Previous physiological studies [e.g., Bieser and Muller-Preuss, Exp. Brain Res. 108, 273-284 (1996); Schulze and Langner, J. Comp. Physiol. A 181, 651-663 (1997); Steinschneider et al., J. Acoust. Soc. Am. 104, 2935-2955 (1998)] have suggested that neural activity in primary auditory cortex (A1) phase-locked to the waveform envelope of complex sounds with low (<300 Hz) periodicities may represent a neural correlate of roughness perception. However, a correspondence between these temporal response patterns and human psychophysical boundaries of roughness has not yet been demonstrated. The present study examined whether the degree of synchronized phase-locked activity of neuronal ensembles in A1 of the awake monkey evoked by complex tones parallels human psychoacoustic data defining the existence region and frequency dependence of roughness. Stimuli consisted of three consecutive harmonics of fundamental frequencies (f(0)s) ranging from 25 to 4000 Hz. The center frequency of the complex tones was fixed at the best frequency (BF) of the cortical sites, which ranged from 0.3 to 10 kHz. Neural ensemble activity in the thalamorecipient zone (lower lamina III) and supragranular cortical laminae (upper lamina III and lamina II) was measured using multiunit activity and current source density techniques and the degree of phase-locking to the f0 was quantified by spectral analysis. In the thalamorecipient zone, the stimulus f0 at which phase-locking was maximal increased with BF and reached an upper limit between 75 and 150 Hz for BFs greater than about 3 kHz. Estimates of limiting phase-locking rates also increased with BF and approximated psychoacoustic values for the disappearance of roughness. These physiological relationships parallel human perceptual data and therefore support the relevance of phase-locked activity of neuronal ensembles in A1 for the physiological representation of roughness.

The functional organization of primary auditory cortex in non primates is generally modeled as a tonotopic gradient with an orthogonal representation of independently mapped binaural interaction columns along the isofrequency contours. Little information is available regarding the validity of this model in the primate brain, despite the importance of binaural cues for sound localization and auditory scene analysis. Binaural and monaural responses of A1 to pure tone stimulation were studied using auditory evoked potentials, current source density and multiunit activity. Key findings include: (i) differential distribution of binaural responses with respect to best frequency, such that 74% of the sites exhibiting binaural summation had best frequencies below 2000 Hz: (ii) the pattern of binaural responses was variable with respect to cortical depth, with binaural summation often observed in the supragranular laminae of sites showing binaural suppression in thalamorecipient laminae; and (iii) dissociation of binaural responses between the initial and sustained action potential firing of neuronal ensembles in A1. These data support earlier findings regarding the temporal and spatial complexity of responses in A1 in the awake state, and are inconsistent with a simple orthogonal arrangement of binaural interaction columns and best frequency in A1 of the awake primate.

Noninvasive neurophysiological studies in humans support the existence of an orthogonal spatial representation of pure tone frequency and complex tone pitch in auditory cortex [Langner et al., J. Comp. Physiol. A 181, 665-676 (1997)]. However, since this topographic organization is based on neuromagnetic responses evoked by wideband harmonic complexes (HCs) of variable fundamental frequency (f0), and thus interharmonic frequency separation (deltaF), critical band filtering effects due to differential resolvability of harmonics may have contributed to shaping these responses. To test this hypothesis, the present study examined responses evoked by three-component HCs of variable f0 in primary auditory cortex (A1) of the awake monkey. The center frequency of the HCs was fixed at the best frequency (BF) of the cortical site. Auditory evoked potential (AEP), multiunit activity, and current source density techniques were used to evaluate A1 responses as a function of f0 (=deltaF). Generally, amplitudes of nearly all response components increased with f0, such that maximal responses were evoked by HCs comprised of low-order resolved harmonics. Statistically significant increases in response amplitude typically occurred at deltaFs between 10% and 20% of center frequency, suggestive of critical bandlike behavior. Complex tone response amplitudes also reflected nonlinear summation in that they could not be predicted by the pure tone frequency sensitivity curves of the cortical sites. A mechanism accounting for the observed results is proposed which involves mutual lateral inhibitory interactions between responses evoked by stimulus components lying within the same critical band. As intracortical AEP components likely to be propagated to the scalp were also strongly modulated by deltaF, these findings indicate that noninvasive recordings of responses to complex sounds may require a consideration of critical band effects in their interpretation.

Background: Nucleoside analogue reverse transcriptase inhibitors are a critical component of antiretroviral therapy in HIV-infected persons. Several of these medications cause painful, dose-limiting peripheral neuropathy (PN), which may develop earlier and more intensely in persons with preexisting neuropathy. The prevalence of baseline peripheral neuropathy in injection drug users (IDUs), one of the largest populations of HIV-infected persons, has not been described, yet has important implications for the selection of antiretroviral therapy. Methods: The authors performed a cross-sectional study of PN in 212 HIV-seronegative and HIV-seropositive IDUs using detailed neurologic histories, physical examinations, quantitative electrophysiologic study, and quantitative sensory testing. Data were used to assign patients to one of four positive categories of PN or one of two negative categories. Results: PN was present in 24.5% of HIV-seronegative IDUs, three to four times the reported frequency for HIV-seronegative persons in the general or male homosexual population. PN was present in 32.1% of HIV-seropositive patients. PN was axonal in nature and associated with increased age and alcohol use. PN was asymptomatic in 81% of HIV-seronegative and 71% of HIV-seropositive patients with PN. Conclusions: There is a high prevalence of PN in HIV-seronegative IDUs. Although these PNs do not seem to predispose HIV-seropositive IDUs to HIV-related PN, they may increase the likelihood of iatrogenic neuropathy. Intravenous drug users may need more diligent monitoring when administered nucleoside analogues than patients in risk groups with lower endemic rates of PN.

Objective: To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN), Methods: A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study's end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm(2) cross-sectional area) in serial bilateral sural nerve biopsies. Results: Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV, In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 mu m) sural nerve myelinated fibers. Conclusions: Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN.

Multiunit activity (MUA) and current source density (CSD) patterns evoked by click trains are examined in primary auditory cortex (A1) of three awake monkeys. Temporal and spectral features of click trains are differentially encoded in A1. Encoding of temporal features occurs at rates of 100-200 Hz through phase-locked activity in the MUA and CSD, is independent of pulse polarity pattern, and occurs in high best frequency (BF) regions of A1. The upper limit of ensemble-wide phase-locking is about 400 Hz in the input to A1, as manifested in the cortical middle laminae CSD and MUA of thalamocortical fibers. In contrast, encoding of spectral features occurs in low BF regions, and resolves both the f0 and harmonics of the stimuli through local maxima of activity determined by the tonotopic organization of the recording sites. High-pass filtered click trains decrease spectral encoding in low BF regions without modifying phase-locked responses in high BF regions. These physiological responses parallel features of human pitch perception for click trains, and support the existence of two distinct physiological mechanisms involved in pitch perception: the first using resolved harmonic components and the second utilizing unresolved harmonics that is based on encoding stimulus waveform periodicity.

We have previously described transgenic mice that harbor a dominant-negative antagonist of the POU protein SCIP (termed ΔSCIP). Native SCIP is expressed in promyelinating Schwann cells, where it represses expression of the myelin structural genes. The ΔSCIP mice display morphologic and behavioral abnormalities, including decreased axonal diameter, increased myelin thickness, developmentally early myelination, and clinical features of neuropathy. To assess the neurophysiologic correlates of these abnormalities, a series of electrophysiologic tests was performed. Despite having smaller diameter axons, mice expressing the ΔSCIP transgene had similar maximum conduction velocities in caudal, sural, and tibial nerves compared to wild-type controls. Therefore, conduction in ΔSCIP animals was faster than predicted by axon diameter alone. Compound amplitude responses were 38% higher in the ΔSCIP caudal nerve. ΔSCIP tibial F-wave responses showed less difference between minimum and maximum latencies than controls, suggesting less variance between fastest and slowest conducting fibers. These data further characterize the functional components of the ΔSCIP phenotype. In addition, these studies address the physiologic sequelae of altering the g-ratio in the absence of demyelination or axonal degeneration. J. Neurosci. Res. 50:821–828, 1997. © 1997 Wiley-Liss, Inc.

In area 17 of the awake macaque, disinhibition by blockade of GABA(A) receptors results in a marked elevation in neuronal excitability, with a particular focus in the supragranular laminae. We examined the possibility that the excitatory supragranular response is N-methyl-D-aspartate (NMDA)-mediated. Laminar activity profiles consisting of flash-evoked field potential, current source density (CSD) and multiunit activity (MUA) measures were obtained during striate cortex penetrations using multicontact electrodes that incorporated single or double microinjection cannulae. Profiles were recorded before and at successive time points after bicuculline induction of disinhibition. Both the noncompetitive NMDA antagonist MK-801 and the competitive antagonist APV reversed bicuculline effects, producing a normal laminar activity profile. NMDA-mediated enhancement of excitatory responses in the supragranular laminae of neocortex is believed to play a role in normal signal processing, as well as in epileptic manifestations.

Colony stimulating factor-1 (CSF-1) was initially identified as a growth factor for mononuclear phagocytes. This study examines the role of CSF-1 in the development of the central nervous system (CNS). CSF-1 treatment of neurons cultured from embryonic brain promoted survival and process outgrowth in a dose-dependent manner. By contrast, CSF-1 treatment of neurons cultured from the osteopetrotic (op/op) mouse, a null mutant for CSF-1, promoted significantly less process outgrowth, suggesting that there are neural abnormalities in op/op animals. Nuclease protection assays were used to determine whether CSF-1 and its receptor are expressed at times appropriate to regulate neural development. Both CSF-1 and its receptor are expressed in developing mouse brain, with a unique pattern of CSF-1 mRNA splice variant expression encoding secreted, and not membrane-bound, growth factor. To determine whether brain function is altered by null mutation of CSF-1, op/op mice were examined using electrophysiologic assays. Brainstem auditory and visual evoked potentials were both abnormal in op/op mice. Further, intracortical recordings revealed aberrant neuronal function within visual cortex and alterations in the cortical circuitry that balances excitation and inhibition. Daily CSF-1 injection of postnatal op/op mice largely rescued the abnormal neural phenotype, confirming that the absence of CSF-1 during development is responsible for the abnormalities. The effects of CSF-1 on cultured embryonic neural cells, the developmentally appropriate expression of CSF-1 and its receptor, and the neurological abnormalities in op/op mice suggest a role for CSF-1 in brain development.

Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are distributed in a modality-specific fashion throughout cortex. N-methyl-D-aspartate (NMDA) receptors play a crucial role in the initiation of long-term memory. Neurochemical mechanisms underlying the transient memory storage required for working memory, however, remain obscure. Auditory sensory memory, which refers to the ability of the brain to retain transient representations of the physical features (e.g., pitch) of simple auditory stimuli for periods of up to approximately 30 sec, represents one of the simplest components of the brain working memory system. Functioning of the auditory sensory memory system is indexed by the generation of a well-defined event-related potential, termed mismatch negativity (MMN). MMN can thus be used as an objective index of auditory sensory memory functioning and a probe for investigating underlying neurochemical mechanisms. Monkeys generate cortical activity in response to deviant stimuli that closely resembles human MMN. This study uses a combination of intracortical recording and pharmacological micromanipulations in awake monkeys to demonstrate that both competitive and noncompetitive NMDA antagonists block the generation of MMN without affecting prior obligatory activity in primary auditory cortex. These findings suggest that, on a neurophysiological level, MMN represents selective current flow through open, unblocked NMDA channels. Furthermore, they suggest a crucial role of cortical NMDA receptors in the assessment of stimulus familiarity/unfamiliarity, which is a key process underlying working memory performance.

Behavioral studies in animals support the view that categorical, phonetic phenomena are based upon specific response properties of the auditory system. This study investigated physiologic responses reflecting the phonetic parameter of voice onset time (VOT). We examined multiunit activity (MUA) in the primary auditory cortex (A1) of awake monkeys elicited by the consonant-vowel syllables /da/ and /ta/ that varied in VOT from 0 to 60 msec. Two temporal response patterns encode VOT. The first pattern contains responses time-locked to stimulus onset and to the onset of voicing. In 10 of 17 electrode penetrations that display this pattern, MUA reflects the VOT perceptual boundary by containing a prominent response to voicing onset only for /ta/ stimuli. The second pattern contains responses phase-locked to the periodic portion of the syllables. MUA exhibiting this temporal pattern does not display categorical-like properties. We conclude that specific temporal response patterns in A1 reflect the perceptual boundary for VOT and may represent a physiologic correlate for categorical perception of this phonetic parameter.

Quantitative sensory testing (QST) is commonly used in the assessment of diabetic neuropathy. However, little data are available on the reliability of tactile and thermal testing devices. Reproducibility of QST measures between centers has not been previously reported. This study was designed to validate QST testing procedures and determine if these devices are suitable for large scale multicenter clinical trials. Finger and toe vibratory (Vf, Vt) and thermal (Tf, Tt) thresholds were determined for ten normal individuals by a two-alternative forced-choice procedure using the Optacon Tactile Tester (OTT) and Thermal Sensitivity Tester (TST). Threshold measurements were reproducible between technologists and had a day-to-day coefficient of variation of Vf 20%, Vt 23%, Tf 41%, and Tt 95%. Thresholds were determined for 140 normal individuals at six centers. Mean threshold values between centers were not significantly different. Center-to-center coefficents of variation (CV) were Vf 44%, Vt 45%, Tf 47%, and Tt 87%. There was no significant difference in threshold measures with regard to sex, side studied, presence of calluses, or skin temperature. Vf thresholds significantly correlated with age (p < 0.01). There was no correlation between either vibratory or thermal thresholds in normal individuals, and nerve conduction velocities (NCV). Thermal and vibratory thresholds were determined for 98 diabetic patients. Diabetic subjects without clinical evidence of neuropathy were not significantly different from normal individuals, but diabetic patients with neuropathy had increased thresholds compared to normals (p < 0.05). We conclude that thermal and vibratory threshold testing with the OTT and TST yields reproducible measurements in normal individuals and provides an objective measure of clinical diabetic neuropathy that is well suited for multicenter trials.

1. The pattern of reorganization in area 3b of adult primates after median or ulnar nerve section suggests that somatic afferents from the dorsum of the hand, carried by the radial nerve, have preferential access to the cortical territories normally expressing glabrous inputs carried by the median and ulnar nerves. A likely mechanism underlying preferential access is preexisting, but silent, radial nerve inputs to the glabrous region of cortex. 2. We tested this by comparing the effects of electrical stimulation of median or ulnar versus radial nerves, on responses in the hand representation of area 3b. Laminar current source density and multiunit activity profiles were sampled with the use of linear array multicontact electrodes spanning the laminae of area 3b. Data were obtained from three squirrel monkeys anesthetized during recording. 3. Compared with colocated median or ulnar nerve responses, the radial nerve response had 1) an initial short-latency response in the middle laminae that was subtle; there was a small transmembrane current flow component without a discernable multiunit activity correlate; and 2) a laminar sequence and distribution of activity that was similar to those of the median or ulnar nerve responses (i.e., initial activation of the middle, followed by upper and lower laminae), but the significant current flow and multiunit response to radial nerve stimulation occurs 12-15 ms later. 4. Normal corepresentation of nondominant dorsum hand (radial) inputs with the dominant (median or ulnar) inputs in the glabrous hand surface representation provides a clear vehicle for the biased patterns of reorganization occurring after peripheral nerve section. The initial, "subtle" activity phase in the nondominant response is believed to reflect intracortical inhibition, and the later "significant" response phase, a rebound excitation, possibly compounded by an indirect or extralemniscal input. The spatiotemporal pattern of nondominant input is proposed to play a role in normal somatosensory perception.

Schizophrenia is a severe mental disorder associated with disturbances in perception and cognition. Event-related potentials (ERP) provide a mechanism for evaluating potential mechanisms underlying neurophysiological dysfunction in schizophrenia. Mismatch negativity (MMN) is a short-duration auditory cognitive ERP component that indexes operation of the auditory sensory (`echoic') memory system. Prior studies have demonstrated impaired MMN generation in schizophrenia along with deficits in auditory sensory memory performance. MMN is elicited in an auditory oddball paradigm in which a sequence of repetitive standard tones is interrupted infrequently by a physically deviant (`oddball') stimulus. The present study evaluates MMN generation as a function of deviant stimulus probability, interstimulus interval, interdeviant interval and the degree of pitch separation between the standard and deviant stimuli. The major findings of the present study are first, that MMN amplitude is decreased in schizophrenia across a broad range of stimulus conditions, and second, that the degree of deficit in schizophrenia is largest under conditions when MMN is normally largest. The pattern of deficit observed in schizophrenia differs from the pattern observed in other conditions associated with MMN dysfunction, including Alzheimer's disease, stroke, and alcohol intoxication.