SABRE hyperpolarisation of vitamin B3 as a function of pH.

In this work we describe how the signal enhancements obtained through the SABRE process in methanol-d4 solution are significantly affected by pH. Nicotinic acid (vitamin B3, NA) is used as the agent, and changing pH is shown to modify the level of polarisation transfer by over an order of magnitude, with significant improvements being seen in terms of the signal amplitude and relaxation rate at high pH values. These observations reveal that manipulating pH to improve SABRE enhancements levels may improve the potential of this method to quantify low concentrations of analytes in mixtures. 1H NMR spectroscopy results link this change to the form of the SABRE catalyst, which changes with pH, resulting in dramatic changes in the magnitude of the ligand exchange rates. The presented data also uses the fact that the chemical shifts of the nicotinic acids NMR resonances are affected by pH to establish that hyperpolarised 1H-based pH mapping with SABRE is possible. Moreover, the strong polarisation transfer field dependence shown in the amplitudes of the associated higher order longitudinal terms offers significant opportunities for the rapid detection of hyperpolarised NA in H2O itself without solvent suppression. 1H and 13C MRI images of hyperpolarised vitamin B3 in a series of test phantoms are presented that show pH dependent intensity and contrast. This study therefore establishes that when the pH sensitivity of NA is combined with the increase in signal gain provided for by SABRE hyperpolarisation, a versatile pH probe results.

Utilisation of water soluble iridium catalysts for signal amplification by reversible exchange.

The catalytic hyperpolarisation of pyridine, 3-hydroxypyridine and oxazole by the Signal Amplification By Reversible Exchange (SABRE) process is achieved by a series of water soluble iridium phosphine and N-heterocyclic carbene dihydride complexes. While the efficiency of the SABRE process in methanol-d4 solution or ethanol-d6 solution is high, with over 400-fold (1)H polarisation of pyridine being produced by [Ir(H)2(NCMe)(py)(IMes)(monosulfonated-triphenylphosphine)]BF4, changing to a D2O or a D2O-ethanol solvent mixture leads to dramatically reduced activity which is rationalised in terms of low H2 solubility.

A Bayesian spatiotemporal model for very large data sets.

Functional MRI provides a unique perspective of neuronal organization; however, these data include many complex sources of spatiotemporal variability, which require spatial preprocessing and statistical analysis. For the latter, Bayesian models provide a promising alternative to classical inference, which uses results from Gaussian random field theory to assess the significance of spatially correlated statistic images. A Bayesian approach generalizes the application of these ideas in that (1) random fields are used to model all spatial parameters, not solely observation error, (2) their smoothness is optimized, and (3) a broader class of models can be compared. The main problem, however, is computational, due to the large number of voxels in a brain volume. Sampling methods are time-consuming; however, approximate inference using variational Bayes (VB) offers a principled and transparent way to specify assumptions necessary for computational tractability. Penny et al. (2005b) described such a scheme using a joint spatial prior and approximated the joint posterior density with one that factorized over voxels. However, a further computational bottleneck is encountered when evaluating the log model evidence used to compare models. This has lead to dividing a brain volume into slices and treating each independently. This amounts to approximating the spatial prior over a full volume with stacked 2D priors. That is, smoothness along the z-axis is not included in the model. Here we describe a VB scheme that approximates the zero mean joint spatial prior with a non-zero mean empirical prior that factors over voxels, thereby overcoming this problem. We do this by modifying the original VB algorithm of Penny et al. using the conditional form of a so-called conditional autoregressive (CAR) prior to update a marginal prior over voxels. We refer to this as a spatially-informed voxel-wise prior (SVP) and use them to spatially regularise general linear model (GLM) and autoregressive (AR) coefficients (over time to model serial correlations). This algorithm scales more favourably with the number of voxels providing a truly 3D spatiotemporal model over volumes containing tens of thousands of voxels. We compare the scaling of compute times with the number of voxels and performance with a joint prior applied to synthetic and single-subject data.

Detection and direction-discrimination of diotic and dichotic ramp modulations in amplitude and phase.

When the source of a tone moves with respect to a listener's ears, dichotic (or interaural) phase and amplitude modulations (PM and AM) are produced. Two experiments investigated the psychophysical characteristics of dichotic linear ramp modulations in phase and amplitude, and compared them with the psychophysics of diotic PM and AM. In experiment 1, subjects were substantially more sensitive to dichotic PM than diotic PM, but AM sensitivity was equivalent in the dichotic and diotic conditions. Thresholds for discriminating modulation direction were smaller than detection thresholds for dichotic AM, and both diotic AM and PM. Dichotic PM discrimination thresholds were similar to detection thresholds. In experiment 2, the effects of ramp duration were examined. Sensitivity to dichotic AM and PM, and diotic AM increased as duration was increased from 20 ms to 200 ms. The functions relating sensitivity to ramp duration differed across the stimuli; sensitivity to dichotic PM increased more rapidly than sensitivity to dichotic or diotic AM. This was also reflected in shorter time-constants and minimum integration times for dichotic PM detection. These findings support the hypothesis that the analysis of dichotic PM and AM rely on separate mechanisms.

Two kinds of transient outward currents, I(A) and I(Adepol), in F76 and D1 soma membranes of the subesophageal ganglia of Helix aspersa.

Transient outward currents were characterized with twin electrode voltage clamp techniques in isolated F76 and D1 neuronal membranes (soma only) of Helix aspersa subesophageal ganglia. In this study, in addition to the transient outward current (A-current, I(A)) described by Connor and Stevens (1971b), another fast outward current, referred to as I(Adepol) here, is described for the first time. This is similar to the current component characterized in Aplysia (Furukawa, Kandel & Pfaffinger, 1992). The separation of these two current components was based on activation and steady-state inactivation curves, holding potentials and sensitivity to 4-aminopyridine (4-AP). In contrast to I(A), I(Adepol) did not require hyperpolarizing conditioning pulses to remove inactivation; it was evoked from a holding potential of -40 mV, at which I(A) is completely inactivated. I(Adepol) shows noticeable activation at around -5 mV, whereas I(A) activates at around -50 mV. The time courses of I(Adepol) activation and inactivation were similar but slower than I(A). It was found that I(Adepol) was more sensitive than I(A) to 4-AP. 4-AP at a concentration of 1 mm blocked I(Adepol) completely, whereas 5-6 mm 4-AP was needed to block I(A) completely. This current is potentially very important because it may, like other A currents, regulate firing frequency but notably, it does not require a period of hyperpolarization to be active.

Second-order modulation detection thresholds for pure-tone and narrow-band noise carriers.

Modulation perception has typically been characterized by measuring detection thresholds for sinusoidally amplitude-modulated (SAM) signals. This study uses multicomponent modulations. "Second-order" temporal modulation transfer functions (TMTFs) measure detection thresholds for a sinusoidal modulation of the modulation waveform of a SAM signal [Lorenzi et al., J. Acoust. Soc. Am. 110, 1030-2038 (2001)]. The SAM signal therefore acts as a "carrier" stimulus of frequency fm, and sinusoidal modulation of the SAM signal's modulation depth (at rate f'm) generates two additional components in the modulation spectrum at fm - f'm and fm + f'm. There is no spectral energy at the envelope beat frequency f'm in the modulation spectrum of the "physical" stimulus. In the present study, second-order TMTFs were measured for three listeners when fm was 16, 64, and 256 Hz. The carrier was either a 5-kHz pure tone or a narrow-band noise with center frequency and bandwidth of 5 kHz and 2 Hz, respectively. The narrow-band noise carrier was used to prevent listeners from detecting spectral energy at the beat frequency f'm in the "internal" stimuli's modulation spectrum. The results show that, for the 5-kHz pure-tone carrier, second-order TMTFs are nearly low pass in shape; the overall sensitivity and cutoff frequency measured on these second-order TMTFs increase when fm increases from 16 to 256 Hz. For the 2-Hz-wide narrow-band noise carrier, second-order TMTFs are nearly flat in shape for fm = 16 and 64 Hz, and they show a high-pass segment for fm = 256 Hz. These results suggest that detection of spectral energy at the envelope beat frequency contributes in part to the detection of second-order modulation. This is consistent with the idea that nonlinear mechanisms in the auditory pathway produce an audible distortion component at the envelope beat frequency in the internal modulation spectrum of the sounds.

Monaural and binaural detection of sinusoidal phase modulation of a 500-Hz tone.

The detectability of phase modulation was measured for three subjects in two-alternative temporal forced-choice experiments. In experiment 1, the detectability of sinusoidal phase modulation in a 1500-ms burst of an 80-dB (SPL), 500-Hz sinusoidal carrier presented to the left ear (monaural condition) was measured. The experiment was repeated with an 80-dB, 500-Hz static (unmodulated) tone at the right ear (dichotic condition). At a modulation rate of 1 Hz, subjects were an order of magnitude more sensitive to phase modulation in the dichotic condition than in the monaural condition. The dichotic advantage decreased monotonically with increasing modulation rate. Subjects ceased to detect movement in the dichotic stimulus above 10 Hz, but a dichotic advantage remained up to a modulation rate of 40 Hz. Thus, although sound movement detection is sluggish, detection of internal phase modulation is not. In experiment 2, thresholds for detecting 2-Hz phase modulation were measured in the dichotic condition as a function of the level of the pure tone in the right ear. The dichotic advantage persisted even when the level of the pure tone was reduced by 50 dB or more. The findings demonstrate a large dichotic advantage which persists to high modulation rates and which depends very little on interaural level differences.

Frontal processing and auditory perception.

Disordered processing of the pattern in sound over time has been observed in a number of clinical disorders, including developmental dyslexia. This study addresses the brain mechanisms required for the perception of such a pattern. We report the systematic evaluation of temporal perception in a patient with a single intact right auditory cortex and a large right frontal lobe lesion. A striking dissociated deficit was demonstrated in the perception of temporal pattern at the level of tens or hundreds of milliseconds. This proves that, contrary to common belief, mechanisms in the pathway up to and including the primary auditory cortex are not sufficient for the normal perception of temporal pattern. This work suggests a need for frontal processing for the normal perception of auditory pattern.

Human brain areas involved in the analysis of auditory movement.

This work tests the hypothesis that a network of areas involving bilateral premotor cortex and right parietal cortex subserves the analysis of sound movement. The components of this network have been examined at the level of individual subjects in a study where 720 fMRI scans were acquired per subject. Additionally, the effect of movement direction was investigated by varying this property systematically. Linear sound ramps that are perceived as movement toward one side of the head or the other were used in an experiment in which the principal contrast was between movement, and a stationary control stimulus made up of identical component interaural phase and amplitude cues. In a group analysis, the network of bifrontal and right parietal areas suggested by previous work was confirmed. The frontal activation included both dorsal premotor activity in the region of the frontal eye fields and discrete ventral premotor activation in an area corresponding to primate areas for multimodal spatial analysis and motor planning. The right parietal activation included both superior and inferior parietal cortex. Analysis of the individual data showed a similar pattern of activation in each subject, with the greatest variability within the right parietal area. The pattern of activation did not vary when the direction of movement was varied, suggesting that both directions of movement are represented in the network we have demonstrated.

Dynamic sensory sensitivity and children's word decoding skills.

The relationship between sensory sensitivity and reading performance was examined to test the hypothesis that the orthographic and phonological skills engaged in visual word recognition are constrained by the ability to detect dynamic visual and auditory events. A test battery using sensory psychophysics, psychometric tests, and measures of component literacy skills was administered to 32 unselected 10-year-old primary school children. The results suggest that children's sensitivity to both dynamic auditory and visual stimuli are related to their literacy skills. Importantly, after controlling for intelligence and overall reading ability, visual motion sensitivity explained independent variance in orthographic skill but not phonological ability, and auditory FM sensitivity covaried with phonological skill but not orthographic skill. These results support the hypothesis that sensitivity at detecting dynamic stimuli influences normal children's reading skills. Vision and audition separately may affect the ability to extract orthographic and phonological information during reading.

Effect of calcium and calcium channel blockers on transient outward current of F76 and D1 neuronal soma membranes in the subesophageal ganglia of Helix aspersa.

Twin-electrode voltage-clamp techniques were used to study the effect of calcium and calcium channel blockers on the transient outward current in isolated F76 and D1 neurones of Helix aspersa subesophageal ganglia in vitro (soma only preparation with no cell processes). On lowering extracellular Ca(2+) concentration from 10 to 2 mm or removing extracellular calcium from the bathing medium, the threshold for this current shifted in a negative direction by 11. 5 and 20 mV, respectively. On the other hand, increasing the extracellular Ca(2+) concentration from 10 to 20 and to 40 mm shifted the steady-state inactivation curves in positive directions on the voltage axis by 7 and 15 mV, respectively. Upon application of calcium channel blockers, Co(2+), La(3+), Ni(2+) and Cd(2+), transient potassium current amplitude was reduced in a voltage-dependent manner, being more effective at voltages close to the threshold. The current was elicited even at a holding potential of -34 mV. The specific calcium channel blockers, amiloride and nifedipine did not shift the activation and steady-state inactivation curves and did not reduce the transient outward current amplitude. It was concluded that the transient outward current is not dependent on intracellular Ca(2+) but that it is modulated by Ca(2+) and di- and trivalent ions extracellularly. The effects of these ions are very unlikely to be due to a surface charge effect because the addition of La(3+) (200 microm) completely reverses the shift in a hyperpolarizing direction when the extracellular Ca(2+) concentration was reduced from 10 to 1 mm and additionally shifts the kinetics further still in a depolarizing direction. The responses seen here are consistent with a specific effect of di- and trivalent ions on the transient outward current channels leading to a modification of gating.

Cortical activation during perception of a rotating wide-field acoustic stimulus.

We describe sound stimuli that produce the perception of complete rotation around the head. Such stimuli are analogous to wide-field motion stimuli used in visual research, though auditory stimuli, unlike visual stimuli, can be perceived at any point around the head; they are the only cues for spatial perception behind the subject. Using PET on six subjects, we have compared regional brain activity during the perception of such motion stimuli, with the perception of a control stimulus producing equivalent amplitude changes without rotation. Rotation produced activation of the premotor cortex bilaterally and the right superior parietal cortex. The premotor activation involved the frontal eye fields and ventral premotor areas. The bifrontal and right parietal activation is consistent with previous demonstrations of activation within a frontoparietal network of areas during perception of a linear motion stimulus. The inferior premotor activation in this experiment may reflect preparation for head turning in response to auditory targets that cannot be tracked visually.

Can sensitivity to auditory frequency modulation predict children's phonological and reading skills?

Understanding how letter units represent particular speech sounds is a crucial skill for developing competent reading skills. However it is not known whether such phonological ability is constrained by basic auditory capacities such as those necessary for detecting the frequency modulations characteristic of many phonemes. Here we show that nearly 40% of the variability in normal children's phonological and reading skills can be predicted from their sensitivity to 2 Hz frequency modulated (FM) tones. This relationship does not hold for sensitivity to 240 Hz FM. Because lower but not higher rates of FM provide information important for speech comprehension, dynamic auditory sensitivity is likely to play an important role in children's phonological and reading skill development.

Morphological and electrophysiological features of F76 and D1 neurones of the sub-oesophageal ganglia of Helix aspersa in vitro and in culture.

Identified neurones F76 and D1 of the suboesophageal ganglia of Helix aspersa were studied in the isolated ganglia in vitro and in culture. The neurones were examined electrophysiologically with current clamp and morphologically either with intracellular injections of Lucifer Yellow or biocytin. These nerve cells had very similar resting membrane potentials and responses to injected current. The projections of D1 and F76 have been characterised, with both neurones having two main axons. The F76 neurones project to the left pallial, right pallial, anal, and visceral nerves as well as to the left and right pleural ganglia. The D1 neurones have similar projections except that they do not project to the anal and visceral nerves. The bilateral symmetry to the pallial nerves and pleural ganglia is discussed. These cells were also studied electrophysiologically after mechanical isolation and culture. F76 and D1 neurones were separated by dissection (no enzymes) and cultured in three ways. In normal snail Ringer they remained viable for up to two weeks with no development. In Ringer preincubated with a ganglia or containing endothelial growth factor, neurite outgrowths were seen. Membrane potentials were significantly lower in cultured neurones than in vitro and the after hyperpolarization never went below resting in cultured cells but it did in vitro.

A common neural substrate for the analysis of pitch and duration pattern in segmented sound?

The analysis of patterns of pitch and duration over time in natural segmented sounds is fundamentally relevant to the analysis of speech, environmental sounds and music. The neural basis for differences between the processing of pitch and duration sequences is not established. We carried out a PET activation study on nine right-handed musically naive subjects, in order to examine the basis for early pitch- and duration-sequence analysis. The input stimuli and output task were closely controlled. We demonstrated a strikingly similar bilateral neural network for both types of analysis. The network is right lateralised and includes the cerebellum, posterior superior temporal cortices, and inferior frontal cortices. These data are consistent with a common initial mechanism for the analysis of pitch and duration patterns within sequences.

A distinct low-level mechanism for interaural timing analysis in human hearing.

The detection of phase or timing differences, and amplitude differences between the two ears are cues for the spatial analysis of sound by humans. Previous physiological and anatomical studies of animals suggest that phase and amplitude differences between the ears may depend on different pathways, though human psychophysical studies suggest that interaural phase and amplitude differences between the two ears may be coded in the same way. Here we describe detailed psychophysical analysis of a subject with multiple sclerosis affecting the brain stem. He has a complete deficit in the detection of phase between the ears with preserved detection of interaural amplitude. The results prove that a distinct mechanism exists in humans for interaural phase detection.

Sensitivity to dynamic auditory and visual stimuli predicts nonword reading ability in both dyslexic and normal readers.

BACKGROUND: Developmental dyslexia is a specific disorder of reading and spelling that affects 3-9% of school-age children and adults. Contrary to the view that it results solely from deficits in processes specific to linguistic analysis, current research has shown that deficits in more basic auditory or visual skills may contribute to the reading difficulties of dyslexic individuals. These might also have a crucial role in the development of normal reading skills. Evidence for visual deficits in dyslexia is usually found only with dynamic and not static stimuli, implicating the magnocellular pathway or dorsal visual stream as the cellular locus responsible. Studies of such a dissociation between the processing of dynamic and static auditory stimuli have not been reported previously. RESULTS: We show that dyslexic individuals are less sensitive both to particular rates of auditory frequency modulation (2 Hz and 40 Hz but not 240 Hz) and to dynamic visual-motion stimuli. There were high correlations, for both dyslexic and normal readers, between their sensitivity to the dynamic auditory and visual stimuli. Nonword reading, a measure of phonological awareness believed crucial to reading development, was also found to be related to these sensory measures. CONCLUSIONS: These results further implicate neuronal mechanisms that are specialised for detecting stimulus timing and change as being dysfunctional in many dyslexic individuals. The dissociation observed in the performance of dyslexic individuals on different auditory tasks suggests a sub-modality division similar to that already described in the visual system. These dynamic tests may provide a non-linguistic means of identifying children at risk of reading failure.

Right parietal cortex is involved in the perception of sound movement in humans.

Changes in the delay (phase) and amplitude of sound at the ears are cues for the analysis of sound movement. The detection of these cues depends on the convergence of the inputs to each ear, a process that first occurs in the brainstem. The conscious perception of these cues is likely to involve higher centers. Using novel stimuli that produce different perceptions of movement in the presence of identical phase and amplitude modulation components, we have demonstrated human brain areas that are active specifically during the perception of sound movement. Both functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) demonstrated the involvement of the right parietal cortex in sound movement perception with these stimuli.

Spatial and temporal auditory processing deficits following right hemisphere infarction. A psychophysical study.

Higher auditory function in a patient was investigated following a right hemisphere infarction between the middle and posterior cerebral artery territories involving the insula. The patient complained of lack of musical appreciation and a battery of tests confirmed a dissociated receptive musical deficit in the presence of normal appreciation of environmental sounds and speech. The ability to detect continuous changes in sound frequency in the form of sinusoidal frequency modulation was preserved. There was, however, a deficit in the analysis of rapid temporal sequences of notes which could underlie his musical deficit. This case provides further evidence for the existence of amusia as a distinct form of auditory agnosia, but does not support the hypothesis that bilateral lesions are required to produce such a deficit. Unexpectedly, the patient was also found to have a deficit in the perception of apparent sound-source movement. We suggest that this deficit is analogous to the visual phenomenon of akinetopsia, and is in accord with PET work suggesting involvement of areas outside primary auditory cortex in sound movement perception. A possible common deficit in auditory temporal and spatial 'scene analysis' is discussed.

Sound movement detection deficit due to a brainstem lesion.

Auditory psychophysical testing was carried out on a patient with a central pontine lesion involving the trapezoid body, who presented with a deficit in sound localisation and sound movement detection. A deficit in the analysis of time and intensity differences between the ears was found, which would explain the deficit in detection of sound movement. The impaired detection of sound movement, due to a lesion interfering with convergence of auditory information at the superior olive, suggests this structure to be critical for human sound movement analysis.