The dynamics of cerebrovascular reactivity shown with transfer function analysis.

Cerebrovascular reactivity (CVR) is often defined as the increase in cerebral blood flow (CBF) produced by an increase in carbon dioxide (CO2) and may be used clinically to assess the health of the cerebrovasculature. When CBF is estimated using blood oxygen level dependent (BOLD) magnetic resonance imaging, CVR values for each voxel can be displayed using a color scale mapped onto the corresponding anatomical scan. While these CVR maps therefore show the distribution of cerebrovascular reactivity, they only provide an estimate of the magnitude of the cerebrovascular response, and do not indicate the time course of the response; whether rapid or slow. Here we describe transfer function analysis (TFA) of the BOLD response to CO2 that provides not only the magnitude of the response (gain) but also the phase and coherence. The phase can be interpreted as indicating the speed of response and so can distinguish areas where the response is slowed. The coherence measures the fidelity with which the response follows the stimulus. The examples of gain, phase and coherence maps obtained from TFA of previously recorded test data from patients and healthy individuals demonstrate that these maps may enhance assessment of cerebrovascular pathophysiology by providing insight into the dynamics of cerebral blood flow control and distribution.

A conceptual model for CO2-induced redistribution of cerebral blood flow with experimental confirmation using BOLD MRI.

Cerebrovascular reactivity (CVR) is the change in cerebral blood flow (CBF) in response to a change in a vasoactive stimulus. Paradoxical reductions in CBF in response to vasodilatory stimulation ('steal') are associated with vascular pathology. However, a pathophysiological interpretation of 'steal' requires a comprehensive conceptual model linking pathology and changes in blood flow. Herein, we extend a simple model explaining steal published in the late 1960s by incorporating concepts of CBF regulation from more recent studies to generate a comprehensive dynamic model. The main elements of the model are: (a) the relationship between changes in CBF and the arterial partial pressure of carbon dioxide (PaCO2) in healthy vascular regions is sigmoidal; (b) vascular regions vasodilate to compensate for decreased perfusion pressure, leading to (c) an encroachment on vasodilatory reserve and, reduced CVR; (d) a vasodilatory stimulus may increase CBF capacity above the flow capacity of major cerebral blood vessels; and (e) this limitation induces competitive intra-cerebral redistribution of flow from territories with low vasodilatory reserve to those with high reserve. We used CVR measurements generated by applying precise, computer-controlled changes in PaCO2 as the vasoactive stimulus, and measured blood oxygen level dependent (BOLD) MRI signals as high resolution surrogates of CBF to test predictions derived from this model. Subjects were 16 healthy adults and 16 patients with known cerebral steno-occlusive diseases. We observed regional sigmoidal PaCO2-BOLD response curves with a range of slopes; graded changes in PaCO2 resulted in redistributions of BOLD signal consistent with the known underlying vascular pathology and predictions of the model. We conclude that this model can be applied to provide a hemodynamic interpretation to BOLD signal changes in response to hypercapnia, and thereby aid in relating CVR maps to pathophysiological conditions.

Measuring cerebrovascular reactivity: what stimulus to use?

Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasodilatory or vasoconstrictive stimulus. Measuring variations of cerebrovascular reactivity between different regions of the brain has the potential to not only advance understanding of how the cerebral vasculature controls the distribution of blood flow but also to detect cerebrovascular pathophysiology. While there are standardized and repeatable methods for estimating the changes in cerebral blood flow in response to a vasoactive stimulus, the same cannot be said for the stimulus itself. Indeed, the wide variety of vasoactive challenges currently employed in these studies impedes comparisons between them. This review therefore critically examines the vasoactive stimuli in current use for their ability to provide a standard repeatable challenge and for the practicality of their implementation. Such challenges include induced reductions in systemic blood pressure, and the administration of vasoactive substances such as acetazolamide and carbon dioxide. We conclude that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time. We suggest that carbon dioxide is the most suitable vasoactive stimulus. We describe recently developed computer-controlled MRI compatible gas delivery systems which are capable of administering reliable and repeatable vasoactive CO2 stimuli.

Decoding the ancient Greek astronomical calculator known as the Antikythera Mechanism.

The Antikythera Mechanism is a unique Greek geared device, constructed around the end of the second century bc. It is known that it calculated and displayed celestial information, particularly cycles such as the phases of the moon and a luni-solar calendar. Calendars were important to ancient societies for timing agricultural activity and fixing religious festivals. Eclipses and planetary motions were often interpreted as omens, while the calm regularity of the astronomical cycles must have been philosophically attractive in an uncertain and violent world. Named after its place of discovery in 1901 in a Roman shipwreck, the Antikythera Mechanism is technically more complex than any known device for at least a millennium afterwards. Its specific functions have remained controversial because its gears and the inscriptions upon its faces are only fragmentary. Here we report surface imaging and high-resolution X-ray tomography of the surviving fragments, enabling us to reconstruct the gear function and double the number of deciphered inscriptions. The mechanism predicted lunar and solar eclipses on the basis of Babylonian arithmetic-progression cycles. The inscriptions support suggestions of mechanical display of planetary positions, now lost. In the second century bc, Hipparchos developed a theory to explain the irregularities of the Moon's motion across the sky caused by its elliptic orbit. We find a mechanical realization of this theory in the gearing of the mechanism, revealing an unexpected degree of technical sophistication for the period.

Clinical features of patients with blepharospasm: a report of 240 patients.

BACKGROUND AND PURPOSE: To characterize patients with benign essential blepharospasm (BEB) by diagnosis, environmental risk factors, and family history. METHODS: Two hundred and forty patients with BEB were evaluated through a clinical examination and questionnaire. The questionnaire reviewed personal medical history, demographic factors, risk factors for the development of blepharospasm and family history of dystonia and other neurological conditions. RESULTS: Benign essential blepharospasm was more commonly found in women (2.8:1) and 93% of the patients were Caucasian. Fifty percent had pure BEB, 31% had BEB/Meige's syndrome, and 4% had BEB and eyelid opening apraxia (+/- Meige's syndrome). A minority of patients reported preceding photophobia (25%) or other eye conditions (22%). The majority were non-smokers, had no exposure to anti-emetic or antipsychotic agents, had a normal birth history, and had no history of head trauma. Seventy-two percent did report a stressful event immediately prior to the development of symptoms. Treatments reported included botulinum toxin (BoNT), oral medications, surgical procedures, and acupuncture. Thirty-two percent of patients reported a family history of focal dystonia, and BEB was the most commonly reported. CONCLUSION: This study confirms previous reports of usual age, sex, caffeine and tobacco use, and family history in patients with blepharospasm. New findings include a report on occupation, lower reports of preceding eye conditions and photophobia, and higher reported stressful events. Further, this study shows a change in treatment with an increase in BoNT use and decrease in surgical procedures.

Improved White Matter Cerebrovascular Reactivity after Revascularization in Patients with Steno-Occlusive Disease.

BACKGROUND AND PURPOSE: One feature that patients with steno-occlusive cerebrovascular disease have in common is the presence of white matter (WM) lesions on MRI. The purpose of this study was to evaluate the effect of direct surgical revascularization on impaired WM cerebrovascular reactivity in patients with steno-occlusive disease. MATERIALS AND METHODS: We recruited 35 patients with steno-occlusive disease, Moyamoya disease (n = 24), Moyamoya syndrome (n = 3), atherosclerosis (n = 6), vasculitis (n = 1), and idiopathic stenosis (n = 1), who underwent unilateral brain revascularization using a direct superficial temporal artery-to-MCA bypass (19 women; mean age, 45.8 ± 16.5 years). WM cerebrovascular reactivity was measured preoperatively and postoperatively using blood oxygen level-dependent (BOLD) MR imaging during iso-oxic hypercapnic changes in end-tidal carbon dioxide and was expressed as %Δ BOLD MR signal intensity per millimeter end-tidal partial pressure of CO2. RESULTS: WM cerebrovascular reactivity significantly improved after direct unilateral superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in the revascularized hemisphere in the MCA territory (mean ± SD, -0.0005 ± 0.053 to 0.053 ± 0.046 %BOLD/mm Hg; P < .0001) and in the anterior cerebral artery territory (mean, 0.0015 ± 0.059 to 0.021 ± 0.052 %BOLD/mm Hg; P = .005). There was no difference in WM cerebrovascular reactivity in the ipsilateral posterior cerebral artery territory nor in the vascular territories of the nonrevascularized hemisphere (P < .05). CONCLUSIONS: Cerebral revascularization surgery is an effective treatment for reversing preoperative cerebrovascular reactivity deficits in WM. In addition, direct-STA-MCA bypass may prevent recurrence of preoperative symptoms.

Behavioural characterisation of the alpha-mannosidosis guinea pig.

alpha-Mannosidosis is a lysosomal storage disorder resulting from a functional deficiency of the lysosomal enzyme alpha-mannosidase. This deficiency results in the accumulation of various oligosaccharides in the lysosomes of affected individuals, causing somatic pathology and progressive neurological degeneration that results in cognitive deficits, ataxia, and other neurological symptoms. We have a naturally occurring guinea pig model of this disease which exhibits a deficiency of lysosomal alpha-mannosidase and has a similar clinical presentation to human alpha-mannosidosis. Various tests were developed in the present study to characterise and quantitate the loss of neurological function in alpha-mannosidosis guinea pigs and to follow closely the progression of the disease. General neurological examinations showed progressive differences in alpha-mannosidosis animals from approximately 1 month of age. Significant differences were observed in hind limb gait width from 2 months of age and significant cognitive (memory and learning) deficits were observed from 3 months of age. Evoked response tests showed an increase in somatosensory P1 peak latency in alpha-mannosidosis guinea pigs from approximately 2 months of age, as well as progressive hearing loss using auditory brainstem evoked responses. The alpha-mannosidosis guinea pig therefore appears to exhibit many of the characteristics of the human disease, and will be useful in evaluating therapies for treatment of central nervous system pathology.

A multimodal cortical network for the detection of changes in the sensory environment.

Sensory stimuli undergoing sudden changes draw attention and preferentially enter our awareness. We used event-related functional magnetic-resonance imaging (fMRI) to identify brain regions responsive to changes in visual, auditory and tactile stimuli. Unimodally responsive areas included visual, auditory and somatosensory association cortex. Multimodally responsive areas comprised a right-lateralized network including the temporoparietal junction, inferior frontal gyrus, insula and left cingulate and supplementary motor areas. These results reveal a distributed, multimodal network for involuntary attention to events in the sensory environment. This network contains areas thought to underlie the P300 event-related potential and closely corresponds to the set of cortical regions damaged in patients with hemineglect syndromes.

Neural correlates of prickle sensation: a percept-related fMRI study.

The painful sensations produced by a laceration, freeze, burn, muscle strain or internal injury are readily distinguishable because each is characterized by a particular sensory quality such as sharp, aching, burning or prickling. We propose that there are specific neural correlates of each pain quality, and here we used a new functional magnetic resonance imaging (fMRI) method to identify time-locked responses to prickle sensations that were evoked by noxious cold stimuli. With percept-related fMRI, we identified prickle-related brain activations in the anterior cingulate cortex (ACC), insula, secondary somatosensory cortex (S2), prefrontal cortex (PFC), premotor cortex (PMC), caudate nucleus and dorsomedial thalamus, indicating that multiple pain, sensory and motor areas act together to produce the prickle sensation.

Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes.

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-4-sulfatase (4S). A feline MPS VI model used to demonstrate efficacy of enzyme replacement therapy is due to the homozygous presence of an L476P mutation in 4-sulfatase. An additional mutation, D520N, inherited independently from L476P and recently identified in the same family of cats, has resulted in three clinical phenotypes. L476P homozygotes exhibit dwarfism and facial dysmorphia due to epiphyseal dysplasia, abnormally low leukocyte 4S/betahexosaminidase ratios, dermatan sulfaturia, lysosomal inclusions in most tissues including chondrocytes, corneal clouding, degenerative joint disease, and abnormal leukocyte inclusions. Similarly, D520N/D520N and L476P/D520N cats have abnormally low leukocyte 4S/betahexosaminidase ratios, mild dermatan sulfaturia, lysosomal inclusions in some chondrocytes, and abnormal leukocyte inclusions. However, both have normal growth and appearance. In addition, L476P/D520N cats have a high incidence of degenerative joint disease. We conclude that L476P/D520N cats have a very mild MPS VI phenotype not previously described in MPS VI humans. The study of L476P/D520N and D520N/ D520N genotypes will improve understanding of genotype to phenotype correlations and the pathogenesis of skeletal dysplasia and joint disease in MPS VI, and will assist in development of therapies to prevent lysosomal storage in chondrocytes.

Enzyme replacement therapy from birth in a feline model of mucopolysaccharidosis type VI.

We report evidence of a dose responsive effect of enzyme replacement therapy in mucopolysaccharidosis type VI cats from birth, at the clinical, biochemical, and histopathological level. Cats treated with weekly, intravenous recombinant human N-acetylgalactosamine-4-sulfatase at 1 and 5 mg/kg, were heavier, more flexible, had greatly reduced or no spinal cord compression, and had almost normal urinary glycosaminoglycan levels. There was near normalization or complete reversal of lysosomal storage in heart valve, aorta, skin, dura, liver, and brain perivascular cells. No reduction in lysosomal vacuolation was observed in cartilage or cornea; however, articular cartilage was thinner and external ear pinnae were larger in some treated cats. Degenerative joint changes were not obviously delayed in treated cats. Skeletal pathology was reduced, with more normalized bone dimensions and with more uniform bone density and trabecular pattern clearly visible on radiographs by 5 to 6 mo; however, differences between 1 and 5 mg/kg dose rates were not clearly distinguishable. At a dose of 0.2 mg/kg, disease was not significantly altered in the majority of parameters examined. Lysosomal storage was present in all tissues examined in the midterm mucopolysaccharidosis type VI fetus and increased rapidly in extent and severity from birth.

Enzyme replacement therapy in a feline model of Maroteaux-Lamy syndrome.

We report studies that suggest enzyme replacement therapy will result in a significant reduction in disease progression and tissue pathology in patients with Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). A feline model for MPS VI was used to evaluate tissue distribution and clinical efficacy of three forms of recombinant human N-acetylgalactosamine-4-sulfatase (rh4S, EC 3.1.6.1). Intravenously administered rh4S was rapidly cleared from circulation. The majority of rh4S was distributed to liver, but was also detected in most other tissues. Tissue half-life was approximately 2-4 d. Three MPS VI cats given regular intravenous infusions of rh4S for up to 20 mo showed variable reduction of storage vacuoles in Kupffer cells and connective tissues, however cartilage chondrocytes remained vacuolated. Vertebral bone mineral volume was improved in two MPS VI cats in which therapy was initiated before skeletal maturity, and increased bone volume appeared to correlate with earlier age of onset of therapy. One cat showed greater mobility in response to therapy.

A Novel MRI Biomarker of Spinal Cord White Matter Injury: T2*-Weighted White Matter to Gray Matter Signal Intensity Ratio.

BACKGROUND AND PURPOSE: T2*-weighted imaging provides sharp contrast between spinal cord GM and WM, allowing their segmentation and cross-sectional area measurement. Injured WM demonstrates T2*WI hyperintensity but requires normalization for quantitative use. We introduce T2*WI WM/GM signal-intensity ratio and compare it against cross-sectional area, the DTI metric fractional anisotropy, and magnetization transfer ratio in degenerative cervical myelopathy. MATERIALS AND METHODS: Fifty-eight patients with degenerative cervical myelopathy and 40 healthy subjects underwent 3T MR imaging, covering C1-C7. Metrics were automatically extracted at maximally compressed and uncompressed rostral/caudal levels. Normalized metrics were compared with t tests, area under the curve, and logistic regression. Relationships with clinical measures were analyzed by using Pearson correlation and multiple linear regression. RESULTS: The maximally compressed level cross-sectional area demonstrated superior differences (P = 1 × 10-13), diagnostic accuracy (area under the curve = 0.890), and univariate correlation with the modified Japanese Orthopedic Association score (0.66). T2*WI WM/GM showed strong differences (rostral: P = 8 × 10-7; maximally compressed level: P = 1 × 10-11; caudal: P = 1 × 10-4), correlations (modified Japanese Orthopedic Association score; rostral: -0.52; maximally compressed level: -0.59; caudal: -0.36), and diagnostic accuracy (rostral: 0.775; maximally compressed level: 0.860; caudal: 0.721), outperforming fractional anisotropy and magnetization transfer ratio in most comparisons and cross-sectional area at rostral/caudal levels. Rostral T2*WI WM/GM showed the strongest correlations with focal motor (-0.45) and sensory (-0.49) deficits and was the strongest independent predictor of the modified Japanese Orthopedic Association score (P = .01) and diagnosis (P = .02) in multivariate models (R2 = 0.59, P = 8 × 10-13; area under the curve = 0.954, respectively). CONCLUSIONS: T2*WI WM/GM shows promise as a novel biomarker of WM injury. It detects damage in compressed and uncompressed regions and contributes substantially to multivariate models for diagnosis and correlation with impairment. Our multiparametric approach overcomes limitations of individual measures, having the potential to improve diagnostics, monitor progression, and predict outcomes.

Clinically Feasible Microstructural MRI to Quantify Cervical Spinal Cord Tissue Injury Using DTI, MT, and T2*-Weighted Imaging: Assessment of Normative Data and Reliability.

BACKGROUND AND PURPOSE: DTI, magnetization transfer, T2*-weighted imaging, and cross-sectional area can quantify aspects of spinal cord microstructure. However, clinical adoption remains elusive due to complex acquisitions, cumbersome analysis, limited reliability, and wide ranges of normal values. We propose a simple multiparametric protocol with automated analysis and report normative data, analysis of confounding variables, and reliability. MATERIALS AND METHODS: Forty healthy subjects underwent T2WI, DTI, magnetization transfer, and T2*WI at 3T in <35 minutes using standard hardware and pulse sequences. Cross-sectional area, fractional anisotropy, magnetization transfer ratio, and T2*WI WM/GM signal intensity ratio were calculated. Relationships between MR imaging metrics and age, sex, height, weight, cervical cord length, and rostrocaudal level were analyzed. Test-retest coefficient of variation measured reliability in 24 DTI, 17 magnetization transfer, and 16 T2*WI datasets. DTI with and without cardiac triggering was compared in 10 subjects. RESULTS: T2*WI WM/GM showed lower intersubject coefficient of variation (3.5%) compared with magnetization transfer ratio (5.8%), fractional anisotropy (6.0%), and cross-sectional area (12.2%). Linear correction of cross-sectional area with cervical cord length, fractional anisotropy with age, and magnetization transfer ratio with age and height led to decreased coefficients of variation (4.8%, 5.4%, and 10.2%, respectively). Acceptable reliability was achieved for all metrics/levels (test-retest coefficient of variation < 5%), with T2*WI WM/GM comparing favorably with fractional anisotropy and magnetization transfer ratio. DTI with and without cardiac triggering showed no significant differences for fractional anisotropy and test-retest coefficient of variation. CONCLUSIONS: Reliable multiparametric assessment of spinal cord microstructure is possible by using clinically suitable methods. These results establish normalization procedures and pave the way for clinical studies, with the potential for improving diagnostics, objectively monitoring disease progression, and predicting outcomes in spinal pathologies.

Perfusion-weighted MR imaging studies in brain hypervascular diseases: comparison of arterial input function extractions for perfusion measurement.

BACKGROUND AND PURPOSE: Brain hypervascular diseases are complex and induce hemodynamic disturbances on brain parenchyma, which are difficult to accurately evaluate by using perfusion-weighted (PWI) MR imaging. Our purpose was to test and to assess the best AIF estimation method among 4 patients with brain hypervascular disease and healthy volunteers. METHODS: Thirty-three patients and 10 healthy volunteers underwent brain perfusion studies by using a 1.5T MR imaging scanner with gadolinium-chelate bolus injection. PWI was performed with the indicator dilution method. AIF estimation methods were performed with local, regional, regional scaled, and global estimated arterial input function (AIF), and PWI measurements (cerebral blood volume [CBV] and cerebral blood flow [CBF]) were performed with regions of interest drawn on the thalami and centrum semiovale in all subjects, remote from the brain hypervascular disease nidus. Abnormal PWI results were assessed by using Z Score, and evaluation of the best AIF estimation method was performed by using a no gold standard evaluation method. RESULTS: From 88% to 97% of patients had overall abnormal perfusion areas of hypo- (decreased CBV and CBF) and/or hyperperfusion (increased CBV and CBF) and/or venous congestion (increased CBV, normal or decreased CBF), depending on the AIF estimation method used for PWI computations. No gold standard evaluation of the 4 AIF estimates found the regional and the regional scaled methods to be the most accurate. CONCLUSION: Brain hypervascular disease induces remote brain perfusion abnormalities that can be better detected by using PWI with regional or regional scaled AIF estimation methods.

Comparing language lateralization determined by dichotic listening and fMRI activation in frontal and temporal lobes in children with epilepsy.

We investigated the relationship between ear advantage scores on the Fused Dichotic Words Test (FDWT), and laterality of activation in fMRI using a verb generation paradigm in fourteen children with epilepsy. The magnitude of the laterality index (LI), based on spatial extent and magnitude of activation in classical language areas (BA 44/45, 21/22, 39) differed significantly for patients classified with unilateral left, compared to bilateral, language representation based on FDWT scores. Concordance with fMRI was higher for those classified with unilateral left, than bilateral language representation on the FDWT. Of note, asymmetry in temporal lobe, rather than frontal lobe, activation was more strongly related to the LI from the dichotic listening test. This study shows that the FDWT can provide a quick and valid estimate of lateralization in pre-surgical candidates, which can be readily adopted for other clinical or research purposes when an estimate of language dominance is desired.

Identifying Significant Changes in Cerebrovascular Reactivity to Carbon Dioxide.

BACKGROUND AND PURPOSE: Changes in cerebrovascular reactivity can be used to assess disease progression and response to therapy but require discrimination of pathology from normal test-to-test variability. Such variability is due to variations in methodology, technology, and physiology with time. With uniform test conditions, our aim was to determine the test-to-test variability of cerebrovascular reactivity in healthy subjects and in patients with known cerebrovascular disease. MATERIALS AND METHODS: Cerebrovascular reactivity was the ratio of the blood oxygen level-dependent MR imaging response divided by the change in carbon dioxide stimulus. Two standardized cerebrovascular reactivity tests were conducted at 3T in 15 healthy men (36.7 ± 16.1 years of age) within a 4-month period and were coregistered into standard space to yield voxelwise mean cerebrovascular reactivity interval difference measures, composing a reference interval difference atlas. Cerebrovascular reactivity interval difference maps were prepared for 11 male patients. For each patient, the test-retest difference of each voxel was scored statistically as z-values of the corresponding voxel mean difference in the reference atlas and then color-coded and superimposed on the anatomic images to create cerebrovascular reactivity interval difference z-maps. RESULTS: There were no significant test-to-test differences in cerebrovascular reactivity in either gray or white matter (mean gray matter, P = .431; mean white matter, P = .857; paired t test) in the healthy cohort. The patient cerebrovascular reactivity interval difference z-maps indicated regions where cerebrovascular reactivity increased or decreased and the probability that the changes were significant. CONCLUSIONS: Accounting for normal test-to-test differences in cerebrovascular reactivity enables the assessment of significant changes in disease status (stability, progression, or regression) in patients with time.

Frontotemporal correlates of impulsivity and machine learning in retired professional athletes with a history of multiple concussions.

The frontotemporal cortical network is associated with behaviours such as impulsivity and aggression. The health of the uncinate fasciculus (UF) that connects the orbitofrontal cortex (OFC) with the anterior temporal lobe (ATL) may be a crucial determinant of behavioural regulation. Behavioural changes can emerge after repeated concussion and thus we used MRI to examine the UF and connected gray matter as it relates to impulsivity and aggression in retired professional football players who had sustained multiple concussions. Behaviourally, athletes had faster reaction times and an increased error rate on a go/no-go task, and increased aggression and mania compared to controls. MRI revealed that the athletes had (1) cortical thinning of the ATL, (2) negative correlations of OFC thickness with aggression and task errors, indicative of impulsivity, (3) negative correlations of UF axial diffusivity with error rates and aggression, and (4) elevated resting-state functional connectivity between the ATL and OFC. Using machine learning, we found that UF diffusion imaging differentiates athletes from healthy controls with significant classifiers based on UF mean and radial diffusivity showing 79-84 % sensitivity and specificity, and 0.8 areas under the ROC curves. The spatial pattern of classifier weights revealed hot spots at the orbitofrontal and temporal ends of the UF. These data implicate the UF system in the pathological outcomes of repeated concussion as they relate to impulsive behaviour. Furthermore, a support vector machine has potential utility in the general assessment and diagnosis of brain abnormalities following concussion.

Vascular Dysfunction in Leukoaraiosis.

BACKGROUND AND PURPOSE: The pathogenesis of leukoaraiosis has long been debated. This work addresses a less well-studied mechanism, cerebrovascular reactivity, which could play a leading role in the pathogenesis of this disease. Our aim was to evaluate blood flow dysregulation and its relation to leukoaraiosis. MATERIALS AND METHODS: Cerebrovascular reactivity, the change in the blood oxygen level-dependent 3T MR imaging signal in response to a consistently applied step change in the arterial partial pressure of carbon dioxide, was measured in white matter hyperintensities and their contralateral spatially homologous normal-appearing white matter in 75 older subjects (age range, 50-91 years; 40 men) with leukoaraiosis. Additional quantitative evaluation of regions of leukoaraiosis was performed by using diffusion (n = 75), quantitative T2 (n = 54), and DSC perfusion MRI metrics (n = 25). RESULTS: When we compared white matter hyperintensities with contralateral normal-appearing white matter, cerebrovascular reactivity was lower by a mean of 61.2% ± 22.6%, fractional anisotropy was lower by 44.9 % ± 6.9%, and CBF was lower by 10.9% ± 11.9%. T2 was higher by 61.7% ± 13.5%, mean diffusivity was higher by 59.0% ± 11.7%, time-to-maximum was higher by 44.4% ± 30.4%, and TTP was higher by 6.8% ± 5.8% (all P < .01). Cerebral blood volume was lower in white matter hyperintensities compared with contralateral normal-appearing white matter by 10.2% ± 15.0% (P = .03). CONCLUSIONS: Not only were resting blood flow metrics abnormal in leukoaraiosis but there is also evidence of reduced cerebrovascular reactivity in these areas. Studies have shown that reduced cerebrovascular reactivity is more sensitive than resting blood flow parameters for assessing vascular insufficiency. Future work is needed to examine the sensitivity of resting-versus-dynamic blood flow measures for investigating the pathogenesis of leukoaraiosis.

Evaluation of fibroblast-mediated gene therapy in a feline model of mucopolysaccharidosis type VI.

Fibroblast-mediated ex vivo gene therapy was evaluated in the N-acetylgalactosamine 4-sulfatase (4S) deficient mucopolysaccharidosis type VI (MPS VI) cat. Skin biopsies were obtained at birth from severely affected MPS VI kittens and used to initiate fibroblast outgrowths for retroviral transduction with the 4S cDNA. 4S gene expression in transduced cells was under the transcriptional control of the MoMLV long terminal repeat promoter or the cytomegalovirus (CMV) immediate-early promoter. Characterisation of gene-transduced fibroblasts demonstrated the cells to be over-expressing 4S activity. Twenty-four to forty million autologous, gene-corrected fibroblasts were implanted under the renal capsule of three MPS VI kittens at 8-16 weeks of age. Transient, low levels of 4S activity were detected in peripheral blood leukocytes shortly after implantation but were not detectable within 3-8 weeks' post-implantation. Long-term biochemical and clinical evaluation of these cats demonstrated identical disease progression to that previously described in untreated, clinically severe MPS VI cats.