PENALIZED FUNCTIONAL REGRESSION

We develop fast fitting methods for generalized functional linear models. An undersmooth of the functional predictor is obtained by projecting on a large number of smooth eigenvectors and the coefficient function is estimated using penalized spline regression. Our method can be applied to many functional data designs including functions measured with and without error, sparsely or densely sampled. The methods also extend to the case of multiple functional predictors or functional predictors with a natural multilevel structure. Our approach can be implemented using standard mixed effects software and is computationally fast. Our methodology is motivated by a diffusion tensor imaging (DTI) study. The aim of this study is to analyze differences between various cerebral white matter tract property measurements of multiple sclerosis (MS) patients and controls. While the statistical developments proposed here were motivated by the DTI study, the methodology is designed and presented in generality and is applicable to many other areas of scientific research. An online appendix provides R implementations of all simulations.

NONLINEAR TUBE-FITTING FOR THE ANALYSIS OF ANATOMICAL AND FUNCTIONAL STRUCTURES

We are concerned with the estimation of the exterior surface of tube-shaped anatomical structures. This interest is motivated by two distinct scientific goals, one dealing with the distribution of HIV microbicide in the colon and the other with measuring degradation in white-matter tracts in the brain. Our problem is posed as the estimation of the support of a distribution in three dimensions from a sample from that distribution, possibly measured with error. We propose a novel tube-fitting algorithm to construct such estimators. Further, we conduct a simulation study to aid in the choice of a key parameter of the algorithm, and we test our algorithm with validation study tailored to the motivating data sets. Finally, we apply the tube-fitting algorithm to a colon image produced by single photon emission computed tomography (SPECT)and to a white-matter tract image produced using diffusion tensor `imaging (DTI).

Hepatic encephalomyelopathy in a calf with congenital portosystemic shunt (CPSS)

A 4-month-old female Holstein Friesian calf was referred to the Veterinary Teaching Hospital, University of Berne, Switzerland for evaluation of ataxia, weakness, apathy and stunted growth. Clinical examination revealed generalized ataxia, propioceptive deficits, decreased menace response and sensibility. Postmortem examination did not reveal macroscopic changes of major organs. Histologically, the brain and the spinal cord lesions were characterized by polymicrocavitation, preferentially affecting the white matter fibers at the junction of grey and white matter and by the presence of Alzheimer type II cells. The liver revealed lesions consistent with a congenital portosystemic shunt, characterized by increased numbers of arteriolar profiles and hypoplasia to absence of portal veins. The pathological investigations along with the animal history and clinical signs indicated a hepatic encephalomyelopathy due to a congenital portosystemic shunt.

Prospective navigator-echo-based real-time triggering of fetal head movement for the reduction of artifacts

The purpose of this study was to evaluate the neuroimaging quality and accuracy of prospective real-time navigator-echo acquisition correction versus untriggered intrauterine magnetic resonance imaging (MRI) techniques. Twenty women in whom fetal motion artifacts compromised the neuroimaging quality of fetal MRI taken during the 28.7 +/- 4 week of pregnancy below diagnostic levels were additionally investigated using a navigator-triggered half-Fourier acquired single-shot turbo-spin echo (HASTE) sequence. Imaging quality was evaluated by two blinded readers applying a rating scale from 1 (not diagnostic) to 5 (excellent). Diagnostic criteria included depiction of the germinal matrix, grey and white matter, CSF, brain stem and cerebellum. Signal-difference-to-noise ratios (SDNRs) in the white matter and germinal zone were quantitatively evaluated. Imaging quality improved in 18/20 patients using the navigator echo technique (2.4 +/- 0.58 vs. 3.65 +/- 0.73 SD, p < 0.01 for all evaluation criteria). In 2/20 patients fetal movement severely impaired image quality in conventional and navigated HASTE. Navigator-echo imaging revealed additional structural brain abnormalities and confirmed diagnosis in 8/20 patients. The accuracy improved from 50% to 90%. Average SDNR increased from 0.7 +/- 7.27 to 19.83 +/- 15.71 (p < 0.01). Navigator-echo-based real-time triggering of fetal head movement is a reliable technique that can deliver diagnostic fetal MR image quality despite vigorous fetal movement.

Cerebral connectivity and psychotic personality traits : A diffusion tensor imaging study

This study aims to investigate the relationship between regional connectivity in the brain white matter and the presence of psychotic personality traits, in healthy subjects with psychotic traits. Thirteen healthy controls were administered the MMPI-2, to assess psychotic traits and, according to MMPI results, a dichotomization into a group of "high-psychotic" and "low-psychotic" was performed. Diffusion tensor imaging (DTI) was used as a non-invasive measure, in order to obtain information about the fractional anisotropy (FA), an intravoxel index of local connectivity and, by means of a voxelwise approach, the between-group differences of the FA values were calculated. The "high-psychotic" group showed higher FA in the left arcuate fasciculus. Subjects with low scores for psychotic traits had significantly higher FA in the corpus callosum, right arcuate fasciculus, and fronto-parietal fibers. In line with previous brain imaging studies of schizophrenia spectrum disorders, our results suggest that psychotic personality traits are related to altered connectivity and brain asymmetry.

Reduced hippocampal anisotropy related to anteriorization of alpha EEG in schizophrenia

Dysfunctions of the hippocampus have been suggested to be related to schizophrenia, and reduced connectivity with other brain regions may be a key for the pathophysiology. The aim of this study was to investigate the effect of white matter anomalies in the hippocampus, as a sign of altered connectivity, on the brain electrical activity. We investigated seven first episode schizophrenic patients and seven age, gender and education-matched controls with diffusion tensor imaging and resting EEG. Fractional anisotropy was computed based on diffusion tensor imaging data for the right and left hippocampus for both groups. No group differences were found in hippocampal fractional anisotropy, EEG spectral power and topography. However a significant correlation was found between more anterior alpha activity and lower fractional anisotropy of both hippocampi in schizophrenics, but not in controls. More anterior alpha activity has been described in schizophrenia. We conclude that this feature might depict a group of schizophrenic patients with reduced hippocampal connectivity.

Cerebral disconnectivity: an early event in schizophrenia

Neuroimaging and electrophysiological investigations have demonstrated numerous differences in brain morphology and function of chronic schizophrenia patients compared to healthy controls. Studying patients at the beginning of their disease without the confounding effects of chronicity, medication, and institutionalization may provide a better understanding of schizophrenia. Recently, at many institutions around the world, special projects have been launched for specialized treatment and research of this interesting patient group. Using the PubMed search engine in this update, the authors summarize recent investigations between January 2002 and September 2006 that focus on whether signs of disconnectivity already exist early in the disease process. They discuss gray and white matter changes, their impact on symptomatology, electroencephalogram-based studies on connectivity, and possible influences of medication.

MRI-based brain volumetry in chronic whiplash patients: no evidence for traumatic brain injury

INTRODUCTION: Cognitive complaints, such as poor concentration and memory deficits, are frequent after whiplash injury and play an important role in disability. The origin of these complaints is discussed controversially. Some authors postulate brain lesions as a consequence of whiplash injuries. Potential diffuse axonal injury (DAI) with subsequent atrophy of the brain and ventricular expansion is of particular interest as focal brain lesions have not been documented so far in whiplash injury. OBJECTIVE: To investigate whether traumatic brain injury can be identified using a magnetic resonance (MR)-based quantitative analysis of normalized ventricle-brain ratios (VBR) in chronic whiplash patients with subjective cognitive impairment that cannot be objectively confirmed by neuropsychological testing. MATERIALS AND METHODS: MR examination was performed in 21 patients with whiplash injury and symptom persistence for 9 months on average and in 18 matched healthy controls. Conventional MR imaging (MRI) was used to assess the volumes of grey and white matter and of ventricles. The normalized VBR was calculated. RESULTS: The values of normalized VBR did not differ in whiplash patients when compared with that in healthy controls (F = 0.216, P = 0.645). CONCLUSIONS: This study does not support loss of brain tissue following whiplash injury as measured by VBR. On this basis, traumatic brain injury with subsequent DAI does not seem to be the underlying mechanism for persistent concentration and memory deficits that are subjectively reported but not objectively verifiable as neuropsychological deficits.

Cerebellar cleft: a form of prenatal cerebellar disruption

In contrast to malformations, cerebellar disruptions have attracted little interest in the literature. We draw attention for the first time to the hypothesis that cerebellar clefts are residual changes following a prenatal cerebellar insult, and represent disruptions. We reviewed the clinical records and MR findings of six patients with a cerebellar cleft, two of whom also had prenatal MRI at 24 weeks of gestation. The clefts were located in the left cerebellar hemisphere in five cases, in the right in one patient. Other typical findings included disorderly alignment of the cerebellar folia and fissures, irregular gray/white matter junction, and abnormal arborization of the white matter in all patients. The cerebellar cleft extended into the fourth ventricle in three cases, and in two children cystic cortical lesions were seen. Supratentorial schizencephaly was found in two patients. In two patients there was a documented fetal cerebellar hemorrhage at 24 weeks of gestation. We conclude that cerebellar clefts are residual changes resulting from a prenatal cerebellar insult and consequently represent disruptions rather than primary malformations. The supratentorial findings are also in agreement with an acquired lesion. The outcome in these children was variable, mainly depending of the presence of supratentorial lesions.

Focal laminar cortical infarcts following aneurysmal subarachnoid haemorrhage

INTRODUCTION: The aim of this prospective study was to analyse small band-like cortical infarcts after subarachnoid haemorrhage (SAH) using magnetic resonance imaging (MRI) with reference to additional digital subtraction angiography (DSA). METHODS: In a 5-year period between January 2002 and January 2007 10 out of 188 patients with aneurysmal SAH were evaluated (one patient Hunt and Hess grade I, one patient grade II, four patients grade III, two patients grade IV, and two patients grade V). The imaging protocol included serially performed MRI with diffusion- and perfusion-weighted images (DWI/PWI) at three time points after aneurysm treatment, and cerebral vasospasm (CVS) was analysed on follow-up DSA on day 7+/-3 after SAH. RESULTS: The lesions were located in the frontal lobe (n=10), in the insular cortex (n=3) and in the parietal lobe (n=1). The band-like infarcts occurred after a mean time interval of 5.8 days (range 3-10 days) and showed unexceptional adjacent thick sulcal clots. Seven out of ten patients with cortical infarcts had no or mild CVS, and in the remaining three patients DSA disclosed moderate (n=2) or severe (n=1) CVS. CONCLUSION: The infarct pattern after aneurysmal SAH includes cortical band-like lesions. In contrast to territorial infarcts or lacunar infarcts in the white matter which develop as a result of moderate or severe proximal and/or distal vasospasm visible on angiography, the cortical band-like lesions adjacent to sulcal clots may also develop without evidence of macroscopic vasospasm, implying a vasospastic reaction of the most distal superficial and intraparenchymal vessels.

Inhibition of L-type amino acid transport with non-physiological amino acids in the Pahenu2 mouse model of phenylketonuria

Phenylketonuria, an autosomal recessive Mendelian disorder, is one of the most common inborn errors of metabolism. Although currently treated by diet, many suboptimal outcomes occur for patients. Neuropathological outcomes include cognitive loss, white matter abnormalities, and hypo- or demyelination, resulting from high concentrations and/or fluctuating levels of phenylalanine. High phenylalanine can also result in competitive exclusion of other large neutral amino acids from the brain, including tyrosine and tryptophan (essential precursors of dopamine and serotonin). This competition occurs at the blood brain barrier, where the L-type amino acid transporter, LAT1, selectively facilitates entry of large neutral amino acids. The hypothesis of these studies is that certain non-physiological amino acids (NPAA; DL-norleucine (NL), 2-aminonorbornane (NB; 2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid), α-aminoisobutyrate (AIB), and α-methyl-aminoisobutyrate (MAIB)) would competitively inhibit LAT1 transport of phenylalanine (Phe) at the blood-brain barrier interface. To test this hypothesis, Pah-/- mice (n=5, mixed gender; Pah+/-(n=5) as controls) were fed either 5% NL, 0.5% NB, 5% AIB or 3% MAIB (w/w 18% protein mouse chow) for 3 weeks. Outcome measurements included food intake, body weight, brain LNAAs, and brain monoamines measured via LCMS/MS or HPLC. Brain Phe values at sacrifice were significantly reduced for NL, NB, and MAIB, verifying the hypothesis that these NPAAs could inhibit Phe trafficking into the brain. However, concomitant reductions in tyrosine and methionine occurred at the concentrations employed. Blood Phe levels were not altered indicating no effect of NPAA competitors in the gut. Brain NL and NB levels, measured with HPLC, verified both uptake and transport of NPAAs. Although believed predominantly unmetabolized, NL feeding significantly increased blood urea nitrogen. Pah-/-disturbances of monoamine metabolism were exacerbated by NPAA intervention, primarily with NB (the prototypical LAT inhibitor). To achieve the overarching goal of using NPAAs to stabilize Phe transport levels into the brain, a specific Phe-reducing combination and concentration of NPAAs must be found. Our studies represent the first in vivo use of NL, NB and MAIB in Pah-/- mice, and provide proof-of-principle for further characterization of these LAT inhibitors. Our data is the first to document an effect of MAIB, a specific system A transport inhibitor, on large neutral amino acid transport.

Diffusion tensor imaging of two unrelated Chinese men with hereditary spastic paraplegia associated with thin corpus callosum

Hereditary spastic paraplegia (HSP) associated with thin corpus callosum is a rare autosomal recessive neurodegenerative disorder characterized by an abnormally thin corpus callosum, normal motor development, slowly progressive spastic paraparesis and cognitive deterioration. To investigate and localize abnormalities in the brains of two Chinese patients with HSP-TCC, with mutations in the spatacsin gene. Diffusion tensor imaging (DTI) was used to determine the mean diffusion (MD) and fractional anisotropy (FA) in the brains of the patients in comparison to 20 healthy subjects. Voxel-based analysis (VBA) of both the diffusion and anisotropy values were performed using statistical parametric mapping (SPM). Significant changes with MD increase and FA reduction were found in the already known lesions including the corpus callosum, cerebellum and thalamus. In addition, changes were also found in regions that appear to be normal in conventional MRI, such as the brain stem, internal capsule, cingulum and subcortical white matter including superior longitudinal fascicle and inferior longitudinal fascicle. Neither increase in FA nor reduction in MD was detected in the brain. Our study provides clear in vivo MR imaging evidence of a more widespread brain involvement of HSP-TCC. MD is more sensitive than FA in detecting lesions in thalamus and subcortical white matter, suggesting that MD may be a better marker of the disease progression.

Gait analysis in normal and spinal contused mice using the TreadScan system

Advances in spinal cord injury (SCI) research are dependent on quality animal models, which in turn rely on sensitive outcome measures able to detect functional differences in animals following injury. To date, most measurements of dysfunction following SCI rely either on the subjective rating of observers or the slow throughput of manual gait assessment. The present study compares the gait of normal and contusion-injured mice using the TreadScan system. TreadScan utilizes a transparent treadmill belt and a high-speed camera to capture the footprints of animals and automatically analyze gait characteristics. Adult female C57Bl/6 mice were introduced to the treadmill prior to receiving either a standardized mild, moderate, or sham contusion spinal cord injury. TreadScan gait analyses were performed weekly for 10 weeks and compared with scores on the Basso Mouse Scale (BMS). Results indicate that this software successfully differentiates sham animals from injured animals on a number of gait characteristics, including hindlimb swing time, stride length, toe spread, and track width. Differences were found between mild and moderate contusion injuries, indicating a high degree of sensitivity within the system. Rear track width, a measure of the animal's hindlimb base of support, correlated strongly both with spared white matter percentage and with terminal BMS. TreadScan allows for an objective and rapid behavioral assessment of locomotor function following mild-moderate contusive SCI, where the majority of mice still exhibit hindlimb weight support and plantar paw placement during stepping.

Correlations between severity of clinical signs and histopathological changes in 60 dogs with spinal cord injury associated with acute thoracolumbar intervertebral disc disease

The outcome of spinal surgery in dogs with absent voluntary motor function and nociception following intervertebral disc (IVD) herniation is highly variable, which likely attests to differences in the severity of spinal cord damage. This retrospective study evaluated the extent to which neurological signs correlated with histologically detected spinal cord damage in 60 dogs that were euthanased because of thoracolumbar IVD herniation. Clinical neurological grades correlated significantly with the extent of white matter damage (P<0.001). However, loss of nociception also occurred in 6/31 (19%) dogs with relatively mild histological changes. The duration of clinical signs, Schiff-Sherrington posture, loss of reflexes and pain on spinal palpation were not significantly associated with the severity of spinal cord damage. Although clinical-pathological correlation was generally good, some clinical signs frequently thought to indicate severe cord injury did not always correlate with the degree of cord damage, suggesting functional rather than structural impairment in some cases.

Magnetic resonance imaging and genetic investigation of a case of Rottweiler leukoencephalomyelopathy.

BACKGROUND Leukoencephalomyelopathy is an inherited neurodegenerative disorder that affects the white matter of the spinal cord and brain and is known to occur in the Rottweiler breed. Due to the lack of a genetic test for this disorder, post mortem neuropathological examinations are required to confirm the diagnosis. Leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate levels is a rare, autosomal recessive disorder in humans that was recently described to have clinical features and magnetic resonance imaging (MRI) findings that are similar to the histopathologic lesions that define leukoencephalomyelopathy in Rottweilers. Leukoencephalopathy with brain stem and spinal cord involvement is caused by mutations in the DARS2 gene, which encodes a mitochondrial aspartyl-tRNA synthetase. The objective of this case report is to present the results of MRI and candidate gene analysis of a case of Rottweiler leukoencephalomyelopathy to investigate the hypothesis that leukoencephalomyelopathy in Rottweilers could serve as an animal model of human leukoencephalopathy with brain stem and spinal cord involvement. CASE PRESENTATION A two-and-a-half-year-old male purebred Rottweiler was evaluated for generalised progressive ataxia with hypermetria that was most evident in the thoracic limbs. MRI (T2-weighted) demonstrated well-circumscribed hyperintense signals within both lateral funiculi that extended from the level of the first to the sixth cervical vertebral body. A neurodegenerative disorder was suspected based on the progressive clinical course and MRI findings, and Rottweiler leukoencephalomyelopathy was subsequently confirmed via histopathology. The DARS2 gene was investigated as a causative candidate, but a sequence analysis failed to identify any disease-associated variants in the DNA sequence. CONCLUSION It was concluded that MRI may aid in the pre-mortem diagnosis of suspected cases of leukoencephalomyelopathy. Genes other than DARS2 may be involved in Rottweiler leukoencephalomyelopathy and may also be relevant in human leukoencephalopathy with brain stem and spinal cord involvement.