Association between dorsolateral prefrontal N-acetyl aspartate and depression in chronic back pain: an in vivo proton magnetic resonance spectroscopy study.

Most studies of pain, including chronic pain, agree that depression and pain are interrelated, although the neurobiology of this relationship remains unknown. Neuroimaging studies suggest a specific role of the prefrontal brain regions in the mechanisms of mood disorders and chronic pain. The present study examines the interrelationships between regional brain N-Acetyl aspartate (NAA) levels (as identified by in vivo proton magnetic resonance spectroscopy in the right and left dorsolateral prefrontal cortex [DLPFC], orbitofrontal cortex, cingulate and thalamus), depression (as measured by the Beck Depression Inventory), and pain (as measured by short form of the McGill Pain Questionnaire) in 10 chronic back pain (CBP) patients with depression, and compared to the relationship between regional brain NAA levels and depression in 10 normal subjects (sex and age-matched). Reduction of NAA levels was demonstrated in the right DLPFC of CBP patients with depression, as compared to the normal controls (p < 0.02, two-tailed t-test). The depression levels in CBP patients were highly correlated with NAA levels in the right DLPFC (r = -0.99, p < 0.0001), and were unrelated to the other studied regional NAA in both groups, including the right DLPFC in normal subjects (p < 10(-6); comparing the difference between r values in the right DLPFC between the two groups). The pain levels in CBP patients were also associated with the right DLPFC (r = -0.62, p < 0.05), although these relationships were much weaker as compared to depression-NAA correlations (p < 0.0001; comparing the difference between r values). The interrelationships between NAA across brain regions were examined using correlation analysis, which detected different connectivity patterns between CBP patients with depression and normal subjects. These findings provide evidence for a stronger association of prefrontal NAA to depression than to pain in CBP, which may reflect the common neurobiological substrate underlying these conditions in CBP patients. Spectroscopic brain mapping of NAA, the marker of neuronal density and function, to the depression and pain measures might be used for segregation of their circuitries in the chronic pain brain.

Prefrontal cortical hyperactivity in patients with sympathetically mediated chronic pain.

Chronic pain continues to impose a large burden of suffering, yet its neural correlates remain poorly understood. In sympathetically mediated chronic pain (SMP), peripheral sympathetic blockade temporarily relieves this pain, so that related neural activity can be studied without perturbing sensory inputs. We used functional magnetic resonance imaging and thermal painful stimuli applied to the chronically painful body site, before and after sympathetic blockade, to examine the cortical network of chronic pain. The chronic SMP state was associated with a widely spread prefrontal hyperactivity, increased anterior cingulate activity and decreased activity in the thalamus contralateral to the body side suffering from SMP, but was unrelated to sensorimotor activity. Ineffective sympathetic blocks, i.e. blocks that did not diminish the SMP pain, did not change the cortical responses to the painful thermal stimulus; while effective placebo resulted in similar responses to those of effective blocks. These findings provide evidence for abnormal brain responses to pain in patients with chronic SMP, which engages prefrontal/limbic networks more extensively than in acute pain-states.

Cognitive interference is associated with neuronal marker N-acetyl aspartate in the anterior cingulate cortex: an in vivo (1)H-MRS study of the Stroop Color-Word task.

The neurobiology of cognitive interference is unknown. Previous brain imaging studies using the Stroop Color-Word (SCW) task indicate involvement of the cingulate cortex cognitive division. The present study examines interrelationships between regional brain N-Acetyl aspartate (NAA) levels (as identified by in vivo proton magnetic resonance spectroscopy in the right and left anterior cingulate cortex (ACC), dorsolateral prefrontal cortex, orbitofrontal cortex and thalamus) and cognitive interference (as measured by the SCW task) in 15 normal subjects. The results show that brain chemistry depends on cognitive interference levels (high vs low). Reduction of NAA levels was demonstrated in the right ACC (ie, cognitive midsupracallosal division) of high interference subjects, as compared to the low interference group (P < 0.01, two-tailed t-test). Chemical-cognitive relationships were analyzed by calculating correlations between regional NAA levels and the SCW task scores. Cognitive interference was highly correlated with the right anterior cingulate NAA (r = 0.76, P < 0.001), and was unrelated to other studied regional NAA, including the left ACC (P < 0.025; comparing the difference between r values in the right and left ACC). The interrelationships between NAA across brain regions were examined using correlation analysis (square matrix correlation maps), which detected different connectivity patterns between the two groups. These findings provide evidence of ACC involvement in cognitive interference suggesting a possibility of neuronal reorganization in the physiological mechanism of interference (most likely due to genetically predetermined control of the number of neurons, dendrites and receptors, and their function). We conclude that spectroscopic brain mapping of NAA, the marker of neuronal density and function, to the SCW task measures differentiates between high and low interference in normal subjects. This neuroimaging/cognitive tool may be useful for documentation of interference in studying cognitive control mechanisms, and in diagnosis of neuropsychiatric disorders where dysfunction of cingulate cortex is expected.

Aging alters the multichemical networking profile of the human brain: an in vivo (1)H-MRS study of young versus middle-aged subjects.

In our most recent study of normal aging, we found decreased concentration of multiple chemicals in the brain of middle-aged subjects, as compared with younger subjects using in vivo proton magnetic resonance spectroscopy ((1)H-MRS). We hypothesized that these age-dependent differences in brain chemistry changes might be a reflection of the multichemical-networking-profile (MCNP) changes during aging. Using (1)H-MRS and correlation analysis, we examined the patterns of regional chemical levels and MCNP within and across multiple brain regions for all nine chemicals of (1)H-MR spectra. The brain chemistry changes and MCNP patterns were compared between 21 young (19--31-year-old) and 31 middle-aged (40--52-year-old) normal volunteers. Middle-aged subjects demonstrated a significant decrease of chemical levels in the prefrontal cortex and sensorimotor cortex (SMC), as compared with the young age group. Of these, neurotransmitters GABA and glutamate in the dorsolateral prefrontal cortex (DLPFC) were altered the most. We also found a significant increase of overall chemical correlation strength in MCNP within and across all studied brain regions with increased age. These changes were caused by alterations in the pattern of negative chemical connectivity across brain regions, which become weaker (less negative) in middle-aged subjects. The interregional chemical connectivity for the cingulate cortex, SMC and the thalamus was changed the most with increased age. Increased levels of chemical correlation strength across brain regions in aging were found for most chemicals studied (including neurotransmitters GABA and glutamate), and not for N-acetyl aspartate. These age-related differences in the connectivity of neurotransmitters were not region dependent. The results suggest that aging is associated with changes of the regional brain chemistry and the brain MCNP. The latter process may reflect an adaptive or compensatory response (possibly related to the elongation of dendrites with aging) to reduced levels of regional brain chemicals. The (1)H-MRS approach proposed here can be used as a valuable tool in the study of the brain chemistry, MCNP and their relationships in normal and abnormal aging.

Imaging the pain of low back pain: functional magnetic resonance imaging in combination with monitoring subjective pain perception allows the study of clinical pain states.

Most brain imaging studies of pain are done using a two-state subtraction design (state-related design). More recently event-related functional magnetic reasonance imaging (fMRI) has also been used for studying pain. Both designs severely limit the application of the technology to clinical pain states. Recently we demonstrated that monitoring time fluctuations of perceived pain could be used with fMRI to identify brain regions involved in conscious, subjective perception of pain. Here we extend the methodology to demonstrate that the same approach can be used to study clinical pain states. Subjects are equipped with a finger-spanning device to continuously rate and log their perceived pain during fMRI data collection. These ratings are convolved with a canonical hemodynamic response function to generate predictor waveforms with which related brain activity can be identified. Chronic low back pain patients and a normal volunteer were used. In one series of fMRI scans the patient simply lies in the scanner and indicates spontaneous fluctuations of the subjective pain. In other fMRI scans, a straight-leg raising procedure is performed to exacerbate the back pain. In the normal volunteer, fMRI scans were done during painful and non-painful straight-leg raisings. The results indicate the feasibility of differentiating between different pain states. We argue that the approach can be generalized to identify brain circuitry underlying diverse clinical pain conditions.

Functional magnetic resonance imaging of somatosensory cortex activity produced by electrical stimulation of the median nerve or tactile stimulation of the index finger.

OBJECT: Functional magnetic resonance (fMR) imaging was used to determine patterns of cerebral blood flow changes in the somatosensory cortex that result from median nerve stimulation (MNS). METHODS: Ten healthy volunteers underwent stimulation of the right median nerve at frequencies of 5.1 Hz (five volunteers) and 50 Hz (five volunteers). The left median nerve was stimulated at frequencies of 5.1 Hz (two volunteers) and 50 Hz (five volunteers). Tactile stimulation (with a soft brush) of the right index finger was also applied (three volunteers). Functional MR imaging data were transformed into Talairach space coordinates and averaged by group. Results showed significant activation (p < 0.001) in the following regions: primary sensorimotor cortex (SMI), secondary somatosensory cortex (SII), parietal operculum, insula, frontal cortex, supplementary motor area, and posterior parietal cortices (Brodmann's Areas 7 and 40). Further analysis revealed no statistically significant difference (p > 0.05) between volumes of cortical activation in the SMI or SII resulting from electrical stimuli at 5.1 Hz and 50 Hz. There existed no significant differences (p > 0.05) in cortical activity in either the SMI or SII resulting from either left- or right-sided MNS. With the exception of the frontal cortex, areas of cortical activity in response to tactile stimulation were anatomically identical to those regions activated by electrical stimulation. In the SMI and SII, activation resulting from tactile stimulation was not significantly different (p > 0.05) from that resulting from electrical stimulation. CONCLUSIONS: Electrical stimulation of the median nerve is a reproducible and effective means of activating multiple somatosensory cortical areas, and fMR imaging can be used to investigate the complex network that exists between these areas.

Cortical responses to thermal pain depend on stimulus size: a functional MRI study.

Cortical activity patterns to thermal painful stimuli of two different sizes were examined in normal volunteers using functional magnetic resonance imaging (fMRI). Seven right-handed subjects were studied when the painful stimulus applied to the right hand fingers covered either 1,074-mm(2)-area large stimulator or 21-mm(2)-area small stimulator. Stimulus temperatures were adjusted to give rise to equivalent moderately painful ratings. fMRI signal increases and decreases were determined for the contralateral parietal and motor areas. When the overall activity in these regions was compared across subjects, increased fMRI activity was observed over more brain volume with the larger stimulator, whereas decreased fMRI activity was seen in more brain volume for the smaller stimulator. The individual subject and group-averaged activity patterns indicated regional specific differences in increased and decreased fMRI activity. The small stimulator resulted in decreased fMRI responses throughout the upper body representation in both primary somatosensory and motor cortices. In contrast, no decreased fMRI signals were seen in the secondary somatosensory cortex and in the insula. In another seven volunteers, the effects of the size of the thermal painful stimulus on vibrotactile thresholds were examined psychophysically. Painful stimuli were delivered to the fingers and vibrotactile thresholds were measured on the arm just distal to the elbow. Consistent with the fMRI results in the primary somatosensory cortex, painful thermal stimuli using the small stimulator increased vibrotactile thresholds on the forearm, whereas similarly painful stimuli using the large stimulator had no effect on forearm vibrotactile thresholds. These results are discussed in relation to the cortical dynamics for pain perception and in relation to the center-surround organization of cortical neurons.

A comparative fMRI study of cortical representations for thermal painful, vibrotactile, and motor performance tasks.

Cortical activity due to a thermal painful stimulus applied to the right hand was studied in the middle third of the contralateral brain and compared to activations for vibrotactile and motor tasks using the same body part, in nine normal subjects. Cortical activity was demonstrated utilizing multislice echo-planar functional magnetic resonance imaging (fMRI) and a surface coil. The cortical activity was analyzed based upon individual subject activity maps and on group-averaged activity maps. The results show significant differences in activations across the three tasks and the cortical areas studied. The study indicates that fMRI enables examination of cortical networks subserving pain perception at an anatomical detail not available with other brain imaging techniques and shows that this cortical network underlying pain perception shares components with the networks underlying touch perception and motor execution. However, the thermal pain perception network also has components that are unique to this perception. The uniquely activated areas were in the secondary somatosensory region, insula, and posterior cingulate cortex. The posterior cingulate cortex activity was in a region that, in the monkey, receives nociceptive inputs from posterior thalamic medial and lateral nuclei that in turn are targets for spinothalamic terminations. Discrete subdivisions of the primary somatosensory and motor cortical areas were also activated in the thermal pain task, showing region-dependent differences in the extent of overlap with the other two tasks. Within the primary motor cortex, a hand region was preferentially active in the task in which the stimulus was painful heat. In the primary somatosensory cortex most activity in the painful heat task was localized to area 1, where the motor and vibratory task activities were also coincident. The study also indicates that the functional connectivity across multiple cortical regions reorganizes dynamically with each task.

Differentiating cortical areas related to pain perception from stimulus identification: temporal analysis of fMRI activity.

In a recent functional magnetic resonance imaging study (fMRI), we reported the cortical areas activated in a thermal painful task and compared the extent of overlap between this cortical network and those activated during a vibrotactile task and a motor task. In the present study we examine the temporal properties of the cortical activations for all three tasks and use linear systems identification techniques to functionally differentiate the cortical regions identified in the painful thermal task. Cortical activity was examined in the contralateral middle third of the brain of 10 right-handed subjects, using echo-planar imaging and a surface coil. In another eight subjects the temporal properties of the thermal task were examined psychophysically. The fMRI impulse response function was estimated from the cortical activations in the vibrotactile and motor tasks and shown to correspond to earlier reports. Given the fMRI impulse response function and the time courses for the thermal stimulus and the associated pain ratings, predictor functions were generated. The correlation between these predictor functions and cortical activations in the painful thermal task indicated a gradual transition of information processing anteroposteriorly in the parietal cortex. Within this region, activity in the anterior areas more closely reflected thermal stimulus parameters, whereas activity more posteriorly was better related to the temporal properties of pain perception. Insular cortex at the level of the anterior commissure was the region best related to the thermal stimulus, and Brodmann's area 5/7 was the region best related to the pain perception. The functional implications of these observations are discussed.

Patterns of lateral sensory cortical activation determined using functional magnetic resonance imaging.

OBJECT: Functional magnetic resonance (fMR) imaging was performed in human volunteers to determine the lateral perisylvian cortical areas activated by innocuous cutaneous stimulation. METHODS: Eight volunteers who underwent 53 separate experiments form the basis of this report. Eight contiguous coronal slices were obtained using echoplanar fMR imaging techniques while participants were at rest and while somatosensory activation stimuli consisting of vibration or air puffs were delivered to various body areas. The data were analyzed using Student's t-test and cluster analysis to determine significant differences between the resting and activated states. The findings were as follows: the areas in the lateral cortex activated by the stimuli were the primary sensory cortex (SI), the second somatosensory area (SII), the insula, the superior parietal lobule, and the retroinsular parietal operculum (RIPO). Somatotopy was demonstrable in SI but not in the other areas identified. There was a surprisingly low correlation between the amount of cortex activated in the various areas, which could mean separate inputs and functions for the areas identified. The highest correlation was found between activity in SII and RIPO (0.69). CONCLUSIONS: The authors maintain that fMR imaging can be used to identify multiple lateral somatosensory areas in humans. Somatotopy is demonstrated in SI but not in the other lateral cortical sensory areas. The correlations between the amounts of cortex activated in the different lateral sensory areas are low. Recognition of the multiple lateral sensory areas is important both for understanding sensory cortical function and for safe interpretation of studies designed to identify the central sulcus by activating SI.

Fingertip representation in the human somatosensory cortex: an fMRI study.

Eight right-handed adult humans underwent functional magnetic resonance imaging (fMRI) of their brain while a vibratory stimulus was applied to an individual digit tip (digit 1, 2, or 5) on the right hand. Multislice echoplanar imaging techniques were utilized during digit stimulation to investigate the organization of the human primary somatosensory (SI) cortex, cortical regions located on the upper bank of the Sylvian fissure (SII region), insula, and posterior parietal cortices. The t test and cluster size analyses were performed to produce cortical activation maps, which exhibited significant regions of interest (ROIs) in all four cortical regions investigated. The frequency of significant ROIs was much higher in SI and the SII region than in the insula and posterior parietal region. Multiple digit representations were observed in the primary somatosensory cortex, corresponding to the four anatomic subdivisions of this cortex (areas 3a, 3b, 1, and 2), suggesting that the organization of the human somatosensory cortex resembles that described in other primates. Overall, there was no simple medial to lateral somatotopic representation in individual subject activity maps. However, the spatial distance between digit 1 and digit 5 cortical representations was the greatest in both SI and the SII region within the group. Statistical analyses of multiple activity parameters showed significant differences between cortical regions and between digits, indicating that vibrotactile activations of the cortex are dependent on both the stimulated digit and cortical region investigated.

Functional magnetic resonance imaging measures of blood flow patterns in the human auditory cortex in response to sound.

Functional Magnetic Resonance Imaging (fMRI) holds exciting potential as a research and clinical tool for exploring the human auditory system. This noninvasive technique allows the measurement of discrete changes in cerebral cortical blood flow in response to sensory stimuli, allowing determination of precise neuroanatomical locations of the underlying brain parenchymal activity. Application of fMRI in auditory research, however, has been limited. One problem is that fMRI utilizing echo-planar imaging technology (EPI) generates intense noise that could potentially affect the results of auditory experiments. Also, issues relating to the reliability of fMRI for listeners with normal hearing need to be resolved before this technique can be used to study listeners with hearing loss. This preliminary study examines the feasibility of using fMRI in auditory research by performing a simple set of experiments to test the reliability of scanning parameters that use a high resolution and high signal-to-noise ratio unlike that presently reported in the literature. We used consonant-vowel (CV) speech stimuli to investigate whether or not we could observe reproducible and consistent changes in cortical blood flow in listeners during a single scanning session, across more than one scanning session, and in more than one listener. In addition, we wanted to determine if there were differences between CV speech and nonspeech complex stimuli across listeners. Our study shows reproducibility within and across listeners for CV speech stimuli. Results were reproducible for CV speech stimuli within fMRI scanning sessions for 5 out of 9 listeners and were reproducible for 6 out of 8 listeners across fMRI scanning sessions. Results of nonspeech complex stimuli across listeners showed activity in 4 out of 9 individuals tested.

A binocular fiberscope for presenting visual stimuli during fMRI.

A binocular pair of fiberscopes relays high-resolution images of CRT displays from an adjacent room to an observer lying in a scanner in functional Magnetic Resonance Imaging (fMRI) studies of visual function. We review the problems that must be overcome by any visual display for use in fMRI, present the specific solution we developed, and discuss its merits. Together, the fiberscope and CRT conveniently display accurately controlled high- and low-contrast wide-field images to an observer in an fMRI scanner.

A quantitative one-dimensional magnetic resonance imaging technique in adjuvant arthritis: the assessment of disease progression and indomethacin efficacy.

OBJECTIVE: To demonstrate the use of a one-dimensional proton (1H) nuclear magnetic resonance (NMR) imaging technique to noninvasively monitor the progression of adjuvant arthritis and its response to indomethacin treatment in Lewis rat leg joints. METHODS: The total hydrogen content of a defined volume of the joint was quantitated at selected time points. The differences in proton T2 relaxation times allowed for characterization and quantitative separation of the fluid (relatively long T2) and nonfluid (relatively short T2) components of hydrogen content in the defined volume. The estimates of hydrogen content of both long and short T2 tissue components were used to assess the severity of the disease and its regression with indomethacin treatment. RESULTS: A progressive increase of the 2 components of hydrogen content in saline treated arthritic rats is consistent with histological examinations. After 19 days of treatment, 0.1 mg/kg/day and 0.5 mg/kg/day of indomethacin reduced the fluid component (primarily from inflammatory edema) in arthritic leg joints by 39 and 77% respectively, compared to the saline treated arthritic rats. The higher dose of indomethacin also significantly reduced the nonfluid component (primarily from cellular content) suggesting a reduced influx of inflammatory cells into the affected areas. The paw volume measurements, radiologic changes, and histopathology also showed the regression of adjuvant arthritis on treatment. CONCLUSION: The study demonstrated that the NMR method has the sensitivity required to assess the treatment efficacy in adjuvant arthritis and suggests its possible utility in early diagnosis and monitoring of therapy in clinical arthritis on human extremities.

Effect of elevation on intravenous extravasations.

Nursing interventions used to treat intravenous extravasations (infiltrations) generally include application of warmth or cold, elevation, and no treatment. In this article, the effect of elevation on infiltrations of 0.45% sodium chloride and 3% saline made intentionally into healthy volunteers is reported. Elevation had no effect on pain, surface area of induration, or volume of infiltrate remaining as quantified by magnetic resonance imaging. A comparison of these data with previously published findings concerning the effect of warmth versus cold on infiltrations shows that no one treatment is better overall in decreasing the symptoms or speeding re-absorption of the infiltrate.

Magnetic orotracheal intubation: a new technique.

We sought to determine the effectiveness of a magnet placed over the thyroid cartilage in the neck to guide an endotracheal tube into the trachea. Forty patients aged 18 to 60 yr with normal airway anatomy (ASA grade I) who required general anesthesia with an endotracheal tube and paralysis for their surgery were chosen and informed consents were obtained. The tip of the epiglottis was exposed with a No. 3 MacIntosh laryngoscope, and a magnet was held over the thyroid cartilage. A catheter with stylet was placed behind the epiglottis allowing the magnet to pull the stylet and catheter close to the glottic opening. The catheter was advanced into the trachea over the stylet and its position was confirmed by auscultating the lungs and by capnography. An extension tube was connected to the catheter, and the endotracheal tube was guided into the trachea over the catheter. The tracheas of 37 patients were intubated on the first attempt with the magnet. The tracheas of the remaining three patients could not be intubated on the first attempt but were successfully intubated without complications on the second attempt. An additional five patients with an anterior larynx whose tracheas could not be intubated with direct laryngoscopy also had tracheal intubation with a magnet. This magnet-guided technique can be used when it is difficult to expose a patient's larynx. It is noninvasive, simple, and can be used without any delay when expensive flexible fiberoptic endoscopes are not readily available. The procedure takes an average of 1 to 2 min.

Differences among intravenous extravasations using four common solutions.

A frequent complication of intravenous therapy is extravasation (infiltration) of the infused fluid into the interstitial tissues. This study compares infiltrates intentionally made using different IV solutions regarding surface assessment and the volume of infiltrate as quantified by magnetic resonance imaging. Solutions differed significantly concerning pain, surface area of induration, and volume at the site of infiltration.

Persistent pain inhibits contralateral somatosensory cortical activity in humans.

To assess cortical activity during pain perception, regional cerebral blood flow (rCBF) studies were done in humans using single photon emission computed tomography (SPECT) with the radiotracer Tc99m-HMPAO and magnetic resonance imaging localization. Normalized SPECT data were analyzed by region of interest and change distribution. Contralateral somatosensory rCBF was decreased when the digits of the hand were immersed in a hot water bath for 3 min which was rated as moderately painful (persistent pain). No decrease was observed when the hand was immersed in tepid water (control). In contrast, cortical rCBF was increased during vibratory and sensorimotor tasks, in the contralateral somatosensory and sensorimotor areas, respectively. These results indicate that pain perception in man is associated with somatosensory cortical inhibition.

Rat pituitary changes observed with magnetic resonance imaging following removal of estrogen stimulus: correlation with histopathology and immunohistology.

The effect of estrogen withdrawal on pituitary glands of rats treated with estradiol-17 beta for various lengths of time was monitored by magnetic resonance imaging (MRI) and histological examination. Estrogen pellets were removed at seven different time points ranging from 4 to 206 days after pellet implantation. High-resolution mid-sagittal MR images of the rat head were made 1 day before pellet implantation, immediately following pellet withdrawal, and 14 and 28 days after pellet withdrawal. Twenty-eight days after pellet withdrawal pituitary glands were fixed and processed for histological examination. Enlarged pituitaries were detected by MRI from 16 days after implantation and onwards. Twenty-eight days after estrogen withdrawal the typical triangular shape of the normal pituitary had returned and pituitary morphology was indistinguishable from that of normal pituitaries in all rats that had been treated with estrogen for up to 114 days. Pituitaries of rats that had received estrogen for 186 days had a normal MR image 28 days after estrogen withdrawal, but microscopic examination revealed multifocal hyperplasias of prolactin-positive cells throughout the pars distalis. MRI of rats treated for 206 days showed tumorously enlarged pituitaries. There was no evidence of tumor regression in these rats 28 days after pellet removal. It was concluded that hypertrophic pituitaries regained a normal size, shape and morphology after estrogen withdrawal, except for a remarkable type of hyperplasia following estrogen treatment for 186 days and a recovery period of 28 days. In tumorous pituitaries no regression of lesions was noticed.