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This study aimed to investigate the relationship between attachment state of mind and perceptual processing of social and non-social, affective, and neutral material. A total of 57 young adults completed the Adult Attachment Interview (AAI) plus an experimental task in which their perceptual thresholds to different types of pictures were assessed. Significant correlations were found between the AAI dimensions and perceptual thresholds for social stimuli such as social interactions or human faces displaying emotional expressions. As expected, no relationships were found between the AAI and perception of neutral stimuli. The pattern of correlations was especially clear for the dismissing dimension. The results suggest that higher vigilance to social stimuli is related to dismissing attachment tendencies and, to a milder degree, to preoccupied tendencies.

We investigated spatio-temporal information processing in the primate motor system. Corticomotoneuronal (CM) cells provide monosynaptic excitatory connections from motor cortex to spinal motoneurons and contribute causally to the time-varying electromyogram (EMG) of their target muscle. A multilayer perceptron (MLP) was used to evaluate the transfer function between neural activity of single CM cells and their target muscle EMG, using data from in-vivo recordings in primate motor cortex. For an optimal MLP performance, i.e., minimal error between recorded target EMG and MLP-derived EMG, the CM cell input period had to span the latency observed between CM cell peak activity and EMG peak activity. We argue that the same spike train may code two types of information: 1) rate coding within the input window accounted for large-amplitude variations in the EMG signal and 2) temporal coding within a window of 40 ms just prior to the EMG output signal accounted for EMG variations of small amplitude. The transfer function of the MLP, thus, combines rate and temporal coding and suggests that CM cell output may also combine these two forms of coding. We predict that mutual constraints of rate and temporal coding would, however, would limit the CM output to code for particular temporal profiles of EMG, possibly adapted to bio-mechanical constraints.

Rotation of a DNA or RNA nucleotide out of the double helix and into a protein pocket ('base flipping') is a mechanistic feature common to some DNA/RNA-binding proteins. Here, we report the structure of HhaI methyltransferase in complex with DNA containing a south-constrained abasic carbocyclic sugar at the target site in the presence of the methyl donor byproduct AdoHcy. Unexpectedly, the locked south pseudosugar appears to be trapped in the middle of the flipping pathway via the DNA major groove, held in place primarily through Van der Waals contacts with a set of invariant amino acids. Molecular dynamics simulations indicate that the structural stabilization observed with the south-constrained pseudosugar will not occur with a north-constrained pseudosugar, which explains its lowered binding affinity. Moreover, comparison of structural transitions of the sugar and phosphodiester backbone observed during computational studies of base flipping in the M.HhaI-DNA-AdoHcy ternary complex indicate that the south-constrained pseudosugar induces a conformation on the phosphodiester backbone that corresponds to that of a discrete intermediate of the base-flipping pathway. As previous crystal structures of M.HhaI ternary complex with DNA displayed the flipped sugar moiety in the antipodal north conformation, we suggest that conversion of the sugar pucker from south to north beyond the middle of the pathway is an essential part of the mechanism through which flipping must proceed to reach its final destination. We also discuss the possibility of the south-constrained pseudosugar mimicking a transition state in the phosphodiester and sugar moieties that occurs during DNA base flipping in the presence of M.HhaI.

Oligodeoxyribonucleotides containing pseudorotationally locked sites derived from bicyclo[3.1.0]hexane pseudosugars have been synthesized using adenosine, thymidine and abasic versions of North- and South-methanocarba nucleosides. The reaction conditions for coupling and oxidation steps of oligonucleotide synthesis have been investigated and optimized to allow efficient and facile solid-phase synthesis using phosphoramidite chemistry. Our studies demonstrate that the use of iodine for P(III) to P(V) oxidation leads to strand cleavage at the sites where the pseudosugar is North. In contrast, the same cleavage reaction was not observed in the case of South pseudosugars. Iodine oxidation generates a 5'-phosphate oligonucleotide fragment on the resin and releases the North pseudosugar into the solution. This side reaction, which is responsible for the extremely low yields observed for the incorporation of the North pseudosugar analogs, has been studied in detail and can be easily overcome by replacing iodine with t-butylhydroperoxide as oxidant.

Cognate recognition between the CD40 receptor and its ligand, CD154, is thought to play a central role in the initiation and propagation of immune responses. We describe the specific down regulation of cell surface associated CD40 protein expression by use of a peptide nucleic acid (PNA) antisense inhibitor, ISIS 208529, that is designed to bind to the 3' end of the exon 6 splice junction within the primary CD40 transcript. Binding of ISIS 208529 was found to alter constitutive splicing, leading to the accumulation of a transcript lacking exon 6. The resulting protein product lacks the transmembrane domain. ISIS 208529-mediated CD40 protein depletion was found to be sequence specific and dose dependent, and was dependent on the length of the PNA oligomer. CD40-dependent induction of IL-12 in primary murine macrophages was attenuated in cells treated with ISIS 208529. Oligolysine conjugation to the PNA inhibitor produced an inhibitor, ISIS 278647, which maintained its specificity and displayed efficacy in BCL1 cells and in primary murine macrophages in the absence of delivery agents. These results demonstrate that PNA oligomers can be effective inhibitors of CD40 expression and hence may be useful as novel immuno-modulatory agents.

The ventral premotor area (F5) is part of the cortical circuit controlling visuomotor grasp. F5 could influence hand motor function through at least two pathways: corticospinal projections and corticocortical projections to primary motor cortex (M1). We found that stimulation of macaque F5, which by itself evoked little or no detectable corticospinal output, could produce a robust modulation of motor outputs from M1. Arrays of fine microwires were implanted in F5 and M1. During terminal experiments under chloralose anesthesia, single stimuli delivered to M1 electrodes evoked direct (D) and indirect (I1,I2, and I3) corticospinal volleys. In contrast, single F5 shocks were ineffective; double shocks (3 msec separation) evoked small I waves but no D wave. However, when the test (T) M1 shock was conditioned (C) by single or double F5 shocks, there was strong facilitation of I2 and I3 waves from M1, with C-T intervals of <1 msec. Intracellular recordings from 79 arm and hand motoneurons (MNs) revealed no postsynaptic effects from single F5 shocks. In contrast, these stimuli produced a robust facilitation of I2 and I3 EPSPs evoked from M1 (60% of MNs); this was particularly marked in hand muscle MNs (92%). Muscimol injection in M1 reduced I waves from F5 and abolished the F5-induced facilitation of late I waves from M1, and of EPSPs associated with them. Thus, some motor effects evoked from F5 may be mediated by corticocortical inputs to M1 impinging on interneurons generating late corticospinal I waves. Similar mechanisms may allow F5 to modulate grasp-related outputs from M1.

In the macaque monkey and in humans, the monosynaptic cortico-motoneuronal system is well developed. It allows the cortical motor areas to make an important direct contribution to the pattern of muscle activity during upper limb movements. There is, in addition, good anatomical evidence for descending corticospinal inputs being able to influence the premotoneuronal networks of the cervical spinal cord, and especially those operating at the segmental level of upper limb motoneurons. While oligosynaptic inhibition has been easy to demonstrate in the macaque, and may be a very important component of descending corticospinal control, it has proved much more difficult to detect signs of oligosynaptic excitation. In contrast, in the squirrel monkey, in which the cortico-motoneuronal system is far less developed, oligosynaptic excitation is prominent. There are important changes in the interplay between direct and indirect pathways in different primates, which may provide important clues on the nature of the corticospinal control of upper limb function.

Results from an affective priming experiment confirm the previously reported influence of trait anxiety on the direction of affective priming in the naming task (Maier, Berner, & Pekrun, 2003): On trials in which extremely valenced primes appeared, positive affective priming reversed into negative affective priming with increasing levels of trait anxiety. Using valenced target words with irregular pronunciation did not have the expected effect of increasing the extent to which semantic processes play a role in naming, as affective priming effects were not stronger for irregular targets than for regular targets. This suggests the predominant operation of a whole-word nonsemantic pathway in reading aloud in German. Data from neutral priming trials hint at the possibility that negative affective priming in participants high in trait anxiety is due to inhibition of congruent targets.

The authors report the case of a 33-year-old woman who exhibited, at the age of 17, a left-sided hemiplegia, which was followed by good motor recovery, though with a permanent deficit in fine finger movements. She had a widespread loss of neural tissue in the right hemisphere (crossed cerebrocerebellar atrophy), including (1) marked atrophy and thinning of the precentral and postcentral gyri; (2) widespread deep white matter destruction, including the corticospinal tract; and (3) crossed cerebellar atrophy. Except over the supplementary motor area (SMA), transcranial magnetic stimulation did not elicit motor evoked potentials in the affected hand. Nevertheless, during opening and closing of the affected hand, functional magnetic resonance imaging showed an activation of the lesioned primary sensorimotor cortex (SMC), as well as of the intact SMA and the parietal areas, but not of the ipsilateral motor areas. The authors speculate that recovery was achieved by a motor command generated in the SMC and the parietal cortex, passing through corticospinal axons originating in the SMA.

We demonstrate that in the macaque monkey there is robust, short-latency facilitation by ventral premotor cortex (area F5) of motor outputs from primary motor cortex (M1) to contralateral intrinsic hand muscles. Experiments were carried out on two adult macaques under light sedation (ketamine plus medetomidine HCl). Facilitation of hand muscle electromyograms (EMG) was tested using arrays of fine intracortical microwires implanted, respectively, in the wrist/digit motor representations of F5 and M1, which were identified by previous mapping with intracortical microstimulation. Single pulses (70-200 microA) delivered to F5 microwires never evoked any EMG responses, but small responses were occasionally seen with double pulses (interval: 3 ms) at high intensity. However, both single- and double-pulse stimulation of F5 could facilitate the EMG responses evoked from M1 by single shocks. The facilitation was large (up to 4-fold with single and 12-fold with double F5 shocks) and occurred with an early onset, with significant effects at intervals of only 1-2 ms between conditioning F5 and test M1 stimuli. A number of possible pathways could be responsible for these effects, although it is argued that the most likely mechanism would be the facilitation, by cortico-cortical inputs from F5, of corticospinal I wave activity evoked from M1. This facilitatory action could be of considerable importance for the coupling of grasp-related neurons in F5 and M1 during visuomotor tasks.

Dynamic recurrent neural networks composed of units with continuous activation functions provide a powerful tool for simulating a wide range of behaviors, since the requisite interconnections can be readily derived by gradient descent methods. However, it is not clear whether more realistic integrate-and-fire cells with comparable connection weights would perform the same functions. We therefore investigated methods to convert dynamic recurrent neural networks of continuous units into networks with integrate-and-fire cells. The transforms were tested on two recurrent networks derived by backpropagation. The first simulates a short-term memory task with units that mimic neural activity observed in cortex of monkeys performing instructed delay tasks. The network utilizes recurrent connections to generate sustained activity that codes the remembered value of a transient cue. The second network simulates patterns of neural activity observed in monkeys performing a step-tracking task with flexion/extension wrist movements. This more complicated network provides a working model of the interactions between multiple spinal and supraspinal centers controlling motoneurons. Our conversion algorithm replaced each continuous unit with multiple integrate-and-fire cells that interact through delayed "synaptic potentials". Successful transformation depends on obtaining an appropriate fit between the activation function of the continuous units and the input-output relation of the spiking cells. This fit can be achieved by adapting the parameters of the synaptic potentials to replicate the input-output behavior of a standard sigmoidal activation function (shown for the short-term memory network). Alternatively, a customized activation function can be derived from the input-output relation of the spiking cells for a chosen set of parameters (demonstrated for the wrist flexion/extension network). In both cases the resulting networks of spiking cells exhibited activity that replicated the activity of corresponding continuous units. This confirms that the network solutions obtained through backpropagation apply to spiking networks and provides a useful method for deriving recurrent spiking networks performing a wide range of functions.

Among the most influential models of automatic affective processing is the spreading activation account (Fazio, Sanbonmatsu, Powell, & Kardes, 1986). However, investigations of this model by different research groups using the pronunciation task in an affective priming paradigm yielded contradictory results. Whereas one research group reported congruency effects, another obtained reversed priming effects (contrast effects), and still another found null effects. In Experiment 1, we were able to show an influence of trait anxiety on the direction of the affective priming effect. By using a multiple priming paradigm in Experiment 2, we were able to link the occurrence of reversed priming effects to increased levels of activation of affective representations. We propose that this relation might underlie the influence of trait anxiety on the direction of affective priming effects. Both experiments indicate that automatic evaluation in an affective network is substantially moderated by personality traits and activation level.

Carrier-mediated delivery holds great promise for significantly improving the cellular uptake and therefore the therapeutic efficacy of antisense oligonucleotides in vivo. A multivalent carbohydrate recognition motif for the asialoglycoprotein receptor has been designed for tissue- and cell-specific delivery of antisense drugs to parenchymal liver cells. To combine low molecular weight with high receptor affinity, the synthetic ligand contains three galactosyl residues attached to a cholane scaffold via epsilon-aminocapramide linkers. Three-dimensional structural calculations indicate that this unique design provides proper spacing and orientation of the three galactosyl residues to accomplish high affinity binding to the receptor. Covalent conjugation of the bulky carbohydrate cluster to oligonucleotides has been achieved by solid-phase synthesis using low-loaded macroporous resins and optimized synthesis protocols.

[structure: see text] Peptide nucleic acid (PNA) monomers containing the tricyclic cytosine analogues phenoxazine, 9-(2-aminoethoxy)phenoxazine (G-clamp), and 9-(3-aminopropoxy)phenoxazine (propyl-G-clamp) have been synthesized. The modified nucleobases were incorporated into PNA oligomers using Boc-chemistry for solid-phase synthesis. PNAs containing single G-clamp modifications exhibit significantly enhanced affinity toward RNA and DNA targets relative to unmodified PNA while maintaining mismatch discrimination. These PNA G-clamp modifications exhibit the highest increase in affinity toward nucleic acid targets reported so far for PNA modifications.

Systemically injected 2'-O-methoxyethyl (2'-O-MOE)-phosphorothioate and PNA-4K oligomers (peptide nucleic acid with four lysines linked at the C terminus) exhibited sequence-specific antisense activity in a number of mouse organs. Morpholino oligomers were less effective, whereas PNA oligomers with only one lysine (PNA-1K) were completely inactive. The latter result indicates that the four-lysine tail is essential for the antisense activity of PNA oligomers in vivo. These results were obtained in a transgenic mouse model designed as a positive readout test for activity, delivery, and distribution of antisense oligomers. In this model, the expressed gene (EGFP-654) encoding enhanced green fluorescence protein (EGFP) is interrupted by an aberrantly spliced mutated intron of the human beta-globin gene. Aberrant splicing of this intron prevented expression of EGFP-654 in all tissues, whereas in tissues and organs that took up a splice site-targeted antisense oligomer, correct splicing was restored and EGFP-654 expression upregulated. The sequence-specific ability of PNA-4K and the 2'-O-MOE oligomers to upregulate EGFP-654 provides strong evidence that systemically delivered, chemically modified oligonucleotides affect gene expression by sequence-specific true antisense activity, validating their application as potential therapeutics.

Background and Purpose: The goal of this study was to characterize cortical reorganization after stroke and its relation with the site of the stroke-induced lesion and degree of motor recovery using functional MRI (fMRI)., Methods: Fourteen stroke patients with an affected upper limb were studied longitudinally. Three fMRI sessions were performed over a period of 1 to 6 months after stroke. Upper limb recovery, Wallerian degeneration of the pyramidal tract, and responses to transcranial magnetic stimulation were assessed., Results: Two main patterns of cortical reorganization were found. Pattern 1 was focusing, in which, after initial recruitment of additional ipsilateral and contralateral areas, activation gradually developed toward a pattern of activation restricted to the contralateral sensorimotor cortex in 9 patients. Five patients were found to have pattern 2, persistent recruitment, in which there was an initial and sustained recruitment of ipsilateral activity. Occurrence of recruitment or focusing seemed to depend mainly on whether the primary motor cortex (M1) was lesioned; persistent recruitment was observed in 3 of 4 patients with M1 injury, and focusing was seen in 8 of 10 patients with spared M1. These patterns had no relation to the degree of recovery; in particular, focusing did not imply recovery. However, there was a clear relation between the degree of recovery and the degree of Wallerian degeneration., Conclusions: These results suggest that ipsilateral recruitment after stroke corresponds to a compensatory corticocortical process related to the lesion of the contralateral M1 and that the process of compensatory recruitment will persist if M1 is lesioned; otherwise, it will be transient.

To further our understanding of the functional roles of different motor cortical areas, we made a quantitative comparison of the density of corticospinal projections from primary motor cortex (M1) and supplementary motor area (SMA) to spinal motor nuclei supplying hand and finger muscles in four macaque monkeys. We also compared the action of corticospinal outputs excited by electrical stimulation of these two areas on upper limb motoneurons recorded in three anaesthetized macaques. The hand representations of SMA and M1 were first identified using structural magnetic resonance imaging scans and intracortical microstimulation. In the anatomical study we then made focal injections of wheatgerm agglutinin- horseradish peroxidase into these representations, which were subsequently confirmed by analysis of retrograde cortical labelling. Densitometric analysis showed that corticospinal projections from M1 were denser and occupied a greater proportion of the hand muscle motor nuclei than did projections from SMA. In caudal Th1 the densest projections from M1 occupied 81% of this motoneuronal area, compared with only 6% from SMA. In the electrophysiological study, bipolar intracortical stimulation of the hand representation of M1 and SMA evoked direct (D) and indirect (I) corticospinal volleys. Volleys elicited by M1 stimulation had larger amplitudes and faster conduction velocities than those evoked from the SMA. Intracellular recordings were made from 84 contralateral upper limb motoneurons. M1 and SMA stimulation evoked markedly different responses in tested motoneurons: EPSPs were larger and more common from M1 (88% of motoneurons) than from SMA (48%). Some motoneurons (16/84) showed evidence of excitatory postsynaptic potentials mediated by monosynaptic action of the D-wave evoked from M1; these early effects were not observed from the SMA. In most motoneurons (74/84) EPSPs had segmental latencies indicating that they were due to monosynaptic action of the I-wave. The results are consistent with cortico-motoneuronal (CM) connections originating from both SMA and M1 converging upon single motoneurons, but those from M1 are far more numerous and exert stronger excitatory effects than from the SMA. Thus although they may function in parallel, the two CM projections probably make different contributions to upper limb motor control.

The tricyclic cytosine analogues phenoxazine and 9-(2-aminoethoxy)-phenoxazine ("G-clamp") are known to significantly enhance the binding affinity of oligonucleotides to their complementary target DNA or RNA strands. To investigate their effect on the nuclease resistance, they were incorporated into model oligomers with a natural phosphodiester backbone, and enzymatic degradation was monitored in an in vitro assay with snake venom phosphodiesterase as the hydrolytic enzyme. In both cases, a single incorporation at the 3'-terminus completely protected the oligonucleotides against 3'-exonuclease attack. Further investigations indicate that the observed high nuclease resistance is not due to the lack of binding affinity to the enzyme's active site, since these modified oligonucleotides were able to inhibit degradation of a natural DNA fragment by bovine intestinal mucosal phosphodiesterase in a dose-dependent manner.

We made a quantitative comparison of the density of macaque corticospinal projections from primary motor cortex (M1) and supplementary motor area (SMA) to spinal motor nuclei supplying hand and finger muscles. We also compared the action of corticospinal outputs from these two areas on 84 upper limb (mostly hand) motoneurones in chloralose-anaesthetised macaques. The hand representations of M1 and SMA were first identified using MRI and intracortical microstimulation. We made focal injections of WGA-HRP into these representations. Densitometric analysis showed that corticospinal projections from M1 were far denser and occupied a much greater proportion of the hand muscle motor nuclei than did SMA projections. Stimulation of M1 and SMA with bipolar intracortical pulses evoked monosynaptic EPSPs. These were significantly larger and more common from M1 (88% of motoneurons) than from SMA (48%). The results demonstrate corticomotoneuronal connections from both M1 and SMA, some converging upon single motoneurons. Both areas give rise to CM projections but that those from M1 are far more numerous and exert stronger excitatory effects than those from the SMA.

There are conflicting views on the functional importance of the system of C3-C4 propriospinal neurones in the macaque, although the two sets of observations from the opposing laboratories are actually quite similar, both making the system appear much weaker than its well-known equivalent in the cat. One group asserts, mainly via evidence derived from experiments with strychnine, that this is a consequence simply of inhibition of the propriospinal neurone. However, we ague here that this judgement is premature and that much more needs to be known about the neurones involved and their connectivity before the analogy with the system in the cat is safe. This is particularly important because of a similar analogy which has been made with respect to measurements in human subjects.

The antisense activity of oligomers with 2'-O-methyl (2'-O-Me) phosphorothioate, 2'-O-methoxyethyl (2'-O-MOE) phosphorothioate, morpholino and peptide nucleic acid (PNA) backbones was investigated using a splicing assay in which the modified oligonucleotides blocked aberrant and restored correct splicing of modified enhanced green fluorescent protein (EGFP) precursor to mRNA (pre-mRNA), generating properly translated EGFP. In this approach, antisense activity of each oligomer was directly proportional to up-regulation of the EGFP reporter. This provided a positive, quantitative readout for sequence-specific antisense effects of the oligomers in the nuclei of individual cells. Nuclear localization of fluorescent labeled oligomers confirmed validity of the functional assay. The results showed that the free uptake and the antisense efficacy of neutral morpholino derivatives and cationic PNA were much higher than that of negatively charged 2'-O-Me and 2'-O-MOE congeners. The effects of the PNA oligomers were observed to be dependent on the number of L-lysine (Lys) residues at the C-terminus. The experiments suggest that the PNA containing Lys was taken up by a mechanism similar to that of cell-penetrating homeodomain proteins and that the Lys tail enhanced intracellular accumulation of PNA oligomer without affecting its ability to reach and hybridize to the target sequence.

Antisense oligonucleotides (ASOs) that bind target pre-mRNA with high affinity have been shown to alter splicing patterns and offer promise as therapeutics. Previous studies have shown that ASOs fully modified with 2'-O-methoxyethyl (2'-O-MOE) sugar residues redirect constitutive and alternative splicing of the murine interleukin-5 receptor-alpha (IL-5Ralpha) chain pre-mRNA in cells, resulting in inhibition of the membrane-bound isoform and enhanced expression of the soluble isoform. Here, we show that antisense peptide nucleic acids (PNAs) alter splicing of the IL-5Ralpha pre-mRNA in a fashion similar to their 2'-O-MOE-modified counterparts of the same sequence. Moreover, using PNA as the splicing modulator, the length of the antisense oligomer could be shortened from 20 to 15 nucleobase units to obtain a comparable effect. Treatment of cells with antisense PNA resulted in dose-dependent, specific downregulation of IL-5Ralpha membrane isoform mRNA expression and enhanced levels of the soluble IL-5Ralpha isoform transcript, with an EC50 equivalent to that observed in parallel with the corresponding 2'-O-MOE ASO. The pronounced activity of antisense PNAs in modulating IL-5Ralpha mRNA splicing observed in our study identifies these compounds as a promising new class of lower molecular weight splicing modulators.

Novel 5'-O-DMT- and MMT-protected 3'-C-methylene-modified thymidine, 5-methyluridine, and 5-methylcytidine H-phosphonates 1-7 with O-methyl, fluoro, hydrogen, and O-(2-methoxyethyl) substituents at the 2'-position have been synthesized by a new effective strategy from the corresponding key intermediates 3'-C-iodomethyl nucleosides and intermediate BTSP, prepared in situ through the Arbuzov reaction. The modified reaction conditions for the Arbuzov reaction prevented the loss of DMT- and MMT-protecting groups, and directly provided the desired 5'-O-DMT- and/or MMT-protected 3'-C-methylene-modified H-phosphonates 1-6 although some of them were also prepared through the manipulation of protecting groups after the P-C bond formation. The modified Arbuzov reaction of 3'-C-iodomethyl-5-methylcytidine 53, prepared from its 5-methyluridine derivative 42, with BTSP provided the 5-methylcytidine H-phosphonate 54, which was further transferred to the corresponding 4-N-(N-methylpyrrolidin-2-ylidene)-protected H-phosphonate monomer 7. 5'-O-MMT-protected 3'-C-methylene-modified H-phosphonates 5, 3, and 7 were converted to the corresponding cyanoethyl H-phosphonates 50, 51, and 56 using DCC as a coupling reagent. One-pot three-step reactions of 50, 51, and 56 provided the desired 3'-C-methylene-modified phosphonamidite monomers 8-10. Some of these new 3'-methylene-modified monomers 1-10 have been successfully utilized for the synthesis of 3'-methylene-modified oligonucleotides, which have shown superior antisense properties including nuclease resistance and binding affinity to the target RNA.

The observation of light metal ions in nucleic acids crystals is generally a fortuitous event. Sodium ions in particular are notoriously difficult to detect because their X-ray scattering contributions are virtually identical to those of water and Na(+.)O distances are only slightly shorter than strong hydrogen bonds between well-ordered water molecules. We demonstrate here that replacement of Na(+) by K(+), Rb(+) or Cs(+) and precise measurements of anomalous differences in intensities provide a particularly sensitive method for detecting alkali metal ion-binding sites in nucleic acid crystals. Not only can alkali metal ions be readily located in such structures, but the presence of Rb(+) or Cs(+) also allows structure determination by the single wavelength anomalous diffraction technique. Besides allowing identification of high occupancy binding sites, the combination of high resolution and anomalous diffraction data established here can also pinpoint binding sites that feature only partial occupancy. Conversely, high resolution of the data alone does not necessarily allow differentiation between water and partially ordered metal ions, as demonstrated with the crystal structure of a DNA duplex determined to a resolution of 0.6 A.

Motor unit (MU) synchronisation during isometric force production in the precision grip was analysed in five subjects performing a visually guided steptracking motor task with three different force levels. With this aim multi-unit electromyographic (EMG) activity of 14 intrinsic and extrinsic finger muscles from 15 experimental sessions was decomposed into the potentials of single MUs. The behaviour of 62 intrinsic and 30 extrinsic MUs in the motor task was quantified. Most MUs displayed a positive correlation between firing rate and grip force. Compared to MUs in extrinsic muscles, intrinsic MUs had steeper regression lines with negative intercepts indicating higher force sensitivity and higher recruitment thresholds. A cross-correlation analysis was performed for 69 intra- and 166 intermuscular MU pairs while steady grip force was exerted at the three force levels. Synchronisation, for at least one force level, was found in 78% of the intra- and 45% of the intermuscular pairs. The occurrence of synchronisation was not stable over the force range tested. Factors influencing the fluctuations in occurrence and strength of synchronisation were investigated. Force increase was not paralleled by increased synchronisation; in contrast, in most MU pairs, especially intermuscular pairs, synchronisation occurred preferentially at the lower force levels. The recruitment threshold appeared to play a determining role in synchronisation: the more similar the thresholds of two MUs, the greater the probability of them being synchronised at this force level. Synchronised MUs fired on average at a lower frequency than non-synchronised ones. Finally, synchronisation at the multi-unit EMG level does not indicate that all underlying MUs are synchronised, nor does the absence of temporal coupling at the multi-unit level indicate that none of the MUs is synchronised.

There is considerable debate as to the relative importance, for cortical control of upper limb movements, of direct cortico-motoneuronal (CM) versus indirect, propriospinal transmission of corticospinal excitation to cervical motoneurons. In the cat, which has no CM connections, a significant proportion of corticospinal excitation reaches forelimb motoneurons via a system of C(3)-C(4) propriospinal neurons (PN). In contrast, in the macaque monkey most motoneurons receive direct CM connections, and, under the same experimental conditions as in the cat, there is little evidence for PN transmission. We have investigated corticospinal transmission in the New World squirrel monkey (Saimiri sciureus) because its CM projections are weaker than in the macaque. Intracellular recordings were made from motoneurons identified from the ulnar, median, and deep radial (DR) nerves in four adult squirrel monkeys under chloralose anesthesia and neuromuscular paralysis. Responses to stimulation of the contralateral medullary pyramid were recorded before and after a lesion to the dorsolateral funiculus (DLF) at C(5), designed to interrupt direct corticospinal inputs to the lower cervical segments and unmask PN-mediated effects. This lesion greatly reduced the proportion of motoneurons showing either CM EPSPs or disynaptic IPSPs, but the proportion showing late EPSPs with segmental latencies beyond the monosynaptic range, evoked by repetitive but not single PT stimuli, was unaffected: 23 of 29 motoneurons (79%) before and 32 of 37 (86%) after the lesion; 41% of these late EPSPs had strictly disynaptic latencies after the lesion, only 14% before. These results are in striking contrast to the macaque (late EPSPs in only 18% of motoneurons before a C(5) lesion, 19% after it). Transmission of the late EPSPs via C(3)-C(4) PNs in the squirrel monkey was indicated by their absence after an additional C(2) DLF lesion. Nearly all tested motoneurons also responded with short latency EPSPs to stimulation in the ipsilateral lateral reticular nucleus. By analogy with the cat, these EPSPs probably reflect antidromic activation of ascending collaterals of C(3)-C(4) PNs with monosynaptic connections to motoneurons; the EPSPs were significantly smaller than in the cat but larger than in the macaque. These results suggest that the positive correlation across species between more advanced hand function and the strength of the CM system is accompanied by a negative correlation between hand function and the strength of the PN system. We hypothesize that in primates with more advanced hand function, the CM system effectively replaces PN-mediated control. This would include a contribution to the control of reaching movements, which are said to be specifically under the control of the PN system in the cat, and we speculate that these differences may be related to the degree of dexterity exhibited by the different species. This interpretation of the results predicts that in man, where the CM system is highly developed, the PN system is unlikely to be responsible for significant transmission of cortical commands to upper limb motoneurons.

[reaction: see text] H-Phosphonate monomers of 2'-O-(2-methoxyethyl) ribonucleosides have been synthesized. Oxidation of oligonucleotide H-phosphonates has been optimized to allow the synthesis of oligonucleotides containing either 2'-deoxy or 2'-O-(2-methoxyethyl) ribonucleoside residues combined with three different phosphate modifications in the backbone, i.e., phosphodiester (PO), phosphorothioate (PS), and phosphoramidate (PN). Phosphodiester linkages were introduced by oxidation with a cocktail of 0.1 M Et(3)N in CCl(4)/Pyr/H(2)O (5:9:1) without affecting phosphorothioate or phosphoramidate linkages. For the synthesis of phosphoramidate-modified oligonucleotides, N(4)-acetyl deoxycytidine-3'-H-phosphonate monomers were used to avoid transamination during the oxidation step.

Polyhalogenated aromatic hydrocarbons, of which 2,3,7, 8-tetrachloro-p-dioxin (TCDD) is the prototype compound, elicit a variety of toxic, teratogenic, and carcinogenic responses in exposed animals and in humans. In cultured cells, TCDD shows marked effects on the regulation of cell cycle progression, including thymocyte apoptosis, induction of keratinocyte proliferation and terminal differentiation, and inhibition of estrogen-dependent proliferation in breast cancer cells. The presence of an LXCXE domain in the dioxin aromatic hydrocarbon receptor (AHR), suggested that the effects of TCDD on cell cycle regulation might be mediated by protein-protein interactions between AHR and the retinoblastoma protein (RB). Using the yeast two-hybrid system, AHR and RB were in fact shown to bind to each other. In vitro pull-down experiments with truncated AHR peptides indicated that at least two separate AHR domains form independent complexes with hypophosphorylated RB. Coimmunoprecipitation of whole cell lysates from human breast carcinoma MCF-7 cells, which express both proteins endogenously, revealed that AHR associates with RB in vivo only after receptor transformation and nuclear translocation. However, the AHR nuclear translocator and transcriptional heterodimerization partner, is not required for (nor is it a part of) the AHR.RB complexes detected in vitro. Ectopic expression of AHR and RB in human osteosarcoma SAOS-2 cells, which lack endogenous expression of both proteins, showed that AHR synergizes with RB to repress E2F-dependent transcription and to induce cell cycle arrest. Furthermore, AHR partly blocked T-antigen-mediated reversal of RB-dependent transcriptional repression. These results uncover a potential function for the AHR in cell cycle regulation and suggest that this function may be that of serving as an environmental sensor that signals cell cycle arrest when cells are exposed to certain environmental toxicants.

We studied the activity of 577 neurons in the C6-T1 spinal cord of three awake macaque monkeys while they generated visually guided, isometric flexion/extension torques about the wrist. Spike-triggered averaging of electromyographic activity (EMG) identified the units' correlational linkages with

The activity of C6-T1 spinal cord neurons was recorded in three macaques while they generated isometric wrist flexion and extension torques in visually guided step-tracking tasks. Electromyographic activity (EMG) was recorded in /=3.5 ms from the trigger. Synchrony interneurons (Sy-INs) were non-PreM-Ins that had spike-related features with latencies <3.5 ms in at least one muscle. Unidentified interneurons (U-INs) showed no features in any of the STAs. A total of 572 task-related spinal neurons were studied; 29 cells were MNs, 97 PreM-INs, 32 Sy-INs, and 414 U-INs. MNs were activated predominantly in a tonic fashion during the ramp-and-hold torques and were active in one direction only. The most common response pattern for interneurons, irrespective of their class, was phasic-tonic activity, followed by purely tonic and purely phasic activity. Most interneurons (77%) were bidirectionally active in both flexion and extension. For all classes of interneurons, units with phasic response components tended to be activated first, before torque onset, followed by tonic units. The onset times of PreM-INs relative to onsets of their target muscles were distributed broadly, with a mean of -25 +/- 128 (SD) ms. For most neurons with tonic response components (all MNs, 71% of PreM-INs, 67% of Sy-INs, and 84% of U-INs), activity during the hold period was correlated significantly with the magnitude of static torque exerted by the monkey. The rate-torque regressions generally had positive slopes with higher mean slopes for extension than for flexion. The phasic response components were correlated significantly with rate of change of torque for a smaller percentage of tested PreM-Ins (50%), Sy-INs (83%), and U-INs (77%). In contrast to other premotor neurons [corticomotoneuronal (CM), rubromotoneuronal (RM), and dorsal root ganglion (DRG) afferents] previously characterized under similar conditions, a larger proportion of the spinal PreM-INs were activated after onset of their target muscles, probably reflecting a larger proportion of PreM-INs driven by peripheral input. The rate-torque slopes of PreM-INs tended to be less steep than those of CM and RM cells. Unlike the CM and DRG PreM afferents, which were activated unidirectionally, most spinal PreM-INs showed bidirectional activity, like RM cells.

1. Synaptic responses to electrical stimulation of the contralateral pyramidal tract were measured in intracellular recordings from 206 upper limb motoneurones in ten chloralose-anaesthetized macaque monkeys. The objective was to search for evidence of a disynaptic excitatory pathway via C3-C4 propriospinal interneurones similar to that in the cat. 2. In monkeys with intact spinal cords, only a small proportion of motoneurones (19%) responded with late EPSPs to repetitive stimulation of the pyramid; only 3% had segmental latencies that were appropriate for a disynaptic pathway. 3. From previous studies in the cat, it was expected that a lesion to the dorsolateral funiculus (DLF) at C5 would interrupt the corticospinal input to the spinal segments supplying upper limb muscles, whilst leaving intact excitation transmitted via a C3-C4 propriospinal system, the descending axons of which travel in the ventral part of the funiculus. In five of the monkeys a lesion was made to the DLF at C5 which spared the ventrolateral columns. It severely reduced the monosynaptic EPSPs and disynaptic IPSPs evoked from the pyramidal tract that were present in the intact monkey spinal cord, and which might have masked the presence of disynaptic EPSPs. However, even after the lesion the proportion of motoneurones with such late EPSPs was still low (18%); 14% of motoneurones had EPSPs within the disynaptic range. 4. In addition, some EPSPs with relatively long segmental latencies (> 1.1 ms) were recorded before and after the C5 lesions, but since these effects could be evoked by single stimuli, had stable latencies and did not facilitate with repetitive shocks, it is likely that they represent monosynaptic EPSPs evoked by slowly conducting corticospinal fibres which survived the lesions. 5. In seven of the monkeys motoneurone responses to stimulation of the ipsilateral lateral reticular nucleus (LRN) were also tested. Most motoneurones showed EPSPs with short latencies (1.2-2.5 ms) and other properties characteristic of monosynaptic activation. This is consistent with the presence of collaterals of C3-C4 propriospinal neurones to the LRN, as demonstrated in the cat. 6. These short-latency EPSPs evoked from the LRN were just as common before (77%) as after (75%) the C5 lesion. They had small amplitudes both before (mean +/- s.d. 1.1 +/- 0.59 mV) and after (1.2 +/- 0.72 mV) the lesion. Unlike the situation in the cat, only a small proportion (16%) of motoneurones activated from the LRN showed late EPSPs after repetitive stimulation of the pyramid. 7. The results provide little evidence for significant corticospinal excitation of motoneurones via a system of C3-C4 propriospinal neurones in the monkey. The general absence of responses mediated by such a system in the macaque, under experimental conditions similar to those in which they are seen in the cat, show that extrapolation of results from the cat to the primate should be made with considerable caution.

Our recent work has revealed new evidence of the importance of direct cortico-motoneuronal (CM) connections for voluntary control of the hand. Most of these connections are derived from corticospinal neurons located in the M1 hand area, although there are some much smaller contributions from other secondary motor areas, such as the supplementary motor area (SMA). Intracellular recordings show that 75% of upper limb motoneurons in the chloralose-anaesthetized macaque monkey receive a monosynaptic projection from the corticospinal tract; evidence for non-monosynaptic, propriospinal excitatory influences from the corticospinal tract was conspicuously lacking in these anaesthetized preparations. Moreover, in the conscious monkey, hand and arm muscle motor unit responses to corticospinal tract input are dominated by single, brief peaks compatible with monosynaptic excitation. CM excitatory post-synaptic potentials, recorded from a comparable sample of hand and arm motoneurons in anaesthetized macaque and squirrel monkeys, were found to be larger and faster rising in the macaque, which is by far the more dexterous of the two species. CM cells facilitating a given muscle in the conscious macaque are distributed over a wide region of M1 cortex, and each contributes a particular pattern of discharge during a skilled task. In addition to their direct effects on target muscles there may be weaker but potentially important effects that derive from the synchronous binding of assemblies of output neurons. Synchronous oscillations between these neurons are particularly prevalent during steady grip, but disappear during digit movement.

We have determined single crystal structures of an A-DNA decamer and a B-DNA dodecamer at 0.83 and 0.95 A, respectively. The resolution of the former is the highest reported thus far for any right-handed nucleic acid duplex and the quality of the diffraction data allowed determination of the structure with direct methods. The structures reveal unprecedented details of DNA fine structure and hydration; in particular, we have reexamined the overall hydration of A- and B-form DNA, the distribution of water around phosphate groups, and features of the water structure that may underlie the B to A transition., (Copyright 2000 John Wiley & Sons, Inc.)

Anatomic evidence suggests that direct corticomotoneuronal (CM) projections to hand motoneurons in the New World squirrel monkey (Saimiri sciureus) are weak or absent, but electrophysiological evidence is lacking. The nature of the corticospinal linkage to these motoneurons was therefore investigated first with the use of transcranial magnetic stimulation (TMS) of the motor cortex under ketamine sedation in five monkeys. TMS produced early responses in hand muscle electromyogram, but thresholds were high (compared with macaque monkey) and the onset latency was variable. Second, stimulation of the pyramidal tract (PT) was carried out with the use of chronically implanted electrodes in ketamine-sedated monkeys; this produced more robust responses that were markedly facilitated by repetitive stimulation, with little decrease in latency on the third compared with the first shock. Finally, postsynaptic potentials were recorded intracellularly from 93 arm and hand motoneurons in five monkeys under general chloralose anesthesia. After a single PT stimulus, the most common response was a small, slowly rising excitatory postsynaptic potential (EPSP), either alone (35 of 93 motoneurons) or followed by an inhibitory postsynaptic potential (39 of 93). The segmental delay of the early EPSPs was within the monosynaptic range (mean 0.85 ms); however, the rise time of these EPSPs was slow (mean 1.3 ms) and their amplitude was small (mean 0.74 mV). These values are significantly slower and smaller than EPSPs in a comparable sample of Old World macaque monkey motoneurons. The results show that CM connections do exist in the squirrel monkey but that they are weak and possibly located on the remote dendrites of the motoneurons. The findings are consistent with earlier anatomic studies. Repetitive PT stimulation produced large, late EPSPs in some motoneurons, suggesting that, in this species, there are relatively strong nonmonosynaptic pathways linking the corticospinal tract to hand motoneurons.

Most of our information about spinal neurons has been derived from experiments with anesthetized or surgically. reduced preparations. To investigate these neurons under normal behavioral conditions, we recorded the activity of single afferent units in cervical dorsal root ganglia and of single interneurons in the cervical spinal cord of macaque monkeys, as they generated alternating flexion and extension torques about the wrist. Spike-triggered averages of rectified electromyographic activity were used to identify "premotor" (PreM) units associated with correlated postspike effects in active muscles. In addition to postspike effects, some spike-triggered averages showed early increases in average muscle activity, which were attributed to synchronous discharges in other PreM units. In recordings of peripheral afferents, 49% of the task-related dorsal root ganglia units produced postspike facilitation (PSF) of at least one forearm muscle, with a mean PSF latency of 5.8 +/- 0.3 ms (SE). The PSF amplitude was measured as the mean percent increase (MPI): the average increase of the PSF as a percentage of the prespike baseline mean. PreM afferent units produced PSF with an average MPI of 4.6 +/- 0.3%. In a study of cervical interneurons, about 13% (72/562) of the task-related cells showed postspike effects. These PreM interneurons had a mean PSF latency of 7.2 +/- 0.3 ms and a mean MPI of 4.6 +/- 0.2%. The MPI values for spinal neurons were similar to the MPIs reported for rubromotoneuronal and corticomotoneuronal cells. PreM neurons usually facilitated a subset of the coactivated muscles called the unit's "muscle field." The PreM afferents facilitated an average of 46% of the synergistically coactivated muscles, while PreM interneurons facilitated an average of 37%. These are comparable with the percentage of muscles facilitated by corticomotoneuronal (40%) and rubromotoneuronal (50%) cells. During the step-tracking task the monkeys generated ramp-and-hold torques about the wrist. The PreM afferents typically became active during either flexion or extension of the wrist, although a few were bidirectionally active. The most common response pattern in PreM afferents was a tonic discharge, followed by phasic and phasic-tonic discharge. The most common patterns exhibited by PreM interneurons were tonic and phasic-tonic responses. PreM afferent units began to discharge on average 51 +/- 13 ms before activation of their target muscle. This early onset supports our hypothesis that these PreM afferents arose from muscle spindles, which is also consistent with their short-latency PSF and their responses to perturbations that stretched their target muscles. The results reveal some salient differences between the discharge properties of dorsal root ganglia neurons, spinal interneurons, and supraspinal PreM cells in the motor cortex and red nucleus. All four PreM populations include tonic, phasic-tonic, and phasic cells, but in significantly different proportions. Most PreM afferents resembled corticomotoneuronal cells in being active only with their target muscles, unlike rubromotoneuronal cells and spinal PreM interneurons, which tended to exhibit more bidirectional discharges.

Electromyographic (EMG) activity was analyzed for the occurrence of synergistic patterns during the steady hold periods of force in the precision grip. To establish the presence of muscle synergies in the amplitude (spatial) domain, the EMG activation levels of pairs of simultaneously active muscles were linearly correlated. Cross-correlations of EMG activity were computed to quantify muscle synergies in the spatiotemporal domain (synchronization). A muscle pair was defined to be synergistically coupled or synchronously activated when the correlation (amplitude domain) or cross-correlation (time domain) was significant for at least two of the three steady state force levels. Muscle synergies in the amplitude domain were found in one-third of the 213 muscle pairs tested, distributed among 47 of the 82 tested muscle combinations. Coactivation was the predominant synergistic pattern, whereas trade-off comprised not more than 23% of the synergies. Cross-correlation peak size varied between 5 and 39% of the autocorrelation size, with delays in the range of +/- 8 ms and base width between 12 and 20 ms. Synchronization was found in one-fourth of the 213 muscle pairs tested and among 35 of the 82 muscle combinations, i.e., less frequently than covariation of EMG activity levels. However, the interindividual prevalence was higher for synchronization than for synergies in the amplitude domain, since, for the synergistic muscle combinations, almost twice as many muscle pairs were found to be synchronized than coupled in the amplitude domain. Synergies in the two domains occurred independently in some pairs and concurrently in other cases, and were observed between muscles moving the thumb, the index finger, or both digits. Synchronization was more frequent in pairs of muscles supplied by branches of the same peripheral nerve (46%) than in those innervated by different nerves (18%). Synergies in the amplitude domain were distributed in similar proportions across intrinsic, extrinsic, and combinations of both types of muscles, whereas synchronization mainly occurred in pairs of intrinsic muscles. When the task was repeated with slightly lower target forces, there were fewer synergies in the amplitude domain (in 52 of the 213 pairs, distributed among 35 of 82 muscle combinations) and their distribution changed, indicating a flexible, force-dependent mechanism. In conclusion, no strictly coherent interindividual pattern of synergies in the spatial domain could be established.

Electromyographic (EMG) activity was examined in six normal subjects, producing low isometric forces between thumb and index finger in a visually guided step-tracking task. Target forces ranged between 0.5 and 3.0 N. EMG activity of all 15 muscles acting on thumb or index finger was screened with simultaneous recordings of up to 8 muscles. Linear regression was applied to quantify the EMG activity as a function of force. The intrinsic muscles and the long flexors of the index finger had a tight relation to force, as indicated by the high correlation coefficient, as did the adductor and short flexor of the thumb. In contrast, the long extensors of the index finger did not show force-related activity. The other muscles, including the long flexor and extensor of the thumb, had varying, on average moderate, correlations to force. The slope of the regression lines, a measure for the amount of EMG modulation with increasing force, revealed the same trends. Thus the majority of the intrinsic muscles were as closely related to force as the long flexors, suggesting a more important role in production of low isometric forces in the grip than previously believed, perhaps even a primary role. Systematic interindividual differences were rarely observed. Analysis of the trial-by-trial variability of EMG activity revealed that for most muscles the observed scatter was produced by varying background activity and was not a random fluctuation of relative increases in activity from one force level to the next.

Neuronal activity was recorded in the ventral premotor cortex of one monkey (Macaca fascicularis) trained to exert finely graded forces with thumb and index finger on a force sensor in a visuomotor step-tracking paradigm. Trials with two or three consecutive ramp-and-hold force steps were presented randomly. Most neurons displayed similar discharge patterns in the two- and three-step trials and were assigned to one of the following classes: phasic, phasic-tonic, tonic, decreasing, and mixed. For more than 50% of the neurons with tonic activity, positive or negative correlations between firing rate and force were statistically significant. The indices of force sensitivity were on average higher for the two-step than for the three-step trials, indicating that the correlations yielded linearity over only a limited force range. The force-related cells were located in two regions of the ventral premotor cortex. One group was ying rostrally within the inferior limb of the arcuate sulcus, from which microstimulation elicited movements of fingers and hand. In the other more caudal region, adjacent to the finger region of primary motor cortex, microstimulation was rarely effective, but all neurons had clear peripheral receptive fields on finger and hand. The data indicate that two populations of neurons, located in the ventral premotor cortex, are related to movement execution. Effective microstimulation also suggests that one of the populations has fairly direct access to the spinal motor apparatus.

1. The contribution of 33 corticomotoneuronal (CM) cells, recorded in the primary motor cortex, to the production of precision grip force has been investigated in four monkeys (Macaca nemestrina). These CM cells were shown, by spike-triggered averaging, to facilitate electromyographic (EMG) activity of hand and forearm muscles. 2. Single-cell recordings were obtained as the monkey performed a low force precision grip task under either isometric or auxotonic conditions. The monkey had to produce independent control of the forces exerted by the thumb and index finger and maintain them for 1-1.5 s. Steady force segments of data were selected trial-by-trial from these hold periods. For each segment the following mean values were determined: 1) CM cell firing rate, 2) EMG activity of facilitated muscles, and 3) index finger, thumb, and total force. 3. Of the 33 CM cells, 18 had a phasic-tonic pattern of discharge during the task, 7 were tonic, 5 had a ramplike increase, and 3 were deactivated during the hold period. 4. Of the 33 cells analyzed, 11 showed a significant positive (P < 0.05) correlation of their mean firing rate with static force; 4 of them had high correlation coefficients (P < 0.001). There was a considerable trial-by-trial variability in the cells' activity-force relationship. Six CM cells had significant negative correlations between their activity and isometric force (5 at the P < 0.001 level), showing lower firing rates with higher forces. 5. The force sensitivity of the CM cells, calculated from the rate-force slopes, was higher for either the thumb or the index finger force. Under isometric conditions the mean rate-force slopes, calculated from the best correlated digit force, was 32.4 Hz/N for eight positively correlated cells and -21.3 Hz/N for the cells with a negative correlation. 6. Correlation between CM cell spike activity and force was more common among neurons with slowly conducting axons (4/6 correlated) than for those with fast axons (13/27). 7. Significant correlations between target muscle EMG and force were always positive. The correlations between CM cell firing rate and target muscle EMG were comparable with those found between firing rate and force. Three of the CM cells with a negative correlation to force also had a negative correlation with EMG in one of their target muscles. 8. Each CM cell facilitated the EMG activity of one to five target muscles; postspike facilitation (PSF) was most common among intrinsic hand muscles (68/82 CM cell/muscle combinations).(ABSTRACT TRUNCATED AT 400 WORDS)

1. Single cell activity was investigated in the precentral motor (MI) and postcentral somatosensory (SI) cortex of the monkey to compare the neuronal activity related to the control of isometric force in the precision grip and to assess the participation of SI in motor control. 2. Three monkeys (Macaca fascicularis) were trained in a visual step-tracking paradigm to generate and precisely maintain force on a transducer held between thumb and index finger. Great care was taken to have the monkeys use only their fingers without moving the wrist or proximal joints. In two monkeys electromyographic (EMG) activity was checked in 23 muscles over several sessions. 3. Five similar classes of task-related firing patterns were found in both SI and MI cortical hand and finger representations, but their relative proportions differed. The majority of the SI neurons were phasically or phasic-tonically active (61%), whereas in MI the neurons that decreased their firing rate with force were most frequent (42%). 4. The timing of activity changes related to the onset of force increase from low to higher levels strongly differed in the two neuronal populations. In SI, only 14% of the task-related neurons increased or decreased their firing rate before the onset of force increase, in contrast to 56% in MI. Only 3% of the SI neurons showed changes before the earliest EMG activation. 5. In both SI and MI neurons with tonic and phasic-tonic, increasing or decreasing discharge patterns disclosed a relationship between neuronal activity and static force. Distinction was made between neurons modulating their activity in a monotonic way and those that were active only at one force level and had a kind of recruitment or deactivation threshold. The latter ones were more frequent in MI than in SI, and in the neuron population with decreasing firing patterns. For the neurons with increases in activity, statistically significant linear correlations between firing rate and force were found more frequently in MI than in SI, where the proportion of nonsignificant correlations was relatively high (35% vs. 15% in MI). In SI the indexes of force sensitivity, calculated from the slopes of the regression lines, covered a wider range than in MI; and their distribution was bimodal, with one mean of 30 Hz/N and the other of 155 Hz/N. In contrast, the mean rate-force slope in MI was 69 Hz/N.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for visually evoked activity in single neurons of area 4 is presented. These neurons modulated their activity in relation to stimuli moving across the visual field of the monkey, without showing habituation. Some of them even had direction sensitivity. Their activity was independent of eye movements and unrelated to muscle contractions. The visually activated neurons were distributed throughout the depth of motor cortex.

Recordings from single neurones in the primary somatosensory (SI) and motor (MI) cortex of monkeys trained to precisely regulate force between thumb and index finger have disclosed the following contrasting properties between neurones in these two cortical regions: (1) the existence of neurones with similar discharge patterns within MI and SI but, between these regions, significantly different distributions of the classes of discharge patterns; (2) a late onset of activity change in SI neurones in relation to force increase as compared to significantly earlier changes in MI neurones; (3) linear relations between firing rate and isometric force for SI and MI neurones, however with a larger range of rate-force slopes in SI as compared to MI; (4) infrequent motor reactions to intracortical microstimulation in SI but frequent reactions in MI; (5) a majority of SI neurones with cutaneous afferent input in contrast to predominant input from deep tissues to MI neurones; and (6) context independent visually evoked activity observed exclusively in MI neurones. These major differences suggest that SI neuronal activity most likely reflects the input from peripheral receptors rather than, as postulated for MI neurones, the participation in movement initiation and the control of muscular contractions.