal fMRI with very short TEs. Our results demonstrate that the ΔS/S does not approach zero, but has a value as high as 3.3% at TE = 11 ms. At TEs > 33 ms we observed the linear relationship between ΔS/S and TE as in previous studies. These data demonstrate that there is a non‐BOLD contribution to signal changes observed in spinal fMRI. We hypothesize that this contribution is a local proton density increase due to increased water exudation from capillaries with increased blood flow during neuronal activation, and term this effect “signal enhancement by extravascular protons” (SEEP). Magn Reson Med 48:122–127, 2002.

Functional magnetic resonance imaging of the human brain based on signal enhancement by extravascular protons (SEEP fMRI).

Functional magnetic resonance imaging (fMRI) studies of the human brain were carried out at 3 Tesla to investigate an fMRI contrast mechanism that does not arise from the blood oxygen‐level dependent (BOLD) effect. This contrast mechanism, signal enhancement by extravascular protons (SEEP), involves only proton‐density changes and was recently demonstrated to contribute to fMRI signal changes in the spinal cord. In the present study it is hypothesized that SEEP fMRI can be used to identify areas of neuronal activity in the brain with as much sensitivity and precision as can be achieved with BOLD fMRI. A detailed analysis of the areas of activity, signal intensity time courses, and the contrast‐to‐noise ratio (CNR), is also presented and compared with the BOLD fMRI results. Experiments were carried out with subjects performing a simple finger‐touching task, or observing an alternating checkerboard pattern. Data were acquired using a conventional BOLD fMRI method (gradient‐echo (GE) EPI, TE = 30 ms), a conventional method with reduced BOLD sensitivity (GE‐EPI, TE = 12 ms), and SEEP fMRI (spin‐echo (SE) EPI, TE = 22 ms). The results of this study demonstrate that SEEP fMRI may provide better spatial localization of areas of neuronal activity, and a higher CNR than conventional BOLD fMRI, and has the added benefit of lower sensitivity to field inhomogeneities. Magn Reson Med 49:433–439, 2003.

Functional magnetic resonance imaging of the human cervical spinal cord with stimulation of different sensory dermatomes

Functional MR imaging (fMRI) of the cervical spinal cord was carried out in 13 healthy volunteers. A cold stimulus was applied, at different times, to three different sensory dermatome regions overlying the right hand and forearm: the thumb side of the palm, the little finger side of the palm, and the forearm below the elbow. Stimulation of these areas is expected to involve the 6(th), 8(th), and 5(th) cervical spinal cord segments respectively. Whereas true activations are expected to correspond to the region being stimulated, false activations such as arising from noise and motion, are not. The results demonstrate that clustering of active pixels into groups based on their intensity time courses discriminates false activations from true activations. Following clustering, the distribution of activity observed with fMRI matched the expected regions of neuronal activation with the different areas of stimulation on the hand and forearm.

Functional MRI of the rat lumbar spinal cord involving painful stimulation and the effect of peripheral joint mobilization

To examine neuronal activation in the spinal cord due to secondary hyperalgesia resulting from intrajoint capsaicin injection, and the effect of physiotherapy manipulation, using functional magnetic resonance imaging (fMRI), in α‐chloralose anesthetized rats.

Characterization of contrast changes in functional MRI of the human spinal cord at 1.5 T

Contrast changes observed in functional magnetic resonance imaging in the human spinal cord were investigated with both motor and sensory tasks over a range of echo times. Data were acquired using a single-shot fast spin-echo sequence at 1.5 Tesla. Data were analyzed with two different correlation thresholds and the effects of altering the order of repeated experiments was also investigated. Plots of the fractional signal change as a function of echo time yielded linear functions with slopes corresponding to relaxation rate changes of -0.30 sec(-1) with sensory stimulation and approximately -0.50 sec(-1) with a motor task. However, the fractional signal change extrapolated to an echo time of zero was significantly greater than zero in each case and was roughly 2.5%. This suggests that in addition to the BOLD effect there is a baseline signal change which occurs concomitant to neuronal activation in the spinal cord.

Capsaicin as a source for painful stimulation in functional MRI

Functional magnetic resonance imaging (fMRI) was used to examine the brain processing of capsaicin‐induced painful stimulation in the α‐chloralose anesthetized rat. Experiments were performed on a 9.4‐T magnet (Magnex, UK) with Avance console (Bruker, Germany) using a surface coil tuned to 400.5 MHz centred over the rat forebrain. Gradient‐echo images of two slices, with an echo time of 25 msec, repetition time of 70 msec, and 50 repetitions, were acquired per experiment. These images were analyzed using a fuzzy cluster analysis technique (EvIdent™). Activation of areas of the brain known to be associated with the processing of pain, namely the anterior cingulate (bilateral), frontal cortex (bilateral), and sensory motor cortex (contralateral), was found in all animals (N = 6) following injection of 25μL of capsaicin (128μg/mL in 7.5% dimethylsulfoxide [DMSO]) into the dorsal forepaw. It is possible to reproduce the pain response in a given animal several times throughout the course of an experiment, provided that sufficient time is allowed between capsaicin injections. This acute phase of capsaicin‐induced pain involving stimulation of C polymodal nociceptors was examined by functional imaging. There was a substantial initial increase in activation in regions of the brain associated with pain and there was a trend towards increasing activation with repeated stimulations. Treatment with morphine (3 mg/kg, intravenously) was found to substantially reduce, if not completely eliminate, the areas of functional activation associated with physiologic pain (anterior cingulate and frontal cortex) after C‐nociceptor stimulation with capsaicin (N = 6). FMRI involving capsaicin‐induced painful stimulation could prove to be an effective tool for the study of novel analgesics and the central nervous system processing of pain. J. Magn. Reson. Imaging 2001;14:341–347.