Predictors of CNS injury as measured by proton magnetic resonance spectroscopy in the setting of chronic HIV infection and CART.

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS). Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr, and Glx/Cr) were measured in the basal ganglia, the frontal white matter, and gray matter, and the best predictive models were selected using a bootstrap-enhanced Akaike information criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr, whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease.

Angiography reveals that fluid-attenuated inversion recovery vascular hyperintensities are due to slow flow, not thrombus.

BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensities (FVH) are commonly encountered on MR imaging studies performed shortly after the onset of acute ischemic stroke. Prior reports have speculated regarding the pathogenesis of this finding, yet definitive correlative angiographic studies have not been performed. We studied the pathophysiologic and hemodynamic correlates of FVH on conventional angiography and concurrent MR imaging sequences. MATERIALS AND METHODS: Retrospective review of FLAIR and gradient-refocused echo MR imaging sequences acquired immediately before conventional angiography for acute stroke was conducted in a blinded fashion. The presence, location, and morphology of FVH were noted and correlated with markers of thrombotic occlusion and collateral flow on angiography. Angiographic collaterals were graded on a 5-point scale incorporating extent and hemodynamic aspects. RESULTS: A prospective ischemic stroke registry of 632 patients was searched to identify 74 patients (mean age, 63.4 +/- 20 years; 48% women) having undergone FLAIR sequences immediately before angiography. Median time from FLAIR to angiography was 2.9 hours (interquartile range, 1.1-4.7 hours). FVH were present in 53/74 (72%) of all acute stroke cases with subsequent angiography. FVH distal to an arterial occlusion were associated with a high grade of leptomeningeal collateral blood flow. CONCLUSIONS: FVH are observed in areas of blood flow proximal and distal to stenosis or occlusion and are noted with more extensive collateral circulation.

Determinants of the distribution and severity of hypoperfusion in patients with ischemic stroke.

BACKGROUND: In acute cerebral ischemia, two variables characterize the extent of hypoperfusion: the volume of hypoperfused tissue and the intensity of hypoperfusion within these regions. We evaluated the determinants of the intensity of hypoperfusion within oligemic regions among patients who were eligible for recanalization therapy for acute ischemic stroke. METHODS: We analyzed data, including pretreatment diffusion-weighted imaging (DWI) and perfusion-weighted imaging, on 119 patients with acute middle cerebral artery infarctions. The intensity of hypoperfusion within oligemic regions was characterized by the hypoperfusion intensity ratio (HIR), defined as the volume of tissue with severe hypoperfusion (Tmax > or = 8 seconds) divided by the volume of tissue with any hypoperfusion (Tmax > or = 2 seconds). Based on the DWI data, we divided the patients into four stroke phenotypes: large cortical, small (< 1 cm diameter) cortical, border-zone, and deep pattern. RESULTS: The mean (SD) volume of severe hypoperfusion was 54.6 (52.5) mL, and that of any hypoperfusion was 140.8 (81.3) mL. The HIR ranged widely, from 0.002 to 0.974, with a median of 0.35 (interquartile range 0.13-0.60). The volume of any hypoperfusion did not predict the intensity of hypoperfusion within the affected region (r = 0.10, p = 0.284). Angiographic collateral flow grade was associated with HIRs (p value for trend = 0.019) and differed among DWI lesion patterns. In multivariate analysis, diastolic pressure on admission (odds ratio 0.959, 95% CI 0.922-0.998) and DWI pattern of deep infarcts (odds ratio 18.004 compared with large cortical pattern, 95% CI 1.855-173.807) were independently associated with a low HIR. CONCLUSIONS: The intensity of hypoperfusion within an oligemic field is largely independent of the size of the oligemia region. Predictors of lesser intensity of hypoperfusion are lower diastolic blood pressure and presence of a deep diffusion-weighted imaging lesion pattern.

Impact of collateral flow on tissue fate in acute ischaemic stroke.

BACKGROUND: Collaterals may sustain penumbra prior to recanalisation yet the influence of baseline collateral flow on infarct growth following endovascular therapy remains unknown. METHODS: Consecutive patients underwent serial diffusion and perfusion MRI before and after endovascular therapy for acute cerebral ischaemia. We assessed the relationship between MRI diffusion and perfusion lesion indices, angiographic collateral grade and infarct growth. Tmax perfusion lesion maps were generated and diffusion-perfusion mismatch regions were divided into Tmax >or=4 s (severe delay) and Tmax >or=2 but <4 s (mild delay). RESULTS: Among 44 patients, collateral grade was poor in 7 (15.9%), intermediate in 20 (45.5%) and good in 17 (38.6%) patients. Although diffusion-perfusion mismatch volume was not different depending on the collateral grade, patients with good collaterals had larger areas of milder perfusion delay than those with poor collaterals (p = 0.005). Among 32 patients who underwent day 3-5 post-treatment MRIs, the degree of pretreatment collateral circulation (r = -0.476, p = 0.006) and volume of diffusion-perfusion mismatch (r = 0.371, p = 0.037) were correlated with infarct growth. Greatest infarct growth occurred in patients with both non-recanalisation and poor collaterals. Multiple regression analysis revealed that pretreatment collateral grade was independently associated with infarct growth. CONCLUSION: Our data suggest that angiographic collateral grade and penumbral volume interactively shape tissue fate in patients undergoing endovascular recanalisation therapy. These angiographic and MRI parameters provide complementary information about residual blood flow that may help guide treatment decision making in acute cerebral ischaemia.

White matter fiber tractography and color mapping of the normal human cerebellum with diffusion tensor imaging.

Diffusion tensor imaging (DTI) color mapping and fiber tractography was used to study the white matter within the cerebellum along with the afferent and efferent tracts associated with the cerebellum in 24 normal human subjects. The most prominent structures that can be readily identified using these DTI techniques are the middle, inferior and superior cerebellar peduncles. Furthermore DTI shows transverse white matter fiber that cross between the two cerebellar hemispheres at the level of the vermis. At the hemispheric level fibers to the dentate, to the emboliform nuclei are clearly visible on DTI as is the afferent pathway represented by the middle cerebellar peduncle. Selective DTI fiber tractography provides very exquisite images of the cerebellar peduncles and of the fibers projecting to and from the cerebellar cortex. This study demonstrates that DTI is complementary to conventional MRI in that DTI elucidates the orientation of white matter fiber bundles that are associated with the cerebellum. Therefore we anticipate that DTI will become an important adjunct to conventional MRI for clinical and basic studies of cerebellar ataxias and congenital disorders involving the cerebellum and brain stem. This work provides a summary of the normal DTI appearance of the cerebellar white matter which will be useful for interpreting DTI results in clinical populations.

Early MRI and outcomes of untreated patients with mild or improving ischemic stroke.

OBJECTIVE: To determine the frequency of early neurologic deterioration with infarct expansion (ENDIE) and poor outcomes among ischemic stroke patients not treated with reperfusion therapies because of rapidly improving or mild symptoms (RIMS) and to study the predictive value of hyperacute MRI in these patients. METHODS: We identified consecutive patients with symptoms of acute stroke undergoing multimodal MRI within 6 hours of onset without evidence of hemorrhage on imaging. Medical records were reviewed for evidence of early neurologic deterioration within 48 hours. All deteriorating patients had repeat MRI to ascertain causes of worsening. Poor outcome was defined as a discharge modified Rankin Scale (mRS) score of > or = 3. RESULTS: We identified 74 patients with stroke symptoms < or = 6 hours from onset. Forty had RIMS, and 39 did not receive reperfusion therapies because of RIMS. Among these 39, 4 experienced ENDIE, and 8 were discharged with mRS score of > or = 3. Eight of the 39 patients had large-vessel occlusions on MR angiography. Three of 8 patients with large-vessel occlusion as against only one of 31 patients without occlusion had ENDIE (odds ratio [OR] 18, 95% CI 1.6 to 209, p = 0.02). Four of 8 patients with large-vessel occlusion as against 4 of 31 patients without occlusion had a discharge mRS score of > or = 3 (OR 7, 95% CI 1.2 to 38, p = 0.04). CONCLUSIONS: About 10% of patients eligible for acute reperfusion therapy excluded on the basis of mild or rapidly improving symptoms show early neurologic deterioration with infarct expansion within 48 hours, and about 20% show poor outcome at discharge. Persisting large-vessel occlusion substantially increases the risk of early worsening and poor functional outcome.

Diffusion tensor MRI shows abnormal brainstem crossing fibers associated with ROBO3 mutations.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is caused by mutations in the ROBO3 gene, critical for the crossing of long ascending medial lemniscal and descending corticospinal tracts in the medulla. Diffusion tensor imaging in a patient with HGGPS revealed the absence of major pontine crossing fiber tracts and no decussation of the superior cerebellar peduncles. Mutations in the ROBO3 gene lead to a widespread lack of crossing fibers throughout the brainstem.

Comprehensive processing, display and analysis for in vivo MR spectroscopic imaging.

Image reconstruction for magnetic resonance spectroscopic imaging (MRSI) requires specialized spatial and spectral data processing methods and benefits from the use of several sources of prior information that are not commonly available, including MRI-derived tissue segmentation, morphological analysis and spectral characteristics of the observed metabolites. In addition, incorporating information obtained from MRI data can enhance the display of low-resolution metabolite images and multiparametric and regional statistical analysis methods can improve detection of altered metabolite distributions. As a result, full MRSI processing and analysis can involve multiple processing steps and several different data types. In this paper, a processing environment is described that integrates and automates these data processing and analysis functions for imaging of proton metabolite distributions in the normal human brain. The capabilities include normalization of metabolite signal intensities and transformation into a common spatial reference frame, thereby allowing the formation of a database of MR-measured human metabolite values as a function of acquisition, spatial and subject parameters. This development is carried out under the MIDAS project (Metabolite Imaging and Data Analysis System), which provides an integrated set of MRI and MRSI processing functions. It is anticipated that further development and distribution of these capabilities will facilitate more widespread use of MRSI for diagnostic imaging, encourage the development of standardized MRSI acquisition, processing and analysis methods and enable improved mapping of metabolite distributions in the human brain.

Hypercapnic exposure in congenital central hypoventilation syndrome reveals CNS respiratory control mechanisms.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses and loss of breathlessness to hypercapnia, yet arouse from sleep to high CO2, suggesting intact chemoreceptor afferents. The syndrome provides a means to differentiate brain areas controlling aspects of breathing. We used functional magnetic resonance imaging to determine brain structures responding to inspired 5% CO2-95% O2 in 14 CCHS patients and 14 controls. Global signal changes induced by the challenge were removed on a voxel-by-voxel basis. A priori-defined volume-of-interest time trends (assessed with repeated measures ANOVA) and cluster analysis based on modeling each subject to a step function (individual model parameter estimates evaluated with t-test, corrected for multiple comparisons) revealed three large response clusters to hypercapnia distinguishing the two groups, extending from the 1) posterior thalamus through the medial midbrain to the dorsolateral pons, 2) right caudate nucleus, ventrolaterally through the putamen and ventral insula to the mid-hippocampus, and 3) deep cerebellar nuclei to the dorsolateral cerebellar cortex bilaterally. Smaller clusters and defined areas of group signal differences in the midline dorsal medulla, amygdala bilaterally, right dorsal-posterior temporal cortex, and left anterior insula also emerged. In most sites, early transient or sustained responses developed in controls, with little, or inverse change in CCHS subjects. Limbic and medullary structures regulating responses to hypercapnia differed from those previously shown to mediate loaded breathing ventilatory response processing. The findings show the significant roles of cerebellar and basal ganglia sites in responding to hypercapnia and the thalamic and midbrain participation in breathing control.

Hypoxia reveals posterior thalamic, cerebellar, midbrain, and limbic deficits in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show deficient respiratory and cardiac responses to hypoxia and hypercapnia, despite apparently intact arousal responses to hypercapnia and adequate respiratory motor mechanisms, thus providing a model to evaluate functioning of particular brain mechanisms underlying breathing. We used functional magnetic resonance imaging to assess blood oxygen level-dependent signals, corrected for global signal changes, and evaluated them with cluster and volume-of-interest procedures, during a baseline and 2-min hypoxic (15% O(2), 85% N(2)) challenge in 14 CCHS and 14 age- and gender-matched control subjects. Hypoxia elicited significant (P < 0.05) differences in magnitude and timing of responses between groups in cerebellar cortex and deep nuclei, posterior thalamic structures, limbic areas (including the insula, amygdala, ventral anterior thalamus, and right hippocampus), dorsal and ventral midbrain, caudate, claustrum, and putamen. Deficient responses to hypoxia included no, or late, changes in CCHS patients with declining signals in control subjects, a falling signal in CCHS patients with no change in controls, or absent early transient responses in CCHS. Hypoxia resulted in signal declines but no group differences in hypothalamic and dorsal medullary areas, the latter being a target for PHOX2B, mutations of which occur in the syndrome. The findings extend previously identified posterior thalamic, midbrain, and cerebellar roles for normal mediation of hypoxia found in animal fetal and adult preparations and suggest significant participation of limbic structures in responding to hypoxic challenges, which likely include cardiovascular and air-hunger components. Failing structures in CCHS include areas additional to those associated with PHOX2B expression and chemoreceptor sites.

fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.

Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by diminished upper airway muscle phasic and tonic activation during sleep, but enhanced activity during waking. We evaluated neural mechanisms underlying these patterns with functional magnetic resonance imaging procedures during baseline and expiratory loading conditions in nine medication-free OSA and 16 control subjects. Both groups developed similar expiratory loading pressures, but appropriate autonomic responses did not emerge in OSA cases. Reduced neural signals emerged in OSA cases within the frontal cortex, anterior cingulate, cerebellar dentate nucleus, dorsal pons, anterior insula and lentiform nuclei. Signal increases in OSA over control subjects developed in the dorsal midbrain, hippocampus, quadrangular cerebellar lobule, ventral midbrain and ventral pons. Fastigial nuclei and the amygdala showed substantially increased variability in OSA subjects. No group differences were found in the thalamus. OSA patients show aberrant responses in multiple brain areas and inappropriate cardiovascular responses to expiratory loading, perhaps as a consequence of previously-demonstrated limbic, cerebellar and motor area gray matter loss.

Diffusion-perfusion MRI characterization of post-recanalization hyperperfusion in humans.

BACKGROUND: Animal and human studies have demonstrated that postischemic hyperperfusion may occur both early and late timepoints following acute cerebral ischemia. OBJECTIVE: To use diffusion-perfusion MRI to characterize hyperperfusion in humans following intra-arterial thrombolysis. METHODS: MRI were performed before treatment, several hours following vessel recanalization, and at day 7 in patients successfully recanalized with intra-arterial thrombolytics. RESULTS: Hyperperfusion was visualized in 5 of 12 patients within several hours after recanalization (mean volume, 18 mL; range, 7 to 40 mL), and in 6 of 11 patients at day 7 (mean volume, 28 mL; range, 4 to 45 mL). Within the core region of hyperperfusion, mean cerebral blood flow was 2.1 times greater than in the contralateral homologous region at the early time point, and 3.1 times greater at day 7. Seventy-nine percent of voxels with hyperperfusion at day 7 demonstrated infarction at day 7, whereas only 36% of voxels (within the initial hypoperfusion region) not showing hyperperfusion at day 7 demonstrated infarction at day 7. Mean pretreatment apparent diffusion coefficient (ADC) and perfusion values were more impaired in voxels that subsequently developed hyperperfusion compared with other at-risk voxels (all p values < 0.0001). There were no significant differences in the degree of clinical improvement in patients with regions of hyperperfusion versus those without, although sample size limited power to detect group differences. CONCLUSIONS: Postischemic hyperperfusion, visualized with perfusion MRI in humans following recanalization by intra-arterial thrombolytic therapy, occurred in about 40% of patients within hours and in about 50% of patients at day 7. Hyperperfusion developed mainly in regions that went on to infarction. Compared with other abnormal regions, tissues that developed postischemic hyperperfusion had greater bioenergetic compromise in pretreatment apparent diffusion coefficient values and greater impairment in pretreatment blood flow measures.

Time-to-echo optimization for spin echo magnetic resonance imaging of liver metastasis using superparamagnetic iron oxide particles.

Superparamagnetic iron oxide (SPIO) particles are used as a contrast agent in liver magnetic resonance imaging (MRI). SPIO particles exert their greatest influence on T2-weighted MR signal intensity. The time-to-echo (TE) value that provides optimal contrast has not been systematically studied over the range of clinically relevant field strengths. The purpose of this study was to quantitatively evaluate the TE dependence of the post-SPIO tumor to liver contrast-to-noise ratio (CNR). The hypothesis was that there is a TE that provides an optimal CNR. Subjects having probable metastatic hepatic lesions secondary to colorectal carcinoma were studied. Pre- and post-SPIO images were acquired at TE-effective (TE(eff)) equal to 46, 76, and 106 msec by using a turbo spin echo pulse sequence at 0.2 T and 1.5 T. The CNR for all lesions greater than 1 cm in diameter was determined in pre- and post-SPIO images. A paired statistical design was used to identify TE-related CNR dependencies. The primary findings were as follows. (1) CNR differences attributable to TE(eff) variation over the range of 46-106 msec were less than 34%. For 0.2 T, TE(eff) = 46 msec yielded a statistically significantly greater CNR than did TE(eff) = 76 or 106 msec. The same was true at the higher field strength, but differences were not significant. (2) Signal-to-noise measures suggested that SPIO reduced the lesion signal. (3) Post-SPIO CNR was significantly greater at 1.5 T than at 0.2 T. The observations indicate that over the field strength range of 0.2-1.5 T, CNR differences attributable to the TE(eff) variation, while being statistically significant in some cases, are small relative to those resulting from the SPIO administration.

Diffusion-perfusion MR evaluation of perihematomal injury in hyperacute intracerebral hemorrhage.

BACKGROUND: It has been suggested that a zone of perihematomal ischemia analogous to an ischemic penumbra exists in patients with primary intracerebral hemorrhage (ICH). Diffusion-perfusion MRI provides a novel means of assessing injury in perihematomal regions in patients with ICH. OBJECTIVE: To characterize diffusion-perfusion MRI changes in the perihematomal region in patients with hyperacute intracerebral hemorrhage. METHOD: Twelve patients presenting with hyperacute, primary ICH undergoing CT scanning and diffusion-perfusion MRI within 6 hours of symptom onset were reviewed. An automated thresholding technique was used to identify decreased apparent diffusion coefficient (ADC) values in the perihematomal regions. Perfusion maps were examined for regions of relative hypo- or hyperperfusion. RESULTS: Median baseline NIH Stroke Scale score was 17 (range, 6 to 28). Median hematoma volume was 13.3 mL (range, 3.0 to 74.8 mL). MRI detected the hematoma in all patients on echo-planar susceptibility-weighted imaging and in all seven patients imaged with gradient echo sequences. In six patients who underwent perfusion imaging, no focal defects were visualized on perfusion maps in tissues adjacent to the hematoma; however, five of six patients demonstrated diffuse ipsilateral hemispheric hypoperfusion. On diffusion imaging, perihematomal regions of decreased ADC values were identified in three of 12 patients. All three subsequently showed clinical and radiologic deterioration. CONCLUSIONS: A rim of perihematomal decreased ADC values was visualized in the hyperacute period in a subset of patients with ICH. The presence of a rim of decreased ADC outside the hematoma correlated with poor clinical outcome. Although perfusion maps did not demonstrate a focal zone of perihematomal decreased blood flow in any patient, most patients had ipsilateral hemispheric hypoperfusion.

Mapping therapeutic response in a patient with malignant glioma.

Short-interval scanning of patients offers a detailed understanding of the natural progression of tumor tissue, as revealed through imaging markers such as contrast enhancement and edema, prior to therapy. Following treatment, short-interval scanning can also provide evidence of attenuation of growth rates. We present a longitudinal imaging study of a patient with glioblastoma multiforme (GBM) scanned 15 times in 104 days on a 3 T MR scanner. Images were analyzed independently by two automated algorithms capable of creating detailed maps of tumor changes as well as volumetric analysis. The algorithms, a nearest-neighbor-based tissue segmentation and a surface-modeling algorithm, tracked the patient's response to temozolomide, showing an attenuation of growth. The need for surrogate imaging end-points, of which growth rates are an example, is discussed. Further, the strengths of these algorithms, the insight gained by short-interval scanning, and the need for a better understanding of imaging markers are also described.

Tracking tumor growth rates in patients with malignant gliomas: a test of two algorithms.

BACKGROUND AND PURPOSE: Two 3D image analysis algorithms, nearest-neighbor tissue segmentation and surface modeling, were applied separately to serial MR images in patients with glioblastoma multiforme (GBM). Rates of volumetric change were tracked for contrast-enhancing tumor tissue. Our purpose was to compare the two image analysis algorithms in their ability to track tumor volume relative to a manually defined standard of reference. METHODS: Three-dimensional T2-weighted and contrast-enhanced T1-weighted spoiled gradient-echo MR volumes were acquired in 10 patients with GBM. One of two protocols was observed: 1) a nearest-neighbor algorithm, which used manually determined or propagated tags and automatically segmented tissues into specific classes to determine tissue volume; or 2) a surface modeling algorithm, which used operator-defined contrast-enhancing boundaries to convert traced points into a parametric mesh model. Volumes were automatically calculated from the mesh models. Volumes determined by each algorithm were compared with the standard of reference, generated by manual segmentation of contrast-enhancing tissue in each cross section of a scan. RESULTS: Nearest-neighbor algorithm enhancement volumes were highly correlated with manually segmented volumes, as were growth rates, which were measured in terms of halving and doubling times. Enhancement volumes generated by the surface modeling algorithm were also highly correlated with the standard of reference, although growth rates were not. CONCLUSION: The nearest-neighbor tissue segmentation algorithm provides significant power in quantifying tumor volume and in tracking growth rates of contrast-enhancing tissue in patients with GBM. The surface modeling algorithm is able to quantify tumor volume reliably as well.

Visualization of sleep influences on cerebellar and brainstem cardiac and respiratory control mechanisms.

Cerebellar and vestibular structures exert substantial influences on breathing and cardiovascular activity, particularly under conditions of extreme challenges. Influences from these structures, as well as from the ventral medullary surface, are greatly modified during sleep states. Vestibular lesions abolish the pronounced phasic autonomic variation found in the rapid eye movement sleep state, and spontaneous ventral medullary surface activity, as assessed by optical procedures, is greatly diminished in that state. Neural responses from the ventral medullary surface to hypotensive challenges are enhanced and appear "undampened" during the rapid eye movement sleep state. Functional magnetic resonance imaging reveals activation to blood pressure challenges in widespread brain areas of humans, and especially in cerebellar sites, such as the fastigial nucleus. A subset of victims of sudden infant death syndrome, a sleep-related disorder, appear to succumb from cardiovascular failure of a shock-like nature, and often show neurotransmitter receptor deficiencies in the ventral medullary surface, caudal midline raphe hypotensive regions, and the inferior olive, a major afferent relay to the cerebellum. Afferent and efferent vestibular/cerebellar structures, or sites within the cerebellum may mediate failure mechanisms in sudden infant death syndrome and a number of other sleep-disordered breathing and cardiovascular syndromes.

Regulatory, financial and ethical aspects of routine clinical magnetic resonance spectroscopy.

After years of technological development, magnetic resonance spectroscopy (MRS) is now being used with increasing frequency as a routine diagnostic tool for medical evaluation of patients. The transition of MRS from the realm of pure research to that of routine clinical application has been accompanied by some confusion regarding regulatory, financial and ethical matters. This contribution summarizes these issues from the author's perspective and calls for increased discussion and learning within the MRS community regarding practical matters associated with routine clinical implementation of MRS.