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Background: There has been little direct examination of how traumatic brain injury (TBI) affects the rate of neurodegeneration for individuals with Alzheimer's disease (AD)., Methods: The study examined 89 cognitively normal adults (65 with and 24 without prior TBI) and 65 with AD (16 with and 49 without prior TBI). Cortical thickness was quantified from T1-weighted MRI scans at baseline and follow-up (mean interval 33.4 months). Partial least squares analysis was used to evaluate the effects of AD and TBI history on the longitudinal change in cortical thickness., Results: Significant group effects were identified throughout the frontal and temporal cortices. Comparison of the AD groups to their control cohorts showed greater relative atrophy for the AD cohort with prior TBI., Conclusion: These results indicate that a history of TBI exacerbates longitudinal declines in cortical thickness among AD patients, providing new insights into the shared pathomechanisms between these neurological conditions., Competing Interests: On behalf of all authors, the corresponding author states that there is no conflict of interest.

There is a growing body of literature using functional MRI to study the acute and long-term effects of concussion on functional brain networks. To date, studies have largely focused on changes in pairwise connectivity strength between brain regions. Less is known about how concussion affects whole-brain network topology, particularly the "small-world" organization which facilitates efficient communication at both local and global scales. The present study addressed this knowledge gap by measuring local and global efficiency of 26 concussed athletes at acute injury, return to play (RTP) and one year post-RTP, along with a cohort of 167 athletic controls. On average, concussed athletes showed no alterations in local efficiency but had elevated global efficiency at acute injury, which had resolved by RTP. Athletes with atypically long recovery, however, had reduced global efficiency at 1 year post-RTP, suggesting long-term functional abnormalities for this subgroup. Analyses of nodal efficiency further indicated that global network changes were driven by high-efficiency visual and sensorimotor regions and low-efficiency frontal and subcortical regions. This study provides evidence that concussion causes subtle acute and long-term changes in the small-world organization of the brain, with effects that are related to the clinical profile of recovery.

Resting state functional magnetic resonance imaging (rs-fMRI) has become an indispensable tool in neuroscience research. Despite this, rs-fMRI signals are easily contaminated by artifacts arising from movement of the head during data collection. The artifacts can be problematic even for motions on the millimeter scale, with complex spatiotemporal properties that can lead to substantial errors in functional connectivity estimates. Effective correction methods must be employed, therefore, to distinguish true functional networks from motion-related noise. Research over the last three decades has produced numerous correction methods, many of which must be applied in combination to achieve satisfactory data quality. Subject instruction, training, and mild restraints are helpful at the outset, but usually insufficient. Improvements come from applying multiple motion correction algorithms retrospectively after rs-fMRI data are collected, although residual artifacts can still remain in cases of elevated motion, which are especially prevalent in patient populations. Although not commonly adopted at present, "real-time" correction methods are emerging that can be combined with retrospective methods and that promise better correction and increased rs-fMRI signal sensitivity. While the search for the ideal motion correction protocol continues, rs-fMRI research will benefit from good disclosure practices, such as: (1) reporting motion-related quality control metrics to provide better comparison between studies; and (2) including motion covariates in group-level analyses to limit the extent of motion-related confounds when studying group differences.

Patients with deep brain stimulation (DBS) implants may be subject to heating during MRI due to interaction with excitatory radiofrequency (RF) fields. Parallel RF transmit (pTx) has been proposed to minimize such RF-induced heating in preliminary proof-of-concept studies. The present work evaluates the efficacy of pTx technique on realistic lead trajectories obtained from nine DBS patients. Electromagnetic simulations were performed using 4- and 8-element pTx coils compared with a standard birdcage coil excitation using patient models and lead trajectories obtained by segmentation of computed tomography data. Numerical optimization was performed to minimize local specific absorption rate (SAR) surrounding the implant tip while maintaining spatial homogeneity of the transmitted RF magnetic field (B 1 + ), by varying the input amplitude and phase for each coil element. Local SAR was significantly reduced at the lead tip with both 4-element and 8-element pTx (median decrease of 94% and 97%, respectively), whereas the median coefficient of spatial variation of B 1 + inhomogeneity was moderately increased (30% for 4-element pTx and 20% for 8-element pTx) compared to that of the birdcage coil (17%). Furthermore, the efficacy of optimized 4-element pTx was verified experimentally by imaging a head phantom that included a wire implanted to approximate the worst-case lead trajectory for localized heating, based on the simulations. Negligible temperature elevation was observed at the lead tip, with reasonable image uniformity in the surrounding region. From this experiment and the simulations based on nine DBS patient models, optimized pTx provides a robust approach to minimizing local SAR with respect to lead trajectory.

Background: Parallel imaging is widely adopted to accelerate functional MRI (fMRI) data acquisition, through various strategies that involve multi-channel receiver coils. However, the non-uniform spatial sensitivity of multi-channel receiver coils may introduce unwanted artifacts when head motion occurs during the few-minute long fMRI scans. Although prospective correction provides a promising solution for alleviating the head motion artifacts in fMRI, the relative position of the fixed multi-channel receiver coils moves in the moving reference frame, potentially resulting in artifactual signal., New Method: We used numerical simulations to investigate this effect on fMRI using two parallel imaging schemes: sensitivity encoding (SENSE) and generalized autocalibrating partially parallel acquisitions (GRAPPA) with acceleration factors 2 and 4, towards characterizing the regime over which parallel-imaging fMRI with prospective motion correction will benefit from updating coil sensitivities to reflect relative positional change between the head and the receiver coil. Moreover, six subjects were scanned with acceleration factors 2 and 4 while performing a simple finger-tapping task with and without overt head motion., Results: Updating coil sensitivities showed significant positive impact on standard deviation and activation maps in presence of overt head motion compared to that obtained with no overt head motion., Comparison With Existing Methods: The parallel imaging fMRI with updated coil sensitivity maps were compared to that with the coil sensitivity maps acquired at the reference position., Conclusions: Head motion in relation to a fixed multi-channel coil can adversely affect the quality of parallel imaging fMRI data; and updating coil sensitivity map can mitigate this effect., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background and Purpose: Our goal was to develop a novel technique for measuring a small number of localized spectra simultaneously and in a time-efficient manner., Materials and Methods: Using appropriate radiofrequency pulses, the magnetization from multiple voxels is excited simultaneously and then separated (reconstructed) by using the individual coil-sensitivity profiles from a multichannel receiver coil. Because no gradients are used for k-space encoding, constrained source space MR spectroscopy provides a time advantage over conventional spectroscopic imaging and an improved signal-to-noise ratio per square root of unit time over single-voxel spectroscopy applied at each successive location. In the present work, we considered prototype application of constrained source space MR spectroscopy for 2 voxels., Results: Experimental data from healthy volunteers and simulation results showed that constrained source space MR spectroscopy is effective at extracting 2 independent spectra even in the challenging scenario of the voxels being closely spaced. Also, from 6 patients with various types of brain cancer we obtained 2-voxel constrained source space MR spectroscopy data, which showed spectra of clinical quality in half the time required to perform successive single-voxel MR spectroscopy., Conclusions: Constrained source space MR spectroscopy provides clinical quality spectra and could be used to probe multiple voxels simultaneously in combination with Hadamard encoding for further scan-time reductions., (© 2015 by American Journal of Neuroradiology.)

The percutaneous absorption of tritiated water ((3)H(2)O) through sulfur mustard (SM) exposed abdominal pig skin was measured using in vitro Franz-type static diffusion cells. The barrier function to water permeation following exposure to liquid SM for 8 min and excision 3h later did not change significantly. A small, but statistically significant difference (P<0.05) in steady state penetration (Jss), permeability coefficient (Kp) and lag time (t(L)) of (3)H(2)O was observed between fresh skin and skin stored frozen (-20 °C) for up to two weeks. Steady-state penetration and Kp values were significantly higher (P < 0.05) in skin stored frozen compared with fresh skin. Fresh naïve skin had an average Kp of 1.65 × 10(-3) cm h(-1), whereas frozen naïve skin was 2.04 × 10(-3) cm h(-1). Fresh SM exposed skin had a mean Kp of 1.72 × 10(-3) cm h(-1), whereas frozen SM exposed skin was 2.31 × 10(-3) cm h(-1). Lag times were also shorter (P<0.05) in skin that had been stored frozen. Frozen, SM-exposed porcine abdominal skin may be used for in vitro penetration studies, but effects of treatment and storage on the barrier layer should be taken into account., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To identify the benefits of ultrasound-guided radiofrequency ablation of Morton's neuroma as an alternative to surgical excision., Materials and Methods: We studied a consecutive cohort of surgical candidates for Morton's neurectomy who we referred, instead, for radiofrequency ablation (RFA). Under local anaesthetic, RFA was performed under ultrasound guidance, by a single radiologist. This out-patient procedure was repeated after 4 weeks if necessary. We followed patients for a minimum of 6 months to assess their change in visual analogue pain scores (VAS), symptom improvement, complications and progression to surgical excision., Results: Thirty feet in 25 patients were studied. There were 4 men and 21 women with an average age of 55 years (range 33-73 years). All had tried previous methods of conservative management. Forty percent presented with 2nd space neuromas and 60% with 3rd space ones. The average number of treatment sessions was 1.6 (range 1-3, mode 1). Prior to treatment, all patients had pain on activity (VAS average: 6.0, range 3-9). Post-treatment there was a statistically significant reduction in pain scores (post-RFA VAS average: 1.7, range 0-8, p < 0.001). The average overall symptom improvement was 76%. There was one minor complication of temporary nerve irritation. Three neuromas (10%) have progressed to surgical excision; 1 patient has ongoing, unchanged pain with no obvious cause. At 6 months, 26 out of 30 feet had a satisfactory outcome., Conclusion: Ultrasound-guided RFA has successfully alleviated patients' symptoms of Morton's neuroma in >85% of cases. Only 10% have proceeded to surgical excision in the short term.

To better understand the contributions of effort on cortical activation associated with motor tasks, healthy participants with varying capacities for isolating the control of individual finger movements performed tasks consisting of a single concurrent abduction of all digits (Easy) and paired finger abduction with digits 2 and 3 abducted together concurrently with digits 4 and 5 (Hard). Brain activity was inferred from measurement using functional magnetic resonance imaging. Effort was measured physiologically using electrodermal responses (EDR) and subjectively using the Borg scale. On average, the Borg score for the Hard task was significantly higher (p=0.007) than for the Easy task (2.9+/-1.1 vs. 1.4+/-0.7, respectively). Similarly, the average normalized peak-to-peak amplitude of the EDR was significantly higher (p=0.002) for the Hard task than for the Easy task (20.4+/-6.5% vs. 12.1+/-4.9%, respectively). The Hard task produced increases in sensorimotor network activation, including supplementary motor area, premotor, sensorimotor and parietal cortices, cerebellum and thalamus. When the imaging data were subdivided based on Borg score, there was an increase in activation and involvement of additional areas, including extrastriate and prefrontal cortices. Subdividing the data based on EDR amplitude produced greater effects including activation of the premotor and parietal cortices. These results show that the effort required for task performance influences the interpretation of fMRI data. This work establishes understanding and methodology for advancing future studies of the link between effort and motor control, and may be clinically relevant to sensorimotor recovery from neurologic injury.

Purpose: Motion is a major confound of image quality in MRI. A method of retrospectively correcting the effects of rotations and translations on the acquired k-space data is presented., Methods: In two phantom experiments of well-controlled translation and rotation, two MRI-compatible infrared cameras recorded motion data that were used subsequently to correct the position and phase of recorded k-space samples. Motion data can be acquired with a temporal resolution of 60 Hz and spatial accuracy of 0.1 mm for translations and 0.2 degree for rotations., Results: Significant improvements of image quality are demonstrated., Conclusions: The key advantages of the technique are that it is easy to implement, does not interfere with or complicate MR data acquisition, and is capable of correcting distortions within a single slice. Therefore, the technique has the potential to improve upon approaches that rely on the registration or realignment of successive imaging slices.

Echo-planar imaging (EPI) -based diffusion tensor imaging (DTI) is particularly prone to spike noise. However, existing spike noise correction methods are impractical for corrupted DTI data because the methods correct the complex MRI signal, which is not usually stored on clinical MRI systems. The present work describes a novel Outlier Detection De-spiking technique (ODD) that consists of three steps: detection, localization, and correction. Using automated outlier detection schemes, ODD exploits the data redundancy available in DTI data sets that are acquired with a minimum of six different diffusion-weighted images (DWIs) with similar signal and noise properties. A mathematical formulation, describing the effects of spike noise on magnitude images, yields appropriate measures for an outlier detection scheme used for spike detection while a normalization-dependent outlier detection scheme is used for spike localization. ODD performs accurately on diverse DTI data sets corrupted by spike noise and can be used for automated control of DTI data quality. ODD can also be extended to other MRI applications with data redundancy, such as dynamic imaging and functional MRI., ((c) 2009 Wiley-Liss, Inc.)

Somatosensory responses to vibrotactile stimulation applied to the index fingertip were recorded with whole-head MEG in eleven healthy young adult participants. Stimulus trains were produced by a pneumatically driven membrane oscillating at 22 Hz for a trial duration of 1 s, separated by interstimulus intervals (ISIs) of 0.5, 1.0, 3.0, and 7.0 s. Data analysis was performed in two frequency bands. Transient onset responses in the lower frequency band (<20 Hz) contained a clearly expressed P50 component. The higher frequency band (18-30 Hz) revealed a gamma-band response (GBR) within the first 200 ms followed by rhythmic activity at the stimulus frequency that continued throughout the stimulus duration, known as the steady-state response (SSR). Dipoles associated with the transient responses and SSRs were localized in two distinct regions within the primary somatosensory cortex (SI), with transient responses located on average 3 mm more medial and inferior than the SSRs. The transient and GBR peak amplitudes increased with ISI, whereas the SSR amplitude showed no ISI dependence. These results may reflect functionally and spatially distinct neural populations. Further investigations are required to assess the implications of these findings for probing the somatosensory system using other functional neuroimaging methods such as fMRI.

Sudden intense sensory stimuli elicit a cascade of involuntary responses, including a short-latency skeletal muscular response ('eyeblink startle response') and longer-latency autonomic responses. These responses are enhanced when subjects anticipate an aversive event compared to periods when subjects are resting ('fear potentiation'). It has been reported previously that the anxiolytic diazepam can suppress fear-potentiation of the eyeblink startle response in human volunteers. The present experiment aimed to confirm and extend these observations by examining the effect of another benzodiazepine, lorazepam, on the eyeblink and skin conductance components of the acoustic startle, and on fear-potentiation of these responses. Eighteen male volunteers participated in three weekly sessions in which they received oral treatment with placebo, lorazepam (1 mg) and lorazepam (2 mg), according to a balanced three-period, crossover, double-blind design. Two hours after ingestion of the treatments, electromyographic responses of the orbicularis oculi muscle and skin conductance responses were evoked by sound pulses during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with significant increase in the amplitude of the electromyographic (EMG) and skin conductance responses; there were also increases in baseline skin conductance, the number and amplitude of 'spontaneous' skin conductance fluctuations and self-rated anxiety. Lorazepam attenuated the effect of THREAT on self-rated anxiety and on the amplitude of the EMG response, but had no significant effect on fear-potentiation of the skin conductance responses. These results extend previous findings of the effect of diazepam on the fear-potentiated eyeblink startle response to lorazepam, and suggest that fear-potentiation of the later autonomic component of the startle response may be less sensitive to benzodiazepines than the fear-potentiated eyeblink response and self-rated anxiety.

The assumption of linear time-invariance (LTI) in the human primary somatosensory cortex (SI) is assessed for fMRI signals generated by variable-duration vibrotactile stimuli. Predictions based on time-shifted summation (TSS) of responses to 2 s stimuli overestimate observed BOLD signal amplitudes in response to longer-duration stimuli, in agreement with previous findings in other primary sensory cortices. To interpret these results, we undertook an alternative approach for LTI assessment by characterizing BOLD signals using two biophysical models. The first model assumes that the input stimulus envelope is proportional to neural activity. The second assumes that neural activity exhibits both transient and steady-state components, consistent with extensive electrophysiological data, and fits the experimental data better. Although nonlinearity remains evident for short stimulus durations, the latter model shows that the TSS procedure to assess LTI overestimates the BOLD signal because the temporal characteristics of neural activity have not been considered adequately. Further research to investigate the BOLD response to time-varying neural activity is required.

If the ureter becomes blocked, the resultant increased pressure may be relieved by inserting a double-J stent (a polymer tube, usually punctuated with holes). A major clinical problem associated with stent use is reflux (retrograde flow of urine from the bladder to the kidney), which may result in infections, scarring, and even renal failure. We develop a mathematical model, treating the ureter as an elastic tube and the stent as a permeable rigid tube within it. We investigate how the number of holes in the stent wall affects the total amount of reflux that occurs when bladder pressure rises, by considering the limits of a highly-permeable stent, and an impermeable stent. We find that, in the scenarios we consider, the highly-permeable stent gives rise to less total reflux than the impermeable one.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (PPI). Here, we report the effects of the 'atypical' antipsychotic drug quetiapine and the 'conventional' antipsychotic haloperidol on these responses. Sixteen males (aged 19-38 years) participated in four sessions at 7-day intervals, in which they received quetiapine 12.5 mg, quetiapine 25 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 2 h after treatment. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage PPI was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Quetiapine 12.5 mg and 25 mg significantly reduced the amplitude of the EMG response without altering its inhibition by prepulses; haloperidol had no effect on EMG response amplitude or PPI. Neither drug affected N1/P2 amplitude or PPI of this response. Quetiapine, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Haloperidol, but not quetiapine, elevated serum prolactin level. The ability of quetiapine to attenuate the startle response may reflect its sedative action.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effects of the serotonin (5-HT)2 receptor antagonist ketanserin and the D2 dopamine receptor blocking antipsychotic drug haloperidol on these responses. Fifteen males (aged 18-35 years) participated in four sessions at 7-day intervals, in which they received ketanserin 20 mg, ketanserin 40 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 3 h after ingestion of haloperidol or 1 h after ingestion of ketanserin. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials), and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Ketanserin 40 mg significantly reduced the amplitude of the EMG response and both doses of ketanserin significantly suppressed prepulse inhibition of the response; haloperidol had no effect on EMG response amplitude or prepulse inhibition. Neither drug affected N1/P2 amplitude or prepulse inhibition of this response. Ketanserin, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Haloperidol, but not ketanserin, elevated serum prolactin level. These results confirm that prepulse inhibition of the startle response and of the N1/P2 complex have different pharmacological sensitivities. The ability of ketanserin to attenuate the startle response may reflect its sedative action, as other drugs with sedative properties have also been found to attenuate the startle response in man. The ability of ketanserin to suppress prepulse inhibition of the startle response is consistent with previous evidence for the involvement of 5-HTergic mechanisms in the regulation of prepulse inhibition in man.

* The working group was set up by the Veterinary Products Committee in response to current concern in both the public domain and in the scientific community about possible health risks related to the routine vaccination of cats and dogs. The working group concluded that vaccination plays a very valuable role in the prevention and control of the major infectious diseases in cats and dogs. Although adverse reactions to vaccination, including lack of efficacy, occasionally occur, the working group concluded that the overall risk/benefit analysis strongly supports their continued use. * Although for some diseases there is evidence of a longer duration of immunity following vaccination than the one year which is typically recommended on the product literature, there is currently insufficient information to propose revaccination intervals other than those proposed by the manufacturer and approved by the regulatory process. * Notwithstanding this, in view of the occasional occurrence of adverse reactions, the working group recommends that the product literature indicates that the regime for booster vaccinations is based on a minimum duration of immunity rather than a maximum. The working group further recommends that the product literature should state that a risk/benefit assessment should be made for each individual animal by the veterinary surgeon in consultation with the owner with respect to the necessity for each vaccine and the frequency of its use. * The evidence suggests that cats appear to be susceptible to the occasional development of sarcomas at sites of injection and there is some further evidence to suggest that, although other products may be involved, this may be more associated with the use of vaccines containing aluminium-based adjuvants. The working group therefore recommends that a generic warning to this effect should appear on the product literature for all feline vaccines administered by injection. The working group also highlighted the need for professional and educational bodies in the UK to bring to the attention of veterinary practitioners appropriate methods for prevention, diagnosis and treatment of this serious condition. * The working group considered in depth the monitoring of adverse reactions, including the advantages and disadvantages of surveillance schemes. A range of options for carrying out further epidemiological (analytical) studies was also considered. However, the working group emphasised that surveillance schemes, and the UK Veterinary Medicines Directorate (VMD) Suspected Adverse Reaction (SAR) Surveillance Scheme in particular, provided a very valuable resource. The large database within the VMD scheme (collected since 1985) was analysed as part of this report. Figures were derived in terms of incidence (reporting rate) of certain clinical signs per 10,000 doses, and risk factors as identified by statistical analysis. However, due to a number of constraints, the analysis was not fully comprehensive and the interaction of possible risk factors was not determined. * Product-related control charts were developed in order to detect changes in incidence rates of adverse reactions (per 10,000 doses sold) both within and between different vaccines. Such charts provide a powerful way to detect changing trends in incidence and, when used in conjunction with product characteristics, they may identify possible causes. In general, the data showed that the incidence of adverse reactions to cat and dog vaccines per 10,000 doses of product sold was relatively low. Although under-reporting is a feature of such surveillance schemes, it does appear that, overall, vaccination of cats and dogs should be considered safe and effective. * Finally, the working group was conscious, while preparing this report, of the extensive media coverage that has been given to the issue of the safety of human vaccines, in particular the mumps, measles and rubella (MMR) vaccine. The working group emphasises that the conclusions and recommendations included in this report relate only to the vaccines used in cats and dogs. The issues identified are specific to the diseases and species examined and no attempt should be made to draw analogous conclusions in relation to vaccines administered to humans.

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30-500 ms before the 'startle-eliciting' stimulus (prepulse inhibition). Here, we report the effects of the 'conventional' antipsychotic drug haloperidol and the 'atypical' antipsychotic clozapine on these responses. Fifteen males (aged 19-54 years) participated in four sessions at 7-day intervals, in which they received clozapine 3 mg, clozapine 6 mg, haloperidol 3 mg and placebo, according to a balanced double-blind design. Electromyographic (EMG) responses of the orbicularis oculi muscle and N1/P2 auditory evoked potentials were recorded in a 20-min session, 3 h after treatment. Subjects received 40 trials in which 1-kHz sounds were presented: (i) 40 ms, 115 dB ('pulse alone' trials) and (ii) 40 ms, 85 dB, followed after 120 ms by 40 ms, 115 dB ('prepulse/pulse' trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. Serum prolactin was measured after each treatment, and autonomic (heart rate, blood pressure, salivation) and psychological (visual analogue self-ratings of mood and alertness, critical flicker fusion frequency) measures were taken before and after each treatment. Clozapine 6 mg significantly reduced the amplitude of the EMG response without altering its inhibition by prepulses. Clozapine 6 mg did not affect the amplitude of the N1/P2 potential, but significantly attenuated prepulse inhibition of that response. Clozapine 3 mg and haloperidol had no significant effect on either response. Clozapine 3 mg and 6 mg, but not haloperidol, reduced subjective alertness and critical flicker fusion frequency. Clozapine 6 mg reduced salivation. Haloperidol, but not clozapine, elevated serum prolactin levels. These results confirm that prepulse inhibition of the startle response and of the N1/P2 complex have different pharmacological sensitivities. The abililty of clozapine to attenuate the startle response may reflect its sedative action. The basis of the abililty of clozapine to suppress prepulse inhibition of the N1/P2 potential remains uncertain.

A new class of devices are described for improving investigation of somatosensory neuronal activation using fMRI. Dubbed magnetomechanical vibrotactile devices (MVDs), the principle of operation involves driving wire coils with small oscillatory currents in the large static magnetic field inherent to MRI scanners. The resulting Lorentz forces can be oriented to generate large vibrations that are easily converted to translational motions as large as several centimeters. Representative data demonstrate the flexibility of MVDs to generate different well-controlled vibratory and tactile stimuli to activate special proprioceptive and cutaneous somatosensory afferent pathways. The implications of these data are discussed with respect to the literature on existing devices for producing sensorimotor activation, as well as expanding the scope of current fMRI investigations., (Copyright 2001 Wiley-Liss, Inc.)

In functional magnetic resonance imaging (fMRI) studies, long experiment times and small intensity changes associated with brain activation frequently lead to image artifacts due to head motion. Methods to minimize and correct for head motion by restraint, fast imaging, and retrospective image registration are typically combined but do not completely solve the problem, particularly for specific patient populations. As an initial step toward optimizing future designs of head restraints and improving motion correction techniques, the head motion characteristics of groups of stroke subjects, age-matched controls, and young adults were investigated with the aid of an MR simulator and a highly accurate position tracking system. Position measurements were recorded during motor tasks involving either the hand or the foot. Head motion was strongly dependent on the subject group and less upon the task conditions based on ANOVA calculations (P < 0.05). The stroke subjects exhibited approximately twice the head motion compared to that of age-matched controls, and the latter's head motion was about twice that of young adults. Moreover, the range of head motion in stroke subjects over all tasks was approximately 2 +/- 1 mm, with the motion occurring predominantly as translation in the superior-inferior direction and pitch rotation (nodding). These results lead to several recommendations on the design of fMRI motor experiments and suggest that improved motion correction strategies are required to examine such patient populations comprehensively., (Copyright 2001 Academic Press.)

This review describes magnetization transfer (MT) contrast in magnetic resonance imaging. A qualitative description of how MT works is provided along with experimental evidence that leads to a quantitative model for MT in tissues. The implementation of MT saturation in imaging sequences and the interpretation of the MT-induced signal change in terms of exchange processes and direct effects are presented. Finally, highlights of clinical uses of MT are outlined and future directions for investigation proposed., (Copyright 2001 John Wiley & Sons, Ltd.)

Functional MRI was performed in two acute stroke patients and six control subjects performing unilateral and bilateral repetitive gripping tasks. Patients were tested at three time points during recovery. Initially, bilateral movement enhanced activation in the primary motor cortex (M1) of the affected hemisphere compared with unilateral paretic hand movement. With recovery, activation of M1 in the affected hemisphere did not differ between unilateral paretic hand and bilateral movement. These preliminary data may have potential implications for acute stroke motor rehabilitation.

Objective: To estimate the prevalence of Huntington disease (HD) in New South Wales on Australian Census Day (6 August) 1996., Design: Survey of records of the Huntington Disease Service and major hospitals, and of neurologists, psychiatrists, clinical geneticists and genetic counsellors., Subjects and Setting: All patients in NSW who, on Census Day 1996, either had a definite diagnosis of HD (motor signs of chorea or ataxia and family history of HD or positive DNA test result) or would have had signs and later received a definite diagnosis (assessed 1 April 1997 to 1 July 1999)., Main Outcome Measures: Prevalence (HD patients per 100,000 population); patient characteristics; year and basis of diagnosis., Results: 380 patients with definite HD were identified, giving a prevalence of HD in NSW in 1996 of 6.29 per 100,000 population (95% CI, 5.68-6.96). A third of HD patients were aged 60 years or older. Diagnosis was confirmed by DNA testing for 171 patients (45%), including 30 (8%) with no recorded family history. Average numbers of new diagnoses per year were 11.8 (1984-1988), 21.8 (1989-1993) and 28.6 (1994-1998). Estimated number of people with a 50% risk of inheriting the HD mutation was 25.2 per 100,000 population. Estimated incidence of HD in 1996 was 0.65 per 100,000 population., Conclusions: Prevalence of HD in NSW is similar to estimated prevalence in other Australian and Western populations. Increasing numbers of cases are being diagnosed, and the 18 chronic care beds currently designated for HD patients in NSW are unlikely to be sufficient.

To characterize changes in the MR parameters of tissues due to thermal coagulation, a series of T(1), T(2), diffusion, and magnetization transfer measurements were performed on a variety of ex vivo tissues: murine slow twitch skeletal muscle, murine cardiac muscle, murine cerebral hemisphere, bovine white matter, murine liver tissue, bovine retroperitoneal adipose tissue, hen egg white, human prostate and human blood. Standardized heat treatments were performed for each tissue type, over the temperature range from 37 degrees C to 90 degrees C. For all tissues, changes in each MR measurement resulting from thermal coagulation were observed above a threshold temperature of approximately 60 degrees C. These changes are explained based on biophysical knowledge of thermal damage mechanisms and the MR properties of normal tissues, and are particularly relevant for interpreting the changes in image contrast that are observed when MRI is used to guide and monitor thermal coagulation therapy procedures. Magn Reson Med 42:1061-1071, 1999., (Copyright 1999 Wiley-Liss, Inc.)

With use of an established physical model, numeric simulations were performed to evaluate current imaging protocols for the two primary applications of magnetization transfer: cerebral magnetic resonance angiography and neuroimaging of white matter disease. The authors found that the current technique is appropriate in the former but suboptimal in the latter. Further clinical investigations could potentially improve magnetization protocols for neuroimaging.

Focused ultrasound heating of ex vivo bovine kidney and liver was monitored using magnetic resonance imaging (MRI) to investigate the quantitative relationship between time-dependent temperature elevations and altered contrast in MR images due to thermal coagulation. Proton resonance frequency shift MR thermometry was performed during heating at 10 sec intervals (single-slice fast spoiled GRASS [FSPGR], theta/TE/TR 30 degrees/11/39 msec, field of view 8 cm, 256 x 256, 3 mm slice thickness, 1 NEX); post-heating MR images were T1-weighted (3D-FSPGR, theta/TE/TR 60 degrees/25/200 msec, 1 mm slice thickness, 3 NEX). Analysis of the resulting temperature versus time data using the Arrhenius relationship and a simple binary discrimination model showed that thermal coagulation occurred with heating at approximately 54 degrees C for 10 sec in both tissues and could be predicted with approximately 625 microm spatial resolution. These results suggest that quantitative MR guidance of thermal coagulation therapy is feasible, and they provide information useful for designing future investigations in vivo.

Detailed measurements of the T1-weighted, T2-weighted, and MT-weighted signal were performed for ex vivo muscle samples heated to various temperatures for different times. Consistent, monotonic increases in signal intensity were observed with progressive thermal coagulation, corresponding to an increase in T2 relaxation time and an increase in MT-weighted signal for temperatures above 60 degrees C. The relationship for T1 relaxation was more complex, showing a decrease in T1 relaxation from 40 to 60 degrees C and an increase above 60 degrees C. These techniques provide a more direct measure of tissue thermal coagulation than that provided by MR thermometry and suggest MR imaging strategies for the optimization and monitoring of thermal coagulation therapy protocols that create thermal damage in target tissues.

The magnetic resonance absorption spectrum, T1 and T2 relaxation time distributions, and magnetization transfer properties of ex vivo breast tissue have been characterized at 1.5 T and 37 degrees C. The fraction of fibroglandular tissue within individual tissue samples (n = 31) was inferred from the tissue volumetric water content obtained by integration of resolvable broad-line fat and water resonances. The spectroscopically estimated water content was strongly correlated with that extracted enzymatically (Pearson correlation coefficient 0.98, P < < 0.01), which enabled the assignment of principal relaxation components for fibroglandular tissue (T2=0.04+/-0.01, T1=1.33+/-0.24 s), and for adipose tissue (T2=0.13+/-0.01, T1=0.23+/-0.01 s, and T2=0.38+/-0.03, T1=0.62+/-0.16 s). Th e relaxation components for fibroglandular tissue exhibited strong magnetization transfer, whereas those for adipose tissue showed little magnetization transfer effect. These results ultimately have applicability to the optimization of clinical magnetic resonance imaging and research investigations of the breast.

Using a two-pool exchange model of magnetization transfer (MT), numeric simulations were developed to predict the time dependence of longitudinal magnetization in both semisolid and liquid pools for arbitrary pulsed radiofrequency (RF) irradiation. Whereas RF excitation of the liquid pool was modeled using the time-dependent Bloch equations, RF saturation of the semisolid pool was described by a time-dependent rate proportional to both the absorption lineshape of the semisolid pool and the square of the RF pulse amplitude. Simulations show good agreement with experimental results for a 4% agar gel aqueous system in which the two-pool kinetics have been well studied previously. These simulations provide a method for interpreting pulsed MT effects, are easily extended to biologic tissues, and provide a basis for optimizing clinical imaging applications that exploit MT contrast.

Three American products and one Canadian product were examined for content uniformity and particle size distribution. The results showed that not all products performed equally well. Some of the products exhibited high sprays early in the canister lifetime and all products demonstrated loss of prime. The particle size distributions were determined using the Andersen cascade impactor (USP Induction Port) and the fine particle fraction was determined using the twin impinger. The results showed that three of the four products had similar particle size distribution profiles. Both the Andersen cascade impactor and the twin impinger yielded the same trends in the amount of drug substance delivered to the fine particle fraction.

To summarize and compare magnetization transfer data from biological tissues, a method was developed to extract the average absorption lineshape of the semi-solid pool directly from magnetization transfer experimental data along with the four other parameters that characterize the two-pool model of exchange. Magnetization transfer data for several biological tissues were analyzed using this method and the resulting "flexible" lineshapes were compared with super-Lorentzian and "Kubo-Tomita" lineshapes. The use of flexible lineshapes noticeably improves the fit of the two-pool model to the data. The derived flexible lineshapes of all the tissues analyzed are physically realistic and show remarkably consistent behavior.

Four commercially available beclomethasone metered dose inhalers were analyzed for both spray content uniformity and particle size. The drug contents of primed and unprimed sprays collected at the beginning of the lifetime of the canister were not significantly different from those collected throughout the experiment. Particle size analysis of the four products using the Andersen Cascade Impactor Mark II showed that the distribution profiles were not identical. An existing HPLC method was modified to quantitate single sprays for content uniformity and to measure the amount on an impactor stage for particle sizing.

MR techniques providing accurate measurement of relative volumetric water content and multicomponent T2 relaxation times from a large volume of interest, have been implemented for characterization of breast tissue in vivo. In a sequence of 20-s breath-holds, data are obtained from much of the breast volume while suppressing signal from the chest wall and torso. Relative water content of each breast is calculated from one-dimensional fat and water profiles obtained using a hybrid two-point Dixon method (TE/TR = 17/5000 ms). Multicomponent T2 relaxation measurements are calculated from T2 decay curves obtained using a CPMG train of rectangular pulses (TE/TR = 8/5000 ms, 140 echoes) preceded by saturation pulses to localize longitudinal magnetization spatially. These techniques, validated in phantoms and human volunteers, are suitable for quantitative study of breast tissue in vivo, and in particular to investigate the potential role of MR for assessment of breast cancer risk.

Monte Carlo simulations were performed to determine whether the multicomponent T2 distribution of tissue can be estimated accurately from T2 decay data acquired in vivo. Simulated data were generated for white matter, fast twitch muscle, and breast tissue. The signal-to-noise ratio, number of data samples, and minimum echo time were varied from the experimental conditions currently achievable with MRI to those achievable for in vitro experiments. Data were fitted by a distribution of T2 values using the T2NNLS algorithm, and statistics characterizing the estimated T2 components were determined. Current MRI techniques were found to provide conditions insufficient for accurate multicomponent T2 analysis on a pixel-by-pixel basis. However, volume localization methods that measure T2 decay from a large volume of interest have potential for this analysis. These results illustrate a general framework for development of new techniques to measure T2 decay accurately in vivo.

Previous investigators have shown that there is a strong association between the fraction of fibroglandular tissue within the breast as determined by X-ray mammography (per cent density) and breast cancer risk. In this study, the quantitative correlation between per cent density and two objective magnetic resonance (MR) parameters of breast tissue, relative water content and mean T2 relaxation time, as investigated for 42 asymptomatic subjects. Using newly developed, rapid techniques MR measurements were performed on a volume-of-interest incorporating equal, representative portions of both breasts. X-ray mammograms of each subject were digitised and analysed semiautomatically to determine per cent density. Relative water content showed a strong positive correlation with per cent density (Pearson correlation coefficient rp = 0.79, P < 0.0001) and mean T2 value showed a strong negative correlation with per cent density (rp = -0.61, P < 0.0001). The MR and X-ray parameters were also associated with sociodemographic and anthropometric risk factors for breast cancer (P < 0.05). The potential use of MR parameters to assess risk of breast cancer and to provide a frequent, non-hazardous monitor of breast parenchyma is discussed.

MR imaging at 1.5 T was used to investigate variations in breast parenchyma during the menstrual cycle. Seven subjects were examined twice weekly over at least one menstrual cycle. A three-point Dixon technique (TE = 19 msec, TR = 2000 msec) provided images of fat, water, and static magnetic field (Bo), from which two quantitative whole breast parameters were calculated: the mean relative volumetric water content, , and the mean volumetric fibroglandular fraction, . Four of seven subjects showed unequivocal cyclic variations in and consistent with expected histologic changes; and values were elevated during menses and reduced in mid-cycle. The maximum deviation measured for each of the four subjects was < or = 10% in and units. These variations probably do not influence significantly the clinical interpretation of unenhanced MR breast images. Quantitative measurements of breast parenchyma, however, should recognize these effects.

The duration of effect of levodopa has been reported by some authors to be shorter in fluctuating parkinsonian patients with long standing disease than in stable patients. Other authors report no difference in the two groups of patients. We assessed motor fluctuations and response duration in 15 Parkinson's disease patients. Three patterns of response were observed: deterioration within one day on placebo and marked fluctuations on levodopa; deterioration after one day on placebo and moderate fluctuations on levodopa; no deterioration during 3 days of placebo and no fluctuations on levodopa. One patient who did not deteriorate or fluctuate did both when restudied 12 years later. This study confirms that, in addition to the short duration response to a single dose of levodopa, there is a long duration response to levodopa which is lost as the disease progresses. Loss of this long duration response to levodopa may be a key factor in the emergence of fluctuations in Parkinson's disease.

Background: The authors devised a histopathologic classification system for interpreting bone marrow biopsy materials in patients with mycosis fungoides and the Sézary syndrome and correlated histopathologic findings with clinical stage and outcome., Methods: Bone marrow specimens from 90 consecutively staged patients were examined for lymphoid infiltrates, benign or cytologically atypical lymphoid aggregates, and large or cytologically transformed cells., Results: Thirty-seven (41%) marrows were involved, two with diffuse lymphomatous infiltrates and 35 with lymphoid aggregates. Twelve of the 35 had lymphoid aggregates consisting of cytologically normal-appearing lymphocytes, and 23 had aggregates composed of cytologically atypical lymphocytes. Eleven patients had greater than 5% large cytologically transformed cells. Patients with infiltrative disease or cytologically atypical aggregates had an inferior survival compared with those with cytologically normal lymphocytes (P2 = 0.0042), and patients with aggregates consisting of cytologically normal lymphocytes had a survival comparable with that of patients with uninvolved marrows (P2 = 0.33). Whereas most patients with cytologically atypical marrows had advanced skin and lymph node involvement, 28% had early skin stage. Bone marrow eosinophilia was noticed in 38% of patients and was not consistently associated with peripheral blood eosinophilia or clinical stage., Conclusions: These results suggest that patients with cytologically atypical lymphoid aggregates or diffuse lymphomatous infiltration of the marrow have an inferior survival regardless of clinical stage, whereas those with lymphoid aggregates consisting of cytologically normal-appearing lymphocytes have a survival indistinguishable from that of patients without lymphoid aggregates.

An autopsy was performed on a 72-y-old Caucasian female who had received a carotid artery injection of thorium dioxide in 1953. The body was dissected in such a manner as to provide for radiobiological evaluation as well as to determine histologically the distribution of Thorotrast in the tissues and its complications. Thorotrast was identified within the liver, spleen, lymph nodes, bone marrow, and surrounding the right carotid artery (the injection site). The cause of death was gastric hemorrhage complicating pancytopenia secondary to refractory anemia with excess of blasts (myelodysplastic syndrome).

Thirty subjects complaining of a decrease in soft contact lens wearing time secondary to dry eye discomfort were selected for our study. All subjects were between the ages of 25 and 40 and selected on the basis of subjective dry eye complaints alone. Five of these subjects had punctum that were too small to facilitate plug placement and were therefore eliminated from further study. Removable silicone punctal plugs were monocularly placed in the lower puncta of the remaining 25 subjects. In an attempt to minimize the placebo effect, both puncta were manipulated equally prior to plug insertion and the patient was not told which eye had been treated. Three weeks following plug placement, blind data assessment showed that 18 of the 25 subjects reported, on average, a 34.6 percent increase in comfortable contact lens wearing time in the treated eye. Three subjects reported no subjective increase in comfortable wearing time and four subjects were unable to tolerate the punctal plugs for more than a week due to plug-related discomfort. Problematic epiphora was not reported in any of the treated eyes. Reversible inferior punctal occlusion, when tolerated, can significantly increase comfortable contact lens wearing time while still allowing enough drainage from the upper puncta to prevent epiphora.

Objective: To compare the effects of single doses of oral levodopa, subcutaneous apomorphine and sublingual apomorphine., Design: Single-blind placebo-controlled comparative study., Setting: Subjects were admitted as day patients to the neurology ward., Patients: Five patients with idiopathic Parkinson's disease and "end of dose deterioration" entered and completed the study., Interventions: Patients were given domperidone (20 mg by mouth three times a day) to prevent nausea and apomorphine (1-3 mg by subcutaneous injection), apomorphine in glycerol (10-30 mg sublingually) or their usual levodopa regimen., Main Outcome Measures: Efficacy, time to onset of effect and duration of effect of oral levodopa, subcutaneous apomorphine and sublingual apomorphine. Tremor amplitude and timed pegboard and gait tasks were used as objective indices of clinical state., Results: Maximal efficacy of the three treatments was comparable (P = 0.28-0.99). Mean latency to onset of effect of both formulations of apomorphine was less than that of levodopa (P = 0.022-0.048) but so was the duration of effect (P = 0.044-0.049)., Conclusions: Sublingual apomorphine may be a convenient means of rapidly terminating "off" periods associated with long term levodopa therapy.

A 58-year-old man had a left jugulodigastric mass, which was found to be cystic by computed tomography, and no evidence of other lesions. Grossly and histologically, the surgical specimen consisted of a thin-walled, fluid-filled cyst lined by squamous epithelium that varied in appearance from benign to invasive squamous cell carcinoma. The findings supported a differential diagnosis of branchial cleft carcinoma (BCCA) versus cystic growth of a lymph node metastasis from an occult malignancy. On this basis, guided biopsies of the upper aerodigestive tract were performed, with strong suspicion of a tonsillar bed lesion. Microscopic examination revealed the primary tumor within tissue excised from the left tonsillar fossa. Comparison of the current case with cases of BCCA and cystic tonsillar metastases from the literature illustrated the potential pitfalls in rendering a diagnosis of BCCA. Recognition of this lesion as a distinctive clinical variant of oropharyngeal carcinoma is warranted.

A modification of the USP HPLC method [ United States Pharmacopeia XXII, pp. 1444-1446] for the assay of the purity of verapamil hydrochloride has been evaluated for the determination of the drug content and related compounds in drug raw material. The method enables the resolution of 16 related compounds from the parent drug and, in most cases, from each other. The minimum quantifiable amount for most related compounds is less than 0.05%. Six drug raw material samples are analysed and the total impurities found to be 0.3% or less. All drug assay values were within the USP recommended limits of 99.0-100.5%.

Described herein is a case of childhood Burkitt's lymphoma initially presenting as a pericardial effusion. A cytological diagnosis was made from a Wright's-Giemsa stained cytospin preparation. Supporting diagnostic evidence was provided by immunological surface marker analysis and electron microscopy. To our knowledge, Burkitt's lymphoma has not hitherto been diagnosed initially from the morphology of cells in pericardial fluid.