Commentary : The value of intraoperative neurophysiological monitoring: evidence, equipoise and outcomes.

The use of intraoperative neurophysiological monitoring (IONM) has grown despite an absence of randomized controlled trials that might unequivocally demonstrate improved outcomes. At issue is how to demonstrate value when other evidence indicates patient harms (opportunity cost) if IONM is withheld for the sake of randomization. In this article we review other non-randomized methods to assess the effects of IONM on post-operative outcomes. We also examine how clinical equipoise may resolve whether (or not) an anticipated controlled study is ethical. We conclude that the value of IONM in a particular surgical setting should be determined by a benefits/harms analysis based on all the available evidence.

Motor evoked potential recovery with surgeon interventions and neurologic outcomes: A meta-analysis and structural causal model for spine deformity surgeries.

OBJECTIVE: To improve estimates of motor evoked potential (MEP) performance during spine deformity surgeries by accounting for potential confounders. METHODS: A meta-analysis of MEPs for spine deformity surgeries determined the probability of a MEP deterioration which recovered by the end of surgery, P(RSC), and the conditional probability of no new post-operative deficit given an RSC, P(NND|RSC), stratified by category of intraoperative adverse event associated with the MEP deterioration. A structural causal model (SCM) and propensity score matching accounted for intraoperative adverse events and patient diagnosis as potential confounders. RESULTS: MEPs changes (either reversible, RSC or irreversible, IRREV) were reported for 295 of 5055 cases (6%) in 21 studies. The probability of no new motor deficit, P(NND), plotted against the probability of a RSC, P(RSC), for studies in the meta-analysis was highly significant (r = 0.71, p < 0.001). P(RSC) was 0.76 for an alert associated with correction, less for osteotomies (0.48, p = 0.0008), and tended to be higher for hypotension (0.92, p = 0.06). P(NND|RSC) was 0.94 for correction, less for positioning (0.82), and osteotomies (0.86), and greater for hypotension (1.0). In the SCM, a RSC after an alert was a highly significant and independent predictor of no new motor deficits (odds 25.2, p < 0.001). CONCLUSION: There are significant differences in P(RSC) for hypotension and osteotomies, and in P(NND) for osteotomies and instrumentation, compared to correction. P(RSC) is a significant and independent predictor of outcomes. SIGNIFICANCE: When MEPs are used for spine deformity surgeries, accounting for adverse events associated with an alert and patient diagnosis as potential confounders is expected to improve RSC prediction of post-operative outcomes and estimates of RSC efficacy in improving outcomes.

Predicted current densities in the brain during transcranial electrical stimulation.

OBJECTIVE: We sought an electrical modeling approach to evaluate the potential application of finite element method (FEM) modeling to predict current pathways and intensities in the brain after transcranial electrical stimulation. METHODS: A single coronal MRI section through the head, including motor cortex, was modeled using FEM. White matter compartments with both anatomically realistic anisotropies in resistivity and with a homogeneous resistivity were modeled. Current densities in the brain were predicted for electrode sites on the scalp and after theoretical application of a conductive head restraint device. RESULTS: Localized current densities were predicted for the model with white matter anisotropies. Differences in predicted peak current densities were related to location of stimulation sites relative to deep sulci in the brain and scalp shunting that was predicted to increase with inter-electrode proximity. A conductive head restraint device was predicted to shunt current away from the brain when a constant current source was used. CONCLUSIONS: The complex geometry of different tissue compartments in the head and their contrasting resistivities may jointly determine the strength and location of current densities in the brain after transcranial stimulation. This might be predictable with FEM incorporating white matter anisotropies. Conductive head restraint devices during surgery may be contraindicated with constant current stimulation. SIGNIFICANCE: Individually optimized tcMEP monitoring and localized transcranial activation in the brain might be possible through FEM modeling.

An evaluation of motor evoked potential surrogate endpoints during intracranial vascular procedures.

OBJECTIVE: MEPs are used as surrogate endpoints to predict the effectiveness of interventions, made in response to MEP deterioration, in avoiding new postoperative deficits. MEP performance in capturing intervention effects on these outcomes was investigated. METHODS: A meta-analysis of studies using MEPs during intracranial vascular surgeries between 2003 and 2014 was performed. MEP diagnostic performance and relative risk of new postoperative deficits for reversible compared with irreversible MEP changes were determined. Intervention efficacy in reversing MEP deterioration and postoperative outcomes was compared across studies. RESULTS: MEP diagnostic performance compared favorably with that of other tests used in medicine, with all likelihood ratios >10. The summary relative risk comparing reversible and irreversible changes was 0.40, indicating a 60% decrease in new deficits for reversible MEP changes. The proportion of MEP deteriorations which recovered was negatively correlated with the proportion of new postoperative deficits (r=-0.81, p<.005). CONCLUSIONS: The effectiveness of interventions in recovering an MEP decline was predictive of preserved neurologic status. MEPs are provisionally qualified as surrogate endpoints given potentially major harms to the patient if they are not used, compared to the minimal harms and costs associated with their use. SIGNIFICANCE: The performance of MEPs as substitute, or surrogate, endpoints during intracranial vascular surgeries for new deficits in motor strength in the immediate postoperative period was directly assessed for ten recent studies.

Somatosensory and motor evoked potentials as biomarkers for post-operative neurological status.

SEPs and MEPs (EPs) are often used as surrogates for postoperative clinical endpoints of muscle strength and sensory status, as these true endpoints are not available during surgery. EPs as surrogate endpoints were evaluated using a three step framework (Analytical Validation, Qualification, Utilization) recently proposed by the Institute of Medicine (USA). EP performance on Analytical Validation may surpass that of some other biomarkers used in medicine (tumor size, cardiac troponin). Qualification of EP surrogates was evaluated with guidelines for causation proposed by A.B. Hill, which supported causal links between surgical events and EP changes and revised estimates of EP diagnostic test performance for three illustrative studies. Qualification was also addressed with a 3×2 contingency analysis which demonstrated decreased deficit proportions for EP declines which recovered after surgeon intervention. Utilization of EP surrogates will depend on surgical procedure and alert criteria. EPs are often used as surrogate endpoints to avoid new postoperative deficits. Although not fully validated, their continued use as surrogates during surgical procedures with the potential for significant morbidity is justified by their potential to help avoid injury and the absence of "second best options."

Laminar organization of receptive field properties in the dorsal lateral geniculate nucleus of the tree shrew (Tupaiaglis belangeri).

A laminar analysis of the receptive field properties of relay cells in the binocular region of the tree shrew dorsal lateral geniculate nucleus (LGN) found three main subdivisions. Lamina 1 (receiving ipsilateral eye input) and lamina 2 (contralateral) comprise a pair of layers that contain only ON-center neurons. Laminae 4 (contralateral) and 5 (ipsilateral) comprise a pair of layers with mostly OFF-center cells (86%). Laminae 3 and 6 (both contralaterally innervated) also form a distinct pair, although lamina 3 contains a mixture of cells with ON-centers (43%) or OFF-centers (57%), and lamina 6 contains mostly cells with ON-OFF centers and suppressive surrounds (81%). Cells located in the interlaminar zones resembled neurons in laminae 3 and 6. In comparison with the cells in the OFF-center laminae 4 and 5, the ON-center cells in laminae 1 and 2 had smaller, more elliptical receptive field centers with stronger responses to flashed visual stimuli. In addition, cells in the ipsilateral eye laminae 1 and 5 showed a greater change in center diameter, with eccentricity from the area centralis, than cells in the contralateral eye laminae 2 and 4. Principal components analysis using six receptive field properties (latency to optic chiasm stimulation, receptive field center diameter, maintained discharge rate, response onset latency, peak spike density, and phasic-tonic index) suggested that the cells in laminae 3 and 6 and the interlaminar zones are W-like. Principal components analysis of the same receptive field properties in laminae 1, 2, 4, and 5 did not reveal differences clearly related to X-like (parvocellular) and Y-like (magnocellular) categories. Ninety-seven percent of the cells tested for linearity of spatial summation in laminae 1, 2, 4, and 5 were linear. We conclude that the dominant organizational features of the tree shrew LGN are the ON-center, OFF-center, and W pairs of layers that project to different regions within the striate cortex.

Quantitative immunocytochemistry using an image analyzer. I. Hardware evaluation, image processing, and data analysis.

In this review we describe how video-based image analysis systems are used to measure immunocytochemically labeled tissue. The general principles underlying hardware and software procedures are emphasized. First, the characteristics of image analyzers are described, including the densitometric measure, spatial resolution, gray scale resolution, dynamic range, and acquisition and processing speed. The errors produced by these instruments are described and methods for correcting or reducing the errors are discussed. Methods for evaluating image analyzers are also presented, including spatial resolution, photometric transfer function, short- and long-term temporal variability, and measurement error. The procedures used to measure immunocytochemically labeled cells and fibers are then described. Immunoreactive profiles are imaged and enhanced using an edge sharpening operator and then extracted using segmentation, a procedure which captures all labeled profiles above a threshold gray level. Binary operators, including erosion and dilation, are applied to separate objects and to remove artifacts. The software then automatically measures the geometry and optical density of the extracted profiles. The procedures are rapid and efficient methods for measuring simultaneously the position, geometry, and labeling intensity of immunocytochemically labeled tissue, including cells, fibers, and whole fields. A companion paper describes non-biological standards we have developed to estimate antigen concentration from the optical density produced by antibody labeling (Nabors et al., 1988).

The visual field in monocularly deprived cats and its permanence.

The present study had two primary aims. The first was to determine the extent of the visual field of the deprived eye of a monocularly deprived cat using visual perimetry techniques, since recent reports have been contrary to previous research. The second aim was to determine whether enucleation of the experienced eye of a monocularly deprived cat was associated with any increase in the extent of the visual field of the deprived eye compared to forced usage (reverse-suture). The results indicate that the extent of the visual field using the deprived eye is limited to the ipsilateral monocular visual field. Further, enucleation of the experienced eye leads to a rapid expansion of the visual field of the deprived eye to include the entire ipsilateral hemifield which does not occur following reverse-suture. Possible reasons for the conflicting reports in the literature are discussed.

The effects of peripheral D-amphetamine, 4-OH amphetamine, and epinephrine on maintained discharge in the locus coeruleus with reference to the modulation of learning and memory by these substances.

D-Amphetamine, 4-OH amphetamine, and epinephrine have been shown in many behavioral studies to facilitate memory when given post-training. The effect of these drugs on the maintained discharge of cells in the locus coeruleus (LC) was investigated using a route of administration (intraperitoneal) and a log-dose range of these drugs comparable to those used in the behavioral experiments. D-Amphetamine profoundly suppressed maintained discharge: an inhibitory effect was observed at every dose (0.1, 1.0, 10.0 mg/kg). In contrast, only the highest dose of 4-OH amphetamine (8.2 mg/kg) inhibited activity in the LC, and this effect was a modest one. Unlike the amphetamines, epinephrine (500 micrograms/kg) elevated maintained discharge. These results are discussed in the context of the hypothesized involvement of the LC in the enhancement of memory by these drugs.

Effects of bicuculline on signal detectability in lateral geniculate nucleus relay cells.

The lateral geniculate nucleus conveys the center-surround organized retinal receptive fields to the cortex in a way that does not significantly alter their spatial structure. However, non-retinal influences may change the 'strength' (detectability) of the signal under conditions of anesthesia, arousal and attention. A previous analysis of receiver operating characteristic curves in cat suggests that a reduction in signal detectability occurs in lateral geniculate nucleus (LGN) relay cells in anesthetized animals in comparison to the retinal afferents. In the present study, it was found that antagonism of GABAA receptors with bicuculline (BIC) increased signal detectability in LGN relay cells in the tree shrew (Tupaia belangeri). This change is consistent with the hypothesis that feedforward and/or feedback GABAergic circuits in the LGN differentially affect the retinogeniculate transfer ratio for visually driven activity versus maintained (spontaneous) activity. Under conditions of arousal or attention, signal detectability may be increased by brainstem activation, thus increasing the flow of information in the visual system.

Effects of bicuculline on receptive field center sensitivity of relay cells in the lateral geniculate nucleus.

The lateral geniculate nucleus (LGN) receives input from the retina that is spatially organized into a receptive-field center and surround. It maintains this organization in the signal that it sends to the visual cortex. Previous studies have focused on changes in the receptive-field 'surround' that are generated at the LGN, possibly as a local contrast enhancement mechanism. The present study suggests a role for the LGN in regulating the receptive-field center sensitivity under the control of GABAergic circuitry. Local microiontophoresis of the GABAA receptor antagonist bicuculline increased the contrast sensitivity of LGN relay cells to many spatial frequencies. Difference of Gaussians analysis showed that the increased was due to an increased sensitivity of the receptive-field center. Similar increases in receptive-field center sensitivity may be produced during behavioral arousal by the action of pontine and mesencephalic pathways upon the activity of the LGN GABAergic circuitry.

Binocular competitive interactions and recovery of visual acuity in long-term monocularly deprived cats.

Changes in visual acuity brought about by altering competitive interactions between the eyes of cats monocularly deprived (MD) from natural eye opening to 7-12 months of age were studied. In MD cats given binocular experience, median visual acuity using the deprived eye was 0.75 c/deg. If the deprived eye was given a slight competitive advantage via reverse-suture, median visual acuity reached 1.52 c/deg. Further, giving the deprived eye the greatest competitive advantage was accomplished by complete removal of the experienced eye which yielded a median deprived eye acuity of 2.3 c/deg. Obstacle avoidance and stimulus size data were also obtained. The previously published electrophysiological effects of these manipulations on striate cortical cells were noted to mirror these increases in visual acuity and this correlation was discussed, as were the effects of analogous manipulations in the monkey and man.

The role of the cerebellum in modulating voluntary limb movement commands.

We recorded the activity of cerebellar Purkinje cells (PCs), primary motor cortical (M1) neurons, and limb EMG signals while monkeys executed a sequential reaching and button pressing task. PC simple spike discharge generally correlated well with the activity of one or more forelimb muscles. Surprisingly, given the inhibitory projection of PCs, only about one quarter of the correlations were negative. The largest group of neurons burst during movement and were positively correlated with EMG signals, while another significant group burst and were negatively correlated. Among the PCs that paused during movement most were negatively correlated with EMG. The strength of these various correlations was somewhat weaker, on average, than equivalent correlations between M1 neurons and EMG signals. On the other hand, there were no significant differences in the timing of the onset of movement related discharge among these groups of PCs, or between the PCs and M1 neurons. PC discharge was modulated largely in phase, or directly out of phase, with muscle activity. The nearly synchronous activation of PCs and muscles yielded positive correlations, despite the fact that the synaptic effect of the PC discharge is inhibitory. The apparent function of this inhibition is to restrain activity in the limb premotor network, shaping it into a spatiotemporal pattern that is appropriate for controlling the many muscles that participate in this task. The observed timing suggests that the cerebellar cortex learns to modulate PC discharge predictively. Through the cerebellar nucleus, this PC signal is combined with an underlying cerebral cortical signal. In this manner the cerebellum refines the descending command as compared with the relatively crude version generated when the cerebellum is damaged.

Movement-related discharge in the cerebellar nuclei persists after local injections of GABA(A) antagonists.

Limb movement-related neurons in the cerebellar nuclei (CN) typically produce bursts of discharge in association with movement. Consequently, given the inhibitory nature of the Purkinje cell (PC) projection to CN, it is puzzling that only a minority of movement-related PCs pause; the majority burst. Some of the movement-related CN activity may be the result of excitation from collaterals of mossy and climbing fiber projections to the cerebellar cortex. The only other input to CN is diffuse and neuromodulatory, from locus ceruleus and raphe nuclei. To investigate the role of the excitatory mossy fiber input, single units in CN were recorded in macaque monkeys during the performance of reaching and manipulation tasks, before and after blocking the PC input with local microinjections of GABA(A) antagonists (bicuculline or SR95531). After these injections, the movement-related modulation of CN discharge was greater and began earlier, compared with the modulation in the preinjection group of neurons. These observations indicate that an important excitatory drive is provided by extracerebellar inputs to CN, most likely from collaterals of mossy fibers. PCs may serve primarily to regulate this activity, by either pausing or bursting as necessary.

Phasic stimulation of the locus coeruleus: effects on activity in the lateral geniculate nucleus.

Neurons in the locus coeruleus (LC) encode information related to behavioral state in a tonic pattern of firing and information related to the occurrence of a sensory stimulus in a phasic pattern of firing. The effects of phasic stimulation of the LC (6 pulses at 30 Hz), designed to approximate its physiological activation by sensory stimuli, were studied in the lateral geniculate nucleus (LGN) of anesthetized rats. Phasic stimulation of the LC significantly increased neuronal firing in the LGN with a mean latency 320 ms from onset of stimulation. Receiver operating characteristic analyses on a trial-by-trial basis showed that phasic LC stimulation can result in a highly discriminable signal in the LGN. This increased neuronal firing rate in the LGN was specific for the site of stimulation and was reduced by the norepinephrine synthesis inhibitor alpha-methyl-p-tyrosine and by intravenous WB-4101 (alpha 1-receptor antagonist). Neurons in the LGN have a single-spike firing mode when sensory information is faithfully relayed from retina to cortex and a burst-firing mode when the transfer of this information is degraded. Phasic LC stimulation reduced burst firing (2-5 ms interspike intervals, ISIs) at low frequencies (< or = 4 Hz) in the LGN, and for some neurons there was an absolute decrease in burst-like ISIs after LC stimulation, despite an increase in mean firing rate.

Primary motor cortical neurons encode functional muscle synergies.

Many different kinematic and kinetic signals have been proposed as possible variables under the control of the primary motor cortex. Despite the presence of direct projections to motor neurons, muscle activation has received less attention as a controlled variable. Furthermore, although it is well known that descending fibers project to multiple motor pools, an objective, quantitative study of the relation between neuronal modulation and the activity of groups of muscles has not previously been reported. We have recorded the discharge of 310 neurons located in the primary motor cortex of two monkeys, along with the activity of a variety of arm and hand muscles. Data were recorded while the monkey reached to and pressed a series of illuminated buttons. The similarity of a given neuron's discharge with respect to each muscle was determined by calculating the linear cross-correlation between its discharge rate and each rectified, filtered electromyogram. A "functional linkage vector" was then constructed, which expressed the similarity of that neuron's discharge to the entire set of muscles. We discovered discrete groups of functional linkage vectors within the high order muscle space for both monkeys which corresponded to functional properties of the neurons measured by other methods. Several of these groups appeared to represent a functional synergy of muscles, such as those required to extend the limb, press a button, or open the hand in preparation for the press. When the dimensionality of this space was reduced by a principal components analysis, the originally identified clusters of neurons remained well separated. These results are consistent with the hypothesis that the discharge of individual neurons in the primary motor cortex encodes the activity of a relatively small number of functionally relevant groups of muscles. It will be important to determine whether these results will also apply to more complex behavior, and to what extent these functional muscle synergy representations remain fixed across behaviors.

Laminar organization and ultrastructure of GABA-immunoreactive neurons and processes in the dorsal lateral geniculate nucleus of the tree shrew (Tupaia belangeri).

The distribution and ultrastructure of neurons and neuropil labeled by an antiserum to gamma-aminobutyric acid (GABA) were examined in the lateral geniculate nucleus (LGN) of the tree shrew (Tupaia belangeri). The LGN of this species segregates center type and cell class into three distinct pairs of laminae: a medial pair (laminae 1 and 2) containing ON-center cells, a more lateral pair (4, 5) containing OFF-center cells, and 2 laminae (3, 6) containing W-like cells. The relationship between this laminar segregation and the distribution of GABA immunoreactivity was investigated in the present study. GABA-immunoreactive neurons and neuropil were present in all six of the laminae. However, both the density of labeled cells (adjusted for neuronal density across laminae) and the density of labeled neuropil showed a medial-to-lateral gradient. The adjusted density of labeled cells was higher laterally than medially, and the density of labeled neuropil was significantly greater in the more lateral OFF-center laminae and W-like laminae than in the medial two ON-center laminae. Thus, inhibitory, GABAergic influences may modulate to different degrees the visual signals in the ON, OFF, and W pathways. Labeled cells had a mean cross-sectional area (107 microns 2) approximately one-half that of unlabeled cells (216 microns 2). They constitute 16-34% of the neurons in the LGN. At the electron microscope level, three different kinds of labeled profile were observed. Vesicle containing profiles like the F2 profiles of cat were postsynaptic to retinal terminals and presynaptic to conventional dendrites. F1 axon terminals with dense clusters of vesicles were also labeled as were some myelinated axons. Another labeled profile, which we suggest should be called an F3 process, was a large dendrite of irregular caliber with punctate groups of vesicles near the synapse. Our results suggest that GABAergic circuitry is an important part of the functional organization in the LGN of the tree shrew.

Functional connectivity between cerebellum and primary motor cortex in the awake monkey.

Simultaneous single neuron and local field potential (LFP) recordings were made in arm-related areas of the cerebellar nuclei (CN) and primary motor cortex (M1) of two monkeys during a reaching and button pressing task. Microstimulation of focal sites in CN caused short latency (median = 3.0 ms) increases in discharge in 25% of 210 M1 neurons. Suppressive effects were less common (13%) and observed at longer latencies (median = 9.9 ms). Stimulation in CN also caused reciprocal facilitation and suppression in averages of antagonist muscle electromyograms (EMGs). The latency of these effects was approximately 8-11 ms. In contrast to the selectivity of unit and EMG effects, stimulation-evoked changes in LFP occurred over a broad range of sites. There were no significant short-latency effects detected in cross-correlation histograms between single neurons in CN and M1. However, CN spike-triggered averages of M1 LFPs were observed in a few cases (10% of 126 cases). In one-half of these, there were effects both before and after the CN spikes, which may reflect causal effects from M1 to CN, as well as from CN to M1. Overall, these results demonstrate a spatially specific, short latency, primarily excitatory pathway from CN to M1. The relatively rare effects at the single neuron level may have resulted from the difficulty in achieving optimal alignment between cerebellar and cerebral sites because of the specificity of these connections.