Cerebellum implicated in sensory acquisition and discrimination rather than motor control.

Recent evidence that the cerebellum is involved in perception and cognition challenges the prevailing view that its primary function is fine motor control. A new alternative hypothesis is that the lateral cerebellum is not activated by the control of movement per se, but is strongly engaged during the acquisition and discrimination of sensory information. Magnetic resonance imaging of the lateral cerebellar output (dentate) nucleus during passive and active sensory tasks confirmed this hypothesis. These findings suggest that the lateral cerebellum may be active during motor, perceptual, and cognitive performances specifically because of the requirement to process sensory data.

Beyond the single study: function/location metanalysis in cognitive neuroimaging.

Cognitive neuroimaging maps the brain locations of mental operations. This process is iterative, as no single study can fully characterize a mental operation or its brain location. This iterative discovery process, in combination with the location-reporting standard (i.e. spatial coordinates) of the cognitive neuroimaging community, has engendered a new form of metanalysis. Response locations from multiple studies have been analyzed collectively so as to better describe the spatial distribution of brain activations, with promising results. New hypotheses regarding elementary mental operations and their respective brain locations are being generated and refined via metanalysis. These hypotheses are being tested and confirmed by subsequent, prospective experiments. Function/location metanalysis is an important new tool for hypothesis generation in cognitive neuroimaging. This form of metanalysis is fundamentally different from the effect-size metanalyses prevalent in other literatures, with unique advantages and challenges.

Increased cholesterol content of erythrocyte and brain membranes in ethanol-tolerant mice.

Mice were treated with ethanol for eight or nine days, using a liquid diet regimen known to produce physical dependence. In previous experiments, synaptosomal plasma membranes and erythrocyte ghosts from such ethanol-treated animals were found to be resistant to the fluidizing effects of ethanol in vitro, as measured by electron paramagnetic resonance. In the present experiments, corresponding membranes were analysed for phospholipid and cholesterol. The ratio of cholesterol to phospholipid was found to be significantly increased in both types of membrane after chronic ethanol treatment. The changed ratio was produced by an increase in cholesterol. There was little or no change in phospholipid content of the membranes. Increased cholesterol may explain the previously observed alteration of physical properties of the membranes.

The dnaK/dnaJ operon of Haemophilus ducreyi contains a unique combination of regulatory elements.

Haemophilus ducreyi, which causes the genital ulcer disease chancroid, requires high basal levels of the 60-kDa heat-shock (hs) protein GroEL in order to survive and adhere to host cells in the presence of common environmental stresses. In contrast, the 70-kDa hs protein, DnaK, a negative modulator of the hs response in prokaryotes, is not produced at as high a level as GroEL. Because of these differences, we were interested in identifying regulatory elements affecting the expression of the H. ducreyi dnaK/dnaJ operon. First, the genes encoding H. ducreyi DnaK (Hsp70) and DnaJ (Hsp40) were sequenced. The deduced amino acid sequences shared 82.8 and 63. 9% identity with the Escherichia coli DnaK and DnaJ homologs, respectively. Despite the presence of highly similar (but not identical) hs promoter sequences preceding both the H. ducreyi groES/groEL and dnaK/dnaJ operons, transcription levels for groEL were found to exceed that of dnaK. Subsequently, other genetic elements that could contribute to a lower basal expression of dnaK in H. ducreyi were identified. These elements include: (1) a complex promoter for dnaK consisting of four transcriptional start points (two for sigma32 and two for sigma70) identified by primer extension; (2) a putative binding site for Fur (a transcriptional repressor of iron-regulated genes) that overlaps the initiating AUG of dnaK; and (3) the potential for extensive secondary structure of the long leader sequences of the dnaK transcripts, which could interfere with efficient translation of DnaK. This unique combination of regulatory elements may be responsible for the relatively low-level expression of dnaK in this fastidious genital pathogen.

Lessons from a proficiency testing event for acid-fast microscopy.

OBJECTIVES: To evaluate the routine performance and the technical parameters of different acid-fast staining methods: Kinyoun, Ziehl-Neelsen (ZN), auramine, and auramine-rhodamine. DESIGN AND PARTICIPANTS: The performance of 167 laboratories was analyzed using prestained and unstained slides. SETTING: Laboratories holding New York State permits. RESULTS: The results revealed that Kinyoun's cold carbol fuchsin method is inferior to both the ZN and fluorochrome (auramine and/or auramine-rhodamine) methods. Even though 91% of the participants used commercial staining kits, the study identified unexpected errors concerning the concentration of carbol fuchsin, time for staining and counterstaining, and the concentration of acid alcohol for decolorization, which may significantly influence the sensitivity. Besides these findings, the present study showed that the examination of < 300 view fields may also decrease the sensitivity of acid-fast microscopy. In addition, we found that the sensitivity and specificity of the ZN and fluorochrome methods are comparable if the procedural standards are followed. CONCLUSIONS: The strict and ongoing quality control of the "simple to perform" acid-fast microscopy and the immediate review of commercially available staining kits are necessary. Because of the rapidity of the fluorochrome method, laboratories with large specimen numbers should use this technique. In all other cases, the ZN method should be used. Moreover, all clinicians should be aware of the method of acid-fast microscopy used and the proficiency of the laboratory in performing the assay.

Imagined spatial transformation of one's body.

This study examined two related phenomena: (a) the judgment of whether a human body part belongs to the left or right half of the body and (b) the imagined spatial transformation of one's body. In three experiments, observers made left-right judgments of a part of a body whose orientation differed from their own by a rotation about one of 13 axes. To do so, they imagined themselves passing to the orientation of the stimulus. Time for (a) left-right judgments and (b) accompanying imagined spatial transformations depended on the extent of the orientation difference (OD) between the observer and stimulus. More important, time for phenomena (a) and (b) depended strongly, and in the same way, on the direction of OD. Further results showed that the rate of imagined spatial transformations can vary strongly for different axes and directions of rotation about an axis. These and other results (e.g., Parsons, 1987a) suggest that temporal and kinematic properties of imagined spatial transformations are more object-specific than could be previously assumed.

The rapid onset of tolerance to ataxic effects of ethanol in mice.

We have developed a precise quantal method for assessing the sensitivity to ethanol in the mouse. Mice placed on a clamped stationary horizontal dowel are scored ataxic or not ataxic depending on whether they are able to remain on the dowel during a 30-s observation period. A threshold blood ethanol concentration is determined by assaying tail blood drawn immediately upon recovery from ethanol-induced ataxia. This threshold is quite reproducible within a population of Swiss-Webster mice (coefficient of variation 9%). The precision of this method allowed us to follow the onset of rapid tolerance during a series of sequential IP ethanol doses. Tolerance persisted overnight in the absence of ethanol, and was found not to increase further with additional ethanol exposure on 2 subsequent days. The observed tolerance was shown not to be due to circadian changes in ethanol sensitivity or repeated practice on the task, indicating a true tissue tolerance.

Exploring the functional neuroanatomy of music performance, perception, and comprehension.

This chapter highlights findings by my colleagues and me in four neuroimaging and neurological studies of music performance, perception, and comprehension. These investigations elucidate the neural subsystems supporting musical pitch, melody, harmony, rhythm, tempo, meter, and duration. In a positron emission tomography (PET) study of pianists, a memorized performance of a musical piece was contrasted with that of scales to localize brain areas specifically supporting music. A second PET study assayed brain areas subserving selectively the comprehension of harmony, melody, and rhythm. Musicians sight-read a score while detecting specific melodic, harmonic, or rhythmic errors in its heard performance. In a third PET study, musicians and nonmusicians discriminated pairs of rhythms with respect to pattern, tempo, meter, or duration. Data in these studies implicated the cerebellum in nonmotor, nonsomatic, sensory, or cognitive processing. In a fourth study, neurological patients with degeneration of the cerebellum were found to be impaired in fine discrimination of pitch. Overall, these data suggest that the neural systems underlying music are distributed throughout the left and right cerebral and cerebellar hemispheres, with different aspects of music processed by distinct neural circuits. Also discussed are key issues for interpreting the role in music of brain areas implicated in neuroimaging studies.

Drug resistance in tuberculosis.

Drug-resistant tuberculosis remains a worldwide problem. New laboratory methods have improved our ability to more rapidly identify resistant strains, but the most effective approach is to prevent the appearance of resistance by appropriate choice of antibiotics and directly-observed therapy. Mycobacterium tuberculosis is treated with familiar and unique drugs; consequently, mechanisms of resistance have some unique features. All drug resistance thus far identified develops by mutational events rather than acquisition of resistance genes from other bacteria. An agenda is presented for countering the appearance of further drug resistance in mycobacteria.

Laboratory diagnosis of chancroid using species-specific primers from Haemophilus ducreyi groEL and the polymerase chain reaction.

To enhance laboratory identification of Haemophilus ducreyi, the causative agent of the genital ulcer disease chancroid, a polymerase chain reaction (PCR) assay was developed using target DNA sequences from the essential H. ducreyi gene, groEL. Positive reactions were obtained in this PCR assay with 139 isolates of H. ducreyi from patients in worldwide locations from the 1940s to the 1990s. In contrast, 24 other bacterial species were negative. When genital ulcer specimens from 162 African patients with clinically diagnosed chancroid were evaluated, 66 were culture positive. The sensitivity of PCR as compared with culture was 89% (59 of 66), and specificity was 79% (76 of 96). However, representative samples of the 20 culture-negative, PCR-positive specimens were confirmed as positive by a second PCR assay using different H. ducreyi-specific primers. Thus, combined results of culture and PCR detected H. ducreyi in 86 specimens, with resolved sensitivities of 92% (79 of 86) for PCR, and 77% (66 of 86) for culture. These results suggest that PCR assays for H. ducreyi have great potential for augmenting or replacing problematic cultural techniques.

Blood brain barrier disturbance and immunoglobulin G levels in the cerebrospinal fluid of the mouse following peripheral infection with the demyelinating strain of Semliki Forest virus.

Immunoglobulin G and albumin levels have been measured in the cerebrospinal fluid and serum of Swiss A2G mice following single intraperitoneal inoculation of Semliki Forest virus. This strain of virus used causes a meningoencephalitis followed by immunologically-mediated demyelination. By the use of the levels of immunoglobulin G and albumin in cerebrospinal fluid and serum to calculate the cerebrospinal fluid: serum ratios and the cerebrospinal fluid immunoglobulin G index, it has been shown that the blood-brain barrier breakdown is mild and restricted to within the first 7-8 days after virus inoculation when the inflammatory response is maximal. Immunoglobulin G index provides a measure of synthesis of immunoglobulin G within the blood-brain barrier. Synthesis has been shown to occur from day 10 onwards up to at least day 61 following infection. Arboviruses are known to persist in central nervous system tissue and it is suggested that a continuing immune response within the central nervous system occurs and is perpetuated by persisting virus. Because of the mode of replication of Semliki Forest virus it is also possible that some of the immune response is directed against central nervous system components.

Effect of amitriptyline on neurotransmitter levels in adult mice following infection with the avirulent strain of Semliki Forest virus.

Infection of adult mice with the avirulent strain of Semliki Forest virus (SFV) led to neurochemical abnormalities, notably depressed levels of catecholamines (CATs) such as noradrenaline (NA), adrenaline (A) and 3-methoxy-4-hydroxyphenylglycol (MHPG) (a metabolite of NA) particularly in the hypothalamus and the inferior colliculus but not in the temporal cortex. In addition, depressed levels of NA and A were also found in the cerebrospinal fluid (CSF) and the serum. Administration of a tricyclic antidepressant drug, amitriptyline, kept the levels of NA, A and MHPG similar to those of the saline-treated control mice in the hypothalamus, inferior colliculus and CSF.

Temporal and kinematic properties of motor behavior reflected in mentally simulated action.

Related perceptual, motor, and cognitive performances were examined to reveal the accuracy of the properties of action spontaneously represented when mentally simulating moving one's hand. The kinematic configuration of the body represented and transformed in mental simulations was not fixed or canonical but corresponded to one's current configuration. Mental simulation time mimicked movement time for natural efficient movement from a posture midway between each of the hand's joint limits into many other postures. Equal time was required for simulated and real movements into more common, comfortable postures; shorter but proportional time was required for simulated movement than real movement into less common postures that involved longer trajectories, coordinated activity at more joints, motion near extremes of joint limits, and uncomfortable kinesthetic sensations. The findings suggest that sensorimotor structures support mental simulations of actions.

Perceived spatial organization of cutaneous patterns on surfaces of the human body in various positions.

The perceived spatial organization of cutaneous patterns was examined in three experiments. People identified letters or numbers traced on surfaces of their body when the relative spatial orientations and positions of the body surfaces and of the stimuli were varied. Stimuli on the front or back of the head were perceived with respect to a frame of reference positioned behind those surfaces, independent of the surfaces' position and orientation. This independence may relate to the way in which the sensory apparatus on the front of the head is used in planning action. Stimuli on other surfaces of the head and body were perceived in relation to the position and orientation of the surface with respect to the whole body or trunk (most of which was usually upright). Stimuli on all transverse/horizontal surfaces were perceived with respect to frames of reference associated with the head/upper chest area. These frames were also used for stimuli on frontoparallel surfaces in front of the upper body. These observations may result from the use of "central" frames of reference that are independent of the head and are associated with the upper body. Stimuli on surfaces in other positions and orientations (with two exceptions) were perceived "externally"--that is, in frames of reference directly facing the stimulated surface. The spatial information processing we found may be fairly general because several of our main findings were also observed in very young children and blind adults and in paradigms studying perception by "active touch" and the spatial organization of the motor production of patterns.

Integrating cognitive psychology, neurology and neuroimaging.

In the last decade, there has been a dramatic increase in research effectively integrating cognitive psychology, functional neuroimaging, and behavioral neurology. This new work is typically conducting basic research into aspects of the human mind and brain. The present review features as examples of such integrations two series of studies by the author and his colleagues. One series, employing object recognition, mental motor imagery, and mental rotation paradigms, clarifies the nature of a cognitive process, imagined spatial transformations used in shape recognition. Among other implications, it suggests that when recognizing a hand's handedness, imagining one's body movement depends on cerebrally lateralized sensory-motor structures and deciding upon handedness depends on exact match shape confirmation. The other series, using cutaneous, tactile, and auditory pitch discrimination paradigms, elucidates the function of a brain structure, the cerebellum. It suggests that the cerebellum has non-motor sensory support functions upon which optimally fine sensory discriminations depend. In addition, six key issues for this integrative approach are reviewed. These include arguments for the value and greater use of: rigorous quantitative meta-analyses of neuroimaging studies; stereotactic coordinate-based data, as opposed to surface landmark-based data; standardized vocabularies capturing the elementary component operations of cognitive and behavioral tasks; functional hypotheses about brain areas that are consistent with underlying microcircuitry; an awareness that not all brain areas implicated by neuroimaging or neurology are necessarily directly involved in the associated cognitive or behavioral task; and systematic approaches to integrations of this kind.