Spike-triggered average; Synchrony; Motor cortex; Muscle Cross-correlating the activity of neighb... more Spike-triggered average; Synchrony; Motor cortex; Muscle Cross-correlating the activity of neighboring motor cortex neurons recorded with independent electrodes in behaving monkeys has revealed synchronization peaks, largely due to common synaptic input. Corticomotoneuronal (CM) cells produced post-spike facilitation (PSF) of rectified forearm electromyograins (EMG); 15 cells synchronized with CM cells showed no PSF. Five pairs of CM cells with overlapping muscle fields exhibited similar synchrony peaks. The contribution of this synchrony to facilitation of common target muscles was assessed by two new methods: selective spike-triggered averaging and convolution. They showed that the PSF is composed predominantly of effects mediated by output of the triggering cell, but may include a broad, shallow component mediated by synchrony with other CM cells.
To elucidate the cortical circuitry controlling primate forelimb muscles we investigated the syna... more To elucidate the cortical circuitry controlling primate forelimb muscles we investigated the synaptic interactions between neighboring motor cortex cells that had postspike output effects in target muscles. In monkeys generating isometric ramp-and-hold wrist torques, pairs of cortical cells were recorded simultaneously with independent electrodes and corticomotoneuronal (“CM”) cells were identified by their postspike effects on target forelimb muscles in spike-triggered averages (SpTAs) of electromyographs (EMGs). The response patterns of the cells were determined in response-aligned averages and their synaptic interactions were identified by cross-correlograms of action potentials. The possibility that synchronized firing between cortical cells could mediate spike-correlated effects in the SpTA of EMG was examined in several ways. Sixty-two pairs consisted of one CM cell and a non-CM cell; 15 of these had correlogram peaks of the same magnitude as that of other pairs, but the synch...
We investigated the synaptic interactions between neighboring motor cortex cells in monkeys gener... more We investigated the synaptic interactions between neighboring motor cortex cells in monkeys generating isometric ramp-and-hold torques about the wrist. For pairs of cortical cells the response patterns were determined in response-aligned averages and their synaptic interactions were identified by cross-correlation histograms. Cross-correlograms were compiled for 215 cell pairs and 84 (39%) showed significant features. The most frequently found feature (65/84 = 77%) was a central peak, straddling the origin and representing a source of common synaptic input to both cells. One third of these also had superimposed lagged peaks, indicative of a serial excitatory connection. Pure lagged peaks and lagged troughs, indicative of serial excitatory or inhibitory linkages, respectively, both occurred in 5% of the correlograms with features. A central trough appeared in 13% of the correlograms. The magnitude of the synaptic linkage was measured as the normalized area of the correlogram feature....
Closed-loop brain-computer interfaces have bidirectional connections that allow activity-dependen... more Closed-loop brain-computer interfaces have bidirectional connections that allow activity-dependent stimulation of the brain, spinal cord, or muscles. Such bidirectional brain-computer interfaces (BBCI) have three major applications that can be used to restore lost motor function. First, the brain could learn to incorporate a long-term artificial recurrent connection into normal behavior, exploiting the brain's ability to adapt to consistent sensorimotor conditions. The obvious clinical application for restoring motor function is to use an artificial recurrent connection to bridge a lost biological connection. Second, activity-dependent stimulation can generate synaptic plasticity on the cellular level. The corresponding clinical application is to strengthen weakened neural connections, such as occur in stroke. A third application involves delivery of activity-dependent deep brain stimulation at subcortical reward sites, which can operantly reinforce the activity that generates t...
George Gerstein and I first met in 1962 when George was transitioning from postdoctoral fellow to... more George Gerstein and I first met in 1962 when George was transitioning from postdoctoral fellow to junior faculty at MIT and I was a graduate student in the Physics Department. We were both converts from physics to neuroscience, and understood the perspectives of a hardcore science, in which mathematical descriptions could be applied and principles derived. George was fruitfully exploring a range of sophisticated analytical strategies to capture and quantify neural dynamics. I had just had the epiphany (on LSD) that the brain was the most interesting physical system in the universe – the source of all conscious experience and behavior, and not least, where I lived. I was intrigued by the riddle of how neural activity generates all this endless experience. I thought that neural explanations of behavior would probably be like statistical mechanical explanations of thermodynamics. Of course the fatal flaw in that notion was the fact that statistical mechanics succeeded because all parti...
Cortical Responses to Vagus Nerve Stimulation Are Modulated by Brain State in Nonhuman Primates
Cerebral Cortex, 2021
Vagus nerve stimulation (VNS) has been tested as therapy for several brain disorders and as a mea... more Vagus nerve stimulation (VNS) has been tested as therapy for several brain disorders and as a means to modulate cortical excitability and brain plasticity. Cortical effects of VNS, manifesting as vagal-evoked potentials (VEPs), are thought to arise from activation of ascending cholinergic and noradrenergic systems. However, it is unknown whether those effects are modulated by brain state at the time of stimulation. In 2 freely behaving macaque monkeys, we delivered short trains of 5 pulses to the left cervical vagus nerve at different frequencies (5-300 Hz) while recording local field potentials (LFPs) from sites in contralateral prefrontal, sensorimotor and parietal cortical areas. Brain states were inferred from spectral components of LFPs and the presence of overt movement: active awake, resting awake, REM sleep and NREM sleep. VNS elicited VEPs in all sampled cortical areas. VEPs comprised early (<70 ms), intermediate (70-250 ms) and late (>250 ms) components. The magnitud...
We describe an integrate-and-fire (IF) spiking neural network that incorporates spike-timing depe... more We describe an integrate-and-fire (IF) spiking neural network that incorporates spike-timing dependent plasticity (STDP) and simulates the experimental outcomes of four different conditioning protocols that produce cortical plasticity. The original conditioning experiments were performed in freely moving non-human primates with an autonomous head-fixed bidirectional brain-computer interface. Three protocols involved closed-loop stimulation triggered from (a) spike activity of single cortical neurons, (b) EMG activity from forearm muscles, and (c) cycles of spontaneous cortical beta activity. A fourth protocol involved open-loop delivery of pairs of stimuli at neighboring cortical sites. The IF network that replicates the experimental results consists of 360 units with simulated membrane potentials produced by synaptic inputs and triggering a spike when reaching threshold. The 240 cortical units produce either excitatory or inhibitory post-synaptic potentials in their target units. I...
IEEE Transactions on Neural Systems and Rehabilitation Engineering, 2019
Designing brain-computer interfaces (BCIs) that can be used in conjunction with ongoing motor beh... more Designing brain-computer interfaces (BCIs) that can be used in conjunction with ongoing motor behavior requires an understanding of how neural activity co-opted for brain control interacts with existing neural circuits. For example, BCIs may be used to regain lost motor function after stroke. This requires that neural activity controlling unaffected limbs is dissociated from activity controlling the BCI. In this study we investigated how primary motor cortex accomplishes simultaneous BCI control and motor control in a task that explicitly required both activities to be driven from the same brain region (i.e. a dual-control task). Single-unit activity was recorded from intracortical, multi-electrode arrays while a non-human primate performed this dual-control task. Compared to activity observed during naturalistic motor control, we found that both units used to drive the BCI directly (control units) and units that did not directly control the BCI (non-control units) significantly changed their tuning to wrist torque. Using a measure of effective connectivity, we observed that control units decrease their connectivity. Through an analysis of variance we found that the intrinsic variability of the control units has a significant effect on task proficiency. When this variance is accounted for, motor cortical activity is flexible enough to perform novel BCI tasks that require active decoupling of natural associations to wrist motion. This study provides insight into the neural activity that enables a dual-control brain-computer interface.
A novel method to characterize connectivity between sites in the cerebral cortex of primates is p... more A novel method to characterize connectivity between sites in the cerebral cortex of primates is proposed in this paper. Connectivity graphs for two macaque monkeys are inferred from Electrocorticographic (ECoG) activity recorded while the animals were alert. The locations of ECoG electrodes are considered as nodes of the graph, the coefficients of the auto-regressive (AR) representation of the signals measured at each node are considered as the signal on the graph and the connectivity strengths between the nodes are considered as the edges of the graph. Maximization of the graph smoothness defined from the Laplacian quadratic form is used to infer the connectivity map (adjacency matrix of the graph). The cortical evoked potential (CEP) map was obtained by stimulating different electrodes and recording the evoked potentials at the other electrodes. The maps obtained by the graph inference and the traditional method of spectral coherence are compared with the CEP map. The results show that the proposed method provides a description of cortical connectivity that is more similar to the stimulation-based measures than spectral coherence. The results are also tested by the surrogate map analysis in which the CEP map is randomly permuted and the distribution of the errors is obtained. It is shown that error between the two maps is comfortably outside the surrogate map error distribution. This indicates that the similarity between the map calculated by the graph inference and the CEP map is statistically significant.
Functional neuroimaging is a powerful non-invasive tool for studying brain function, using change... more Functional neuroimaging is a powerful non-invasive tool for studying brain function, using changes in blood-oxygenation as a proxy for underlying neuronal activity. The neuroimaging signal correlates with both spiking, and various bands of the local field potential (LFP), making the inability to discriminate between them a serious limitation for interpreting hemodynamic changes. Here, we record activity from the striate cortex in two anesthetized monkeys (Macaca mulatta), using simultaneous functional near-infrared spectroscopy (fNIRS) and intra-cortical electrophysiology. We find that low-frequency LFPs correlate with hemodynamic signal’s peak amplitude, whereas spiking correlates with its peak-time and initial-dip. We also find spiking to be more spatially localized than low-frequency LFPs. Our results suggest that differences in spread of spiking and low-frequency LFPs across cortical surface influence different parameters of the hemodynamic response. Together, these results demo...
The “initial-dip” is a transient decrease frequently observed in functional neuroimaging signals,... more The “initial-dip” is a transient decrease frequently observed in functional neuroimaging signals, immediately after stimulus onset, and is believed to originate from a rise in deoxy-hemoglobin (HbR) caused by local neural activity. It has been shown to be more spatially specific than the hemodynamic response, and is believed to represent focal neuronal activity. However, despite being observed in various neuroimaging modalities (such as fMRI, fNIRS, etc), its origins are disputed and its neuronal correlates unknown. Here, we show that the initial-dip is dominated by a decrease in total-hemoglobin (HbT). We also find a biphasic response in HbR, with an early decrease and later rebound. However, HbT decreases were always large enough to counter spiking-induced increases in HbR. Moreover, the HbT-dip and HbR-rebound were strongly coupled to highly localized spiking activity. Our results suggest that the HbT-dip helps prevent accumulation of spiking-induced HbR-concentration in capillar...
The functional role of cortical beta oscillations, if any, remains unresolved. During oscillation... more The functional role of cortical beta oscillations, if any, remains unresolved. During oscillations the periodic fluctuation in excitability of entrained cells modulates transmission of neural impulses and periodically enhances synaptic interactions. The extent to which oscillatory episodes affect activity-dependent synaptic plasticity remains to be determined. In non-human primates we delivered single-pulse electrical cortical stimulation to a "stimulated" site in sensorimotor cortex triggered on a specific phase of ongoing beta (12-25 Hz) field potential oscillations recorded at a separate "triggering" site. Corticocortical connectivity from the stimulated to the triggering as well as to other (non-triggering) sites was assessed by cortically-evoked potentials, elicited by test stimuli to the stimulated site delivered outside of oscillatory episodes. In separate experiments, connectivity was assessed by intracellular recordings of evoked excitatory post-synaptic potentials. The conditioning paradigm produced transient (1-2 s long) changes in connectivity between the stimulated and the triggering site that outlasted the duration of the oscillatory episodes. The Lead Contact Stavros Zanos, MD PhD Author Contributions SZ, DC and EF conceived the idea and designed the experiments. SZ, IR and others collected the data. SZ, IR and others analyzed the data. SZ, IR and EF wrote the paper.
Resting-state connectivity patterns have been observed in humans and other mammal species, and ca... more Resting-state connectivity patterns have been observed in humans and other mammal species, and can be recorded using a variety of different technologies. Functional connectivity has been previously compared between species using resting-state fMRI, but not in electrophysiological studies. We compared connectivity with implanted electrodes in humans (electrocorticography) to macaques and sheep (microelectrocorticography), which are capable of recording neural data at high frequencies with spatial precision. We specifically examined synchrony, implicated in functional integration between regions. We found that connectivity strength was overwhelmingly similar in humans and monkeys for pairs of two different brain regions (prefrontal, motor, premotor, parietal), but differed more often within single brain regions. The two connectivity measures, correlation and phase locking value, were similar in most comparisons. Connectivity strength agreed more often between the species at higher fre...
Slow wave sleep (SWS) has been identified as the sleep stage involved in consolidating newly acqu... more Slow wave sleep (SWS) has been identified as the sleep stage involved in consolidating newly acquired information. A growing body of evidence has shown that delta (1-4 Hz) oscillatory activity, the characteristic electroencephalographic signature of SWS, is involved in coordinating interaction between the hippocampus and the neocortex and is thought to take a role in stabilizing memory traces related to a novel task. This case report describes a new protocol that uses neuroprosthetics training of a non-human primate to evaluate the effects of surface cortical electrical stimulation triggered from SWS cycles. The results suggest that stimulation phase-locked to SWS oscillatory activity promoted learning of the neuroprosthetic task. This protocol could be used to elucidate mechanisms of synaptic plasticity underlying off-line learning during sleep and offers new insights into the role of brain oscillations in information processing and memory consolidation.
Bimanual movements involve the interactions between both primary motor cortices. These interactio... more Bimanual movements involve the interactions between both primary motor cortices. These interactions are assumed to involve phase-locked oscillatory brain activity referred to as inter-hemispheric functional coupling. So far, inter-hemispheric functional coupling has been investigated as a function of motor performance. These studies report mostly a negative correlation between the performance in motor tasks and the strength of functional coupling. However, correlation might not reflect a causal relationship. To overcome this limitation, we opted for an alternative approach by manipulating the strength of inter-hemispheric functional coupling and assessing bimanual motor performance as a dependent variable. We hypothesize that an increase/decrease of functional coupling deteriorates/facilitates motor performance in an out-of-phase bimanual finger-tapping task. Healthy individuals were trained to volitionally regulate functional coupling in an operant conditioning paradigm using real-...
Operant conditioning of neural activity has typically been performed under controlled behavioral ... more Operant conditioning of neural activity has typically been performed under controlled behavioral conditions using food reinforcement. This has limited the duration and behavioral context for neural conditioning. To reward cell activity in unconstrained primates, we sought sites in nucleus accumbens (NAc) whose stimulation reinforced operant responding. In three monkeys, NAc stimulation sustained performance of a manual target-tracking task, with response rates that increased monotonically with increasing NAc stimulation. We recorded activity of single motor cortex neurons and documented their modulation with wrist force. We conditioned increased firing rates with the monkey seated in the training booth and during free behavior in the cage using an autonomous head-fixed recording and stimulating system. Spikes occurring above baseline rates triggered single or multiple electrical pulses to the reinforcement site. Such rate-contingent, unit-triggered stimulation was made available for...
F1000 - Post-publication peer review of the biomedical literature, 2015
High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being us... more High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being used to deduce how the brain encodes coordinated muscle activity and movement. However, the full movement repertoire that can be elicited from the forelimb representation of primary motor cortex (M1) using this method has not been systematically determined. Our goal was to acquire a comprehensive M1 forelimb representational map of movement endpoints elicited with HFLD-ICMS, using stimulus parameters optimal for evoking stable forelimb spatial endpoints. The data reveal a 3D forelimb movement endpoint workspace that is represented in a patchwork fashion on the 2D M1 cortical surface. Although cortical maps of movement endpoints appear quite disorderly with respect to movement space, we show that the endpoint locations in the workspace evoked with HFLD-ICMS of two adjacent cortical points are closer together than would be expected if the organization were random. Although there were few obvious consistencies in the endpoint maps across the two monkeys tested, one notable exception was endpoints bringing the hand to the mouth, which was located at the boundary between the hand and face representation. Endpoints at the extremes of the monkey's workspace and locations above the head were largely absent. Our movement endpoints are best explained as resulting from coactivation of agonist and antagonist muscles driving the joints toward equilibrium positions determined by the length-tension relationships of the muscles.
Sensory Neurophysiology and Reaction Time Performance in Nonhuman Primates
Animal Psychophysics: the design and conduct of sensory experiments, 1970
It was clear from the conference that information is rapidly accumulating on sensory behavior in ... more It was clear from the conference that information is rapidly accumulating on sensory behavior in animals. Psychophysical relationships between stimulus and response parameters recently derived from animal subjects have been shown to be as reliable and precise as those obtained from man. Moreover, through analysis of these stimulus-response functions we are acquiring a better understanding of the influence of various stimulus parameters on behavior. One of the basic themes of the conference concerned the extension of our understanding of sensory functions to include the role of afferent neural structures in behavior. Contemporary behavioral procedures yielding psychophysical functions in animals provide a vehicle for such an extension. Simply stated, this approach suggests that we begin to study afferent neural activity in behaviorally trained animals from which precise measures of psychophysical relationships may be concurrently obtained.
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