Dysregulation of arousal and amygdala-prefrontal systems in paranoid schizophrenia

OBJECTIVE: The authors investigated impaired differentiation of limbic-prefrontal systems by autonomic arousal in schizophrenia. It was predicted that paranoid patients would be distinguished by a disjunction of hyperarousal but reduced amygdala and medial prefrontal activity relative to both healthy comparison subjects and patients with nonparanoid schizophrenia. METHOD: Pictures depicting facial expressions of fear were presented to 27 schizophrenia patients (13 paranoid, 14 nonparanoid) and 22 matched healthy comparison subjects in an implicit perception task to evoke limbic activity. Simultaneous functional magnetic resonance imaging and skin conductance arousal recordings were acquired during presentation of faces expressing fear or neutral emotion. Responses to fear stimuli were further examined by contrasting those that were associated with a skin conductance response ("with arousal") and those that were not ("without arousal"). RESULTS: In the comparison subjects, arousal dissociated amygdala/medial prefrontal ("visceral") networks and hippocampus/lateral prefrontal ("context") networks for fear perception. Excessive arousal responses were elicited in the schizophrenia subjects, but there was an associated reduction in amygdala/medial prefrontal activity. This disjunction was pronounced in paranoid patients relative to both healthy subjects and nonparanoid patients. Paranoid patients also showed a relatively greater prefrontal deficit for "without-arousal" responses. CONCLUSIONS: This is the first study to reveal a functional disconnection in autonomic and central systems for processing threat-related signals in patients with paranoid schizophrenia. Paranoid cognition may reflect an internally generated cycle of misattribution regarding incoming fear signals due to a breakdown in the regulation of these systems.     

Segmental nerve conduction velocity in vibration-exposed shipyard workers

Objectives Segmental sensory nerve conduction velocity (SNCV) was measured from the wrists to the hands and digits of a population of vibration-exposed shipyard workers. This study was designed to investigate whether SNCV was selectively slowed in the fingers and whether a laboratory approach could be adapted for robust field use.Methods Wrist–palm, palm–proximal digit, and digital segments were determined from stimulation at the wrist with recording electrodes placed distally and adjusted to individual anatomy. The cohort was selected on the basis of current use of vibratory tools.Results Wrist–palm and digital segments were slower than palm–proximal digit segments for dominant and non-dominant hands and for both ulnar and median nerves. In the dominant-hand median nerve of participants with current exposure, the SNCV was 41.4 m/s (SD 8.0) for the wrist–palm segment, 50.8 (SD 9.5) for the palm segment, and 42.1 m/s (SD 9.3) for the digital segment. Temperature had an important effect on nerve conduction velocity but not equally across segments. Other explanatory variables had modest effect on SNCV.Conclusions Reduced SNCV in the digits may be a consequence of industrial exposure to vibration. Each sensory nerve segment appeared to have a different characteristic velocity and different pattern of association with skin temperature. There are differences between median and ulnar nerve segments, with potentially important consequences when standard distances are used to assess wrist–digit velocity.     

Detailed clinical assessment of neurological function in symptomatic shipyard workers

Forty eight patients with extensive occupational exposure to pneumatic grinding tools were evaluated at a university sponsored occupational health clinic. All patients were interviewed and examined by a physician and assessed neurologically with standard clinical, functional motor, quantitative vibrotactile, and electrodiagnostic tests. Sensorineural symptoms were nearly universal; 47 patients (98%) reported numbness and tingling of the hands and fingers. Among clinical tests, two point discrimination and 30 Hz vibration perception were most frequently abnormal. In order to evaluate associations between quantitative test results and sensorineural symptoms, patients were stratified into two groups of symptom severity according to a consensus sensorineural staging system. The tests that discriminated best between the groups of more and less symptomatic patients were hand strength dynamometry, and vibrotactile thresholds. Age standardised 120 Hz vibrotactile thresholds were significantly raised in digit II in 41% of hand measurements. Nerve conduction studies were neither significantly different between more and less symptomatic groups nor correlated with clinical and quantitative sensory tests. Twenty five per cent of the patients had slowing of sensory conduction velocities in the median nerve at the wrist (less than 48 m/s). Of this subset of patients only two showed abnormal slowing of the median nerve distal to the wrist, but half also showed ulnar nerve slowing (less than 47 m/s).This observation highlights the difficulty of differentiating median nerve entrapment from diffuse distal neuropathy in workers exposed to vibration and points to the need for concomitant quantitative sensory and functional motor assessment.     

Wavelets and functional magnetic resonance imaging of the human brain

The discrete wavelet transform (DWT) is widely used for multiresolution analysis and decorrelation or "whitening" of nonstationary time series and spatial processes. Wavelets are naturally appropriate for analysis of biological data, such as functional magnetic resonance images of the human brain, which often demonstrate scale invariant or fractal properties. We provide a brief formal introduction to key properties of the DWT and review the growing literature on its application to fMRI. We focus on three applications in particular: (i) wavelet coefficient resampling or "wavestrapping" of 1-D time series, 2- to 3-D spatial maps and 4-D spatiotemporal processes; (ii) wavelet-based estimators for signal and noise parameters of time series regression models assuming the errors are fractional Gaussian noise (fGn); and (iii) wavelet shrinkage in frequentist and Bayesian frameworks to support multiresolution hypothesis testing on spatially extended statistic maps. We conclude that the wavelet domain is a rich source of new concepts and techniques to enhance the power of statistical analysis of human fMRI data.     

Unsupervised analysis of fMRI data using kernel canonical correlation

We introduce a new unsupervised fMRI analysis method based on kernel canonical correlation analysis which differs from the class of supervised learning methods (e.g., the support vector machine) that are increasingly being employed in fMRI data analysis. Whereas SVM associates properties of the imaging data with simple specific categorical labels (e.g., -1, 1 indicating experimental conditions 1 and 2), KCCA replaces these simple labels with a label vector for each stimulus containing details of the features of that stimulus. We have compared KCCA and SVM analyses of an fMRI data set involving responses to emotionally salient stimuli. This involved first training the algorithm (SVM, KCCA) on a subset of fMRI data and the corresponding labels/label vectors (of pleasant and unpleasant), then testing the algorithms on data withheld from the original training phase. The classification accuracies of SVM and KCCA proved to be very similar. However, the most important result arising form this study is the KCCA is able to extract some regions that SVM also identifies as the most important in task discrimination and these are located manly in the visual cortex. The results of the KCCA were achieved blind to the categorical task labels. Instead, the stimulus category is effectively derived from the vector of image features.     

Intrasynaptosomal free calcium concentration is increased by phorbol esters via a 1,4-dihydropyridine-sensitive (L-type) Ca2+ channel

Incubation of non-depolarised fura-2-loaded rat cortical synaptosomes with 12-tetradecanoylphorbol-13-monoacetate (TPA) results in a dose-dependent increase in calcium concentration (to a maximum of 140%). It is dependent on extrasynaptosomal Ca2+, is partially blocked by 1 microM verapamil and effectively blocked by 100 microM verapamil (greater than or equal to 90%). Nifedipine (1 microM), nicardipine (1 microM) and omega-conotoxin fraction GVIA from Conus geographus (50 nM) (omega-CgTx) also cause blockade (greater than or equal to 90%) of the increase. The sensitivity of the TPA-induced increase in calcium concentration to omega-CgTx, nicardipine and nifedipine, but not to low concentrations of verapamil (1 microM), suggests that the TPA-induced rise in calcium concentration is mediated by increased Ca2+ influx through 1,4-dihydropyridine-sensitive Ca2+ channels. Incubation of synaptosomes with the inactive phorbol ester phorbol-13-monoacetate (TMA) does not result in any significant dose-dependent increase in calcium concentration. The data which are presented are consistent with (i) the proposal that phorbol ester-induced increases in calcium concentration are the result of Ca2+ influx through an L-type Ca2+ channel and (ii) the existence of functioning L-type Ca2+ channels on rat brain synaptosomes.     

A comparison of the effects of the selective 5-HT uptake inhibitor WY 27587 on 5-HT uptake into platelets and synaptosomes in the rat

N-[( 1-[(6-Fluoro-2-naphthalenyl)methyl]- 4-piperidinyl]amino]carbonyl]-3-pyridine carboxamide (Wy 27587), is 320 times more potent as an inhibitor of the uptake of 5-HT than of the uptake of noradrenaline into synaptosomes from the brain of the rat with a Ki against the uptake of 5-HT of 9.2 +/- 1.4 nM. It was also a potent competitive inhibitor of the uptake of 5-HT in platelets of the rat, with a Ki value of 2.9 +/- 1.5 nM. Ex vivo studies indicated that oral administration of Wy 27587 in the rat caused a prolonged inhibition of the uptake of 5-HT into platelets; inhibition reached a maximum 15 min after administration and the ID50 was 1.5 +/- 0.3 mg/kg.     

The disposition and metabolism of [14C]fluconazole in humans.

The disposition and metabolism of 14C-labeled fluconazole (100 microCi) was determined in three healthy male subjects after administration of a single oral capsule containing 50 mg of drug. Blood samples, total voided urine, and feces were collected at intervals after dosing for up to 12 days post-dose. Pharmacokinetic analysis of fluconazole concentrations showed a mean plasma half-life of 24.5 hr. Mean apparent plasma clearance and apparent volume of distribution were 0.23 ml/min/kg and 0.5 liter/kg, respectively. There was no evidence of any significant concentrations of metabolites circulating either in plasma or blood cells. Mean total radioactivity excreted in urine and feces represented 91.0 and 2.3%, respectively, of the administered dose. Mean excretion of unchanged drug in urine represented 80% of the administered dose; thus, only 11% was excreted in urine as metabolites. Only two metabolites were present in detectable quantities, a glucuronide conjugate of unchanged fluconazole and a fluconazole N-oxide, which accounted for 6.5 and 2.0% of urinary radioactivity, respectively. No metabolic cleavage products of fluconazole were detected.     

Presynaptic alpha 2-adrenoceptor and kappa-opiate receptor occupancy promotes closure of neuronal (N-type) calcium channels

Synaptosomes prepared from rat cerebral cortex by homogenization in isotonic sucrose and centrifugation on four-step discontinuous percoll density gradients were loaded with the fluorescent indicator fura-2 to allow measurement of intrasynaptosomal free calcium concentrations [( Ca2+]i). Incubation of fura-2 loaded synaptosomes with either the kappa-opiate agonist U-50,488H (0.1-100 microM) or the alpha 2-adrenoceptor agonist clonidine (0.1-100 microM), resulted in a dose-dependent reduction in [Ca2+]i and these changes were completely antagonised by prior inclusion of naloxone (20 microM) or idazoxan (RX781094) (2 microM) respectively. When the 1,4-dihydropyridine Ca2+-channel blocker nifedipine (1 microM) was incubated with synaptosomes for 1 min, there was a 17.0% decrease in [Ca2+]i and when it was combined with either U-50,488H (1 microM) or clonidine (1 microM) there was a reduction in [Ca2+]i of 35.0 and 48.1% respectively i.e. the effects were additive. The increases in the depression of [Ca2+]i produced by these drug combinations were antagonised by the inclusion of naloxone (20 microM) or idazoxan (2 microM) which resulted in decreases in free [Ca2+]i of 26.5 and 14.1% respectively. These data indicate that the effects of clonidine and U-50,488H are not mediated by L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil

Functional magnetic resonance imaging (fMRI) can be used to detect regional brain responses to changes in sensory stimuli. We have used fMRI to determine the amount of visual and auditory cortical activation in 12 normal subjects and 12 subjects with the narcoleptic syndrome, using a multiplexed visual and auditory stimulation paradigm. In both normal and narcoleptic subjects, mean cortical activation levels during the presentation of periodic visual and auditory stimulation showed no appreciable differences with either age or sex. Normal subjects showed higher levels of visual activation at 10:00 hours than 15:00 hours, with a reverse pattern in narcoleptic subjects (P = 0.007). The group differences in spatial extent of cortical activation between control and narcoleptic subjects were small and statistically insignificant. The alerting action, and imaging response, to a single oral dose of the sleep-preventing drug modafinil 400 mg were then determined and compared with placebo in both the 12 normal (8 given modafinil, 4 placebo) and 12 narcoleptic subjects (8 modafinil, 4 placebo). Modafinil caused an increase in self-reported levels of alertness in 7 of 8 narcoleptic subjects, but there was no significant difference between mean pretreatment and post-treatment activation levels as determined by fMRI for either normal or narcoleptic syndrome subjects given modafinil. However, in the modafinil-treated group of 8 normal and 8 narcoleptic subjects, there was a clock time independent correlation between the initial level of activation as determined by the pretreatment scan and the post-treatment change in activation (visual, P = 0.002; and auditory, P = 0.001). No correlation was observed in placebo-treated subjects (P = 0.99 and 0.77, respectively). Although limited by the small number of subjects, and the lack of an objective measure of alertness, the findings of this study suggest that low cortical activation levels in both normal and narcoleptic subjects are increased following the administration of modafinil. Functional magnetic resonance imaging may be a valuable addition to established studies of attention.