Joseph C. Arezzo

Topography and intracranial sources of somatosensory evoked potentials in the monkey. I. early components

Averaged somatosensory evoked potentials (SEP) were recorded in the monkey from arrays of surface electrodes overlying the brain, cervical cord and peripheral nerve; from epidural electrodes over the cerebral convexity; and from movable intracerebral electrodes. The initial cortically generated responses peak at mean latencies of 10 and 12 msec following stimulation of the median nerve at the wrist. Preceding these potentials 5 small positive wavelets were identified in scalp and epidural recordings. The sources of the latter three of these waves have been identified, based in part on the observation of amplitude maxima in depth recordings within cerebrum and brain stem. P7.2 is primarily generated within the thalamocortical radiations, whereas P5.3 and P6.2 reflect bursts of highly synchronized action potentials travelling along the medial lemniscus. Recordings of multiple unit activity within these tracts confirmed the source identifications made on the basis of potential distribution. Continuing activity within the more caudal portions of the somatosensory pathways produces potentials that sum with those generated more rostrally. This circumstance precludes the identification of the intracranial source of a surface recorded potential by demonstrating a concurrent wave form at a single location within the brain. It is necessary to examine the intracranial potential distribution and trace the potential from the surface to its maximum in order to identify its source with confidence. P3.1 and P3.8 were identified only as farfield potentials in intracranial recordings from the pons and more rostral regions. They were ascribed to activity of primary somatosensory neurons ascending in the dorsal columns on the basis of their timing, surface distribution and amplitude vs. interstimulus interval functions. The early SEP components recorded in the monkey closely resembled in configuration and topography those recorded from human subjects, although the latter were longer in latency, reflecting differences in length of the somatosensory pathways in the two species.

Nerve growth factor administration protects against experimental diabetic sensory neuropathy

Small fiber sensory neuropathy is one of the most common complications of diabetes mellitus. Currently there is no adequate therapy to prevent this often debilitating problem. Nerve growth factor (NGF) is a protein that promotes the survival and integrity of a large percentage of sensory neurons including the small fiber pain transmitting neurons which are often prominently affected in diabetic neuropathy. We report here that exogenously administered NGF is capable of preventing the behavioral and biochemical manifestations of diabetic sensory neuropathy in a streptozocin induced rat model. NGF administration prevented the elevation of tailflick threshold (a measure of the rats response to a thermal noxious stimulus) which occurred in streptozocin-induced diabetic rats. Further, it prevented the induced reduction in levels of the neuropeptides substance P and calcitonin gene related peptide measured from cervical dorsal root ganglia. Finally, NGF did not ameliorate the prolonged latency of the compound action potentials measured from the caudal nerve of the tail. In view of these results, a clinical trial of NGF in diabetic neuropathy has now commenced.

Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy

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/mm2 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 μm) 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.

Striate cortical contribution to the surface-recorded pattern-reversal VEP in the alert monkey.

The striate cortical contribution to the surface pattern-reversal visual evoked potential (VEP) was investigated in awake monkeys during performance of a visual fixation task, by examining laminar profiles of VEP, current source density (CSD) and concomitant multiunit activity (MUA) in Area 17, recorded simultaneously at incremental depths using multicontact electrodes. Stimuli were black/white bar gratings centered on the fixation point. The typical surface pattern-reversal VEP over striate cortex consists of a prominent positivity peaking at 50-70 msec (P60), followed by a large negativity peaking at approx. 80 msec (N80), and then by a late broad positivity, peaking between 120 and 150 msec (P125). P60 is often preceded by a small negativity peaking at 45-55 msec (N50), and on rare occasions a small positivity (P40) is also observed. N50 is generated primarily by current sinks in Lamina 4C. P60 arises from large current sources in the supragranular laminae. N80 and P125 appear to be composite waveforms reflecting complex contributions from local activity and from activity occurring outside of the foveal/immediate parafoveal representation in Area 17. The basic physiologic sequence elicited by patterned stimulation is similar to that elicited by diffuse luminance or by electrical stimulation, but is characterized by more prominent supra- and infragranular activation. It is consistent with the cellular and synaptic anatomy of Area 17: initial activation of the thalamorecipient subdivisions of Lamina 4C, followed by activation of mid/upper Lamina 4 and of supra- and infragranular laminae. Our results suggest the possibility of differentiating synaptic stages and cellular processes reflected in the human VEP, based on homologies with simian VEP components.

The sources and intracerebral distribution of auditory evoked potentials in the alert rhesus monkey

Average auditory evoked potentials (AEP) to click stimuli were recorded from chronically implanted electrodes in alert rhesus monkeys. The cortical sources of each AEP component were identified on the basis of transcortical polarity inversions. The active loci were limited to the supratemporal plane (STP) and to a region within precentral motor cortex. Small and inconstant responses were generated in the lateral superior temporal gyrus and no locally generated activity was detected in frontal granular cortex. The responses from STP were complex, with early components generated mainly within auditory koniocortex and later components in surrounding regions. Each of these components was volume-conducted widely, both above and below the STP, and they projected onto various regions of dorsolateral surface cort(x. The volume-conducted potentials from the STP summed with the potentials generated in motor cortex to produce a complex resultant waveform. Barbiturate anesthesia abolished all but the primary AEP and reduced the volume-conducted projection of this response at the cortical surface. The configuration and intracranial distribution of the monkey AEP were compared to human intracerebral and scalp AEP recordings.

Intracortical generators of the flash VEP in monkeys

Flash visual evoked potentials (VEPs) in unanesthetized monkeys were recorded from the cortical surface and from closely spaced intracortical sites together with associated multiple unit activity (MUA). The VEP depth profiles were subjected to current source density (CSD) analysis to delineate the laminar pattern of transmembrane current flows manifested by extracellular source and sinks. The initial surface recorded components (P15 and P18) were generated subcortically within the thalamocortical radiations. The distribution of current sources and sinks associated with two subsequent surface negative components. N24 and N40. demonstrates their generation within laminae IVA and IVCb respectively, both parvocellular thalamorecipient layers. Oscillatory potentials resembling those seen in human VEPs are observed riding on N40; analysis of MUA in conjunction with sources and sinks coincident with these wavelets provides evidence that they derive from both thalamocortical and cortical activity. MUA in the 20-60 msec range shows phasic increases throughout lamina IV, which are maximum in amplitude within lamina IVA. This increased firing is concurrent with the sinks observed within the parvocellular thalamorecipient sublaminae IVCb and IVA. A subsequent component, P65, coincident with a decrease in MUA to below the spontaneous level co-located with a lamina IVCb current source, probably arises from intracortically generated inhibitory activity within IVCb. The next VEP component, a surface negative potential at 95 msec, is coincident with current sources and sinks in lamina III, and is consistent with stellate cell input to supragranular elements. VEP components after N95 are not associated with either MUA or CSD activity and are probably generated in extrastriate cortex. Human counterparts of the simian VEP are proposed.

Click train encoding in primary auditory cortex of the awake monkey: Evidence for two mechanisms subserving pitch perception

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.

Cellular generators of the cortical auditory evoked potential initial component

Cellular generators of the initial cortical auditory evoked potential (AEP) component were determined by analyzing laminar profiles of click-evoked AEPs, current source density, and multiple unit activity (MUA) in primary auditory cortex of awake monkeys. The initial AEP component is a surface-negative wave, N8, that peaks at 8-9 msec and inverts in polarity below lamina 4. N8 is generated by a lamina 4 current sink and a deeper current source. Simultaneous MUA is present from lower lamina 3 to the subjacent white matter. Findings indicate that thalamocortical afferents are a generator of N8 and support a role for lamina 4 stellate cells. Relationships to the human AEP are discussed.

Neural generators of early cortical somatosensory evoked potentials in the awake monkey

Controversy continues to exist regarding the generators of the initial cortical components of the somatosensory evoked potential (SEP). This issue was explored by detailed epidural and intracortical mapping of somatosensory evoked activity in Old World monkeys. In depth recordings, 3 complementary procedures were utilized: (1) the intracortical and subcortical distribution of SEPs was determined from approximately 4000 locations; (2) concomitant profiles of multiple unit activity (MUA) were recorded as an estimate of local action potential profiles; (3) 1-dimensional calculations of current source density (CSD) were used to outline the timing and pattern of regional transmembrane current flow. Our analysis confirms the participation of multiple cortical areas, located on either side of the central sulcus, in the generation of the initial cortical SEP components. Earliest activity P10, was localized to area 3, followed within milliseconds by activation of areas 1, 2 (P12), and 4 (P13). In SI (Brodmanns areas 3, 1 and 2), the initial SEP components reflect the depolarization of lamina 4 stellate cells and the subsequent activation of adjacent pyramidal cells in laminae 3 and 5. The genesis of later cortical components (P20, N45) represents the composite of activity distributed across multiple cortical laminae and the interaction of overlapping excitatory and inhibitory events. These findings have direct implications for the clinical interpretation of SEP waveforms.

Contribution of extrastriate area V4 to the surface-recorded flash VEP in the awake macaque

This study compared striate and extrastriate contributions to the surface-recorded flash VEP. Laminar visual evoked potential, current source density and multiunit activity profiles were obtained with multicontact electrodes from areas V1 and V4 in three awake macaques. As found earlier, the major striate contribution is to early (N40, P55-80) components. Major contributions to the later (N95, P120, Late Negativity) components arise from V4. Early, afferent-triggered inhibition in V4 also produces a small contribution to N40. Response latencies in V4 vs V1 suggest an input to V4, bypassing V1, emphasizing a parallel processing component of visual system organization.