Gabriella Cerri

Macaque ventral premotor cortex exerts powerful facilitation of motor cortex outputs to upper limb motoneurons.

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.

Excitability changes in human corticospinal projections to muscles moving hand and fingers while viewing a reaching and grasping action

Excitability of the H‐reflex in the relaxed flexor digitorum superficialis (FDS) muscle was tested in five subjects observing a reaching and grasping action. The amplitude of the FDS H‐reflex was modulated with a peak occurring during the hand‐opening phase of the observed movement. When the H‐reflex was facilitated by subliminal transcranial magnetic stimulation (TMS), the modulation was larger than for an unconditioned reflex of similar size. This suggests that the primary motor cortex excitability is modulated by action viewing and reasonably causes the motoneuronal excitability changes. Moreover, motor evoked potentials (MEPs) were elicited by supraliminal TMS in FDS, flexor carpi radialis (FCR) and first dorsal interosseus (FDI) when observing the same movement. MEP amplitude was modulated in FDS with the same time‐course as the H‐reflex, the peak excitability occurring during hand opening. In FDI, however, the maximal excitability occurred during finger closing while in FCR no correlation was found with the movement phases. Finally the EMG activity of FCR, FDS and FDI was recorded while the subjects were actually performing a grasping movement similar to the one observed. In all subjects and for each muscle there was a clear‐cut correspondence between the time‐course of the excitability modulation of MEPs and the temporal pattern of EMG recruitment. In conclusion, the present study suggests that ‘motor resonance’ subliminally activates the same motor pathways that would be overtly recruited in each observer when actually performing the observed movement, reproducing the personal strategy adopted in the same task.

Excitability changes in resting forearm muscles during voluntary foot movements depend on hand position: a neural substrate for hand-foot isodirectional coupling

When associating hand and foot voluntary oscillations, isodirectional coupling is preferred irrespective of hand position (prone or supine). To investigate the neural correlates of this coupling modality, excitability of the motor projections innervating the resting forearm was tested during cyclic voluntary flexion-extensions of the ipsilateral foot. H-reflexes, in some experiments facilitated by subliminal Transcranial Magnetic Stimulation (TMS), and Compound Muscle Action Potentials (CMAPs), evoked by supraliminal TMS, were elicited in Flexor Carpi Radialis (FCR) and Extensor Carpi Radialis (ECR) muscles at five intervals during the foot movement cycle. With the hand prone, a sinusoidal excitability modulation was observed in wrist flexors and extensors, but reversed in phase: in FCR, excitability increased during plantar-flexion and decreased during dorsiflexion, while in ECR the opposite occurred. This reciprocal organisation was confirmed by the excitability modulation of CMAPs evoked simultaneously in the two antagonists. When the hand was supinated, the H-reflex modulation reversed in phase, i.e., FCR excitability increased during foot dorsiflexion and decreased during plantar-flexion. In both muscles and hand positions tested, when the muscle-to-movement phase-lag was increased by inertial loading of the foot, H-reflex excitability modulations remained phase linked to muscular contractions, not to movement. Together, these results suggest that the subliminal excitability modulation of hand movers has a common central origin with the parallel overt activation of foot movers, is reciprocally organised, and is direction- not muscle-dependent. It may therefore represent the neural substrate for isodirectional coupling of hand (prone or supine) with the foot.

Tailoring neurophysiological strategies with clinical context enhances resection and safety and expands indications in gliomas involving motor pathways

BACKGROUND Resection of motor pathway gliomas requires the intraoperative recognition of essential cortical-subcortical motor structures. The degree of involvement of motor structures is variable, and increases as result of treatments patients are submitted to. Intraoperative neurophysiology offers various stimulation modalities, which efficiency is based on the ability to recognize essential sites with the highest possible resolution in most clinical conditions. Two stimulation paradigms evolved for intraoperative guidance of motor tumors removal: the 60 Hz-technique [low frequency (LF)] and the pulse-technique [high frequency-(HF)], delivered by bipolar or monopolar probe respectively. Most surgical teams rely on to either of the 2 techniques. The key point is the integration of the choice of the stimulation modality with the clinical context. METHODS In 591 tumors involving the corticospinal tract, the use of HF and LF was tailored to the clinical context defined by patient clinical history and tumor features (by imaging). The effect was evaluated on the feasibility of mapping, the impact on immediate and permanent morbidity, the extent of resection, and the number of patients treated. RESULTS By integrating the choice of the probe and the stimulation protocol with patient clinical history and tumor characteristics, the best probe-frequency match was identified for the different sets of clinical conditions. This integrative approach allows increasing the extent of resection and patient functional integrity, and greatly expands the number of patients who could benefit from surgery. CONCLUSIONS The integration of stimulation modalities with clinical context enhances the extent and safety of resection and expands the population of patients who could benefit from surgical treatment.

Motoneuronal pre‐compensation for the low‐pass filter characteristics of muscle. A quantitative appraisal in cat muscle units

1 The relevance of motoneurone dynamic sensitivity in compensating for the low‐pass filter properties of muscle was assessed by stimulating cat muscle units (MUs) with impulse discharges generated by two current‐to‐rate converters: (i) a spinal motoneurone, sensitive to both the input intensity and its first derivative, and (ii) a linear current‐to‐rate converter, i.e. a neurone model with the same static sensitivity as the motoneurone but lacking dynamic sensitivity. 2 Discharges generated by injection of sine‐wave currents in three motoneurones of the ‘fast’ type and in the three related model versions were applied to the axon of forty‐six MUs. The MU isometric tension was modulated at the frequency of the current sine wave (0.5‐20 Hz). Phase and gain of the current‐to‐force transduction were measured. 3 When MUs were driven by the model, the force lagged the current by 90 deg at 1 Hz in slow MUs and at around 5 Hz in fast MUs. Under motoneurone drive, the 90 deg phase lag was attained at frequencies about twice as high. 4 The gain of the transduction (peak‐to‐peak force modulation/peak‐to‐peak current modulation) decayed when the modulation frequency was increased. In all but five units, the cut‐off frequency, Fco (gain attenuated by −3 dB), was higher when the unit was motoneurone driven (FcoCell) then when it was model driven (FcoMod). In both conditions, Fco was inversely correlated with the MUs time‐to‐peak. The advantage conferred by the motoneurone dynamic sensitivity was expressed by the Fco ratio (FcoCell/FcoMod). Across the MU population this ratio ranged from 0.6‐2.8, was inversely correlated with the time‐to peak, and was directly correlated with the half‐tension rate, i.e. the impulse rate at which MUs develop 50 % of their maximal tetanic force. The largest improvement (Fco ratio > 2.0) was found in units with mechanical features similar to those presumably coupled ‘in vivo’ to the motoneurones utilized for stimulation. 5 This estimate was confirmed in experiments in which trains of pulses, generated by injection of ramp currents in another motoneurone and the related model, were used to activate eight MUs, selected for being similar to that connected ‘in vivo’ to the motoneurone. As expected, for any given current slope the rising phase of isometric tension was steeper when units were motoneurone driven than when they were model driven. The gain (force slope/current slope) was plotted against the ramp slope to identify the cut‐off slope, Sco, at which the gain was attenuated by −3 dB. In this homogeneous MU sample, the ratio expressing the advantage of the motoneurone drive (ScoCell/ScoMod, equivalent to the Fco ratio), ranged from 2.62‐2.97, values comparable with those observed in sine‐wave experiments when the motoneurone and muscle units were properly matched.

Bilateral motor resonance evoked by observation of a one-hand movement: role of the primary motor cortex

In humans, observation of movement performed by others evokes a subliminal motor resonant response, probably mediated by the mirror neurone system, which reproduces the motor commands needed to execute the observed movement with good spatial and temporal fidelity. Motor properties of the resonant response were here investigated with the ultimate goal of understanding the principles operating in the transformation from observation to internal reproduction of movement. Motor resonance was measured as the modulation of excitability of spinal motoneurones, evoked by the observation of a cyclic flexion‐extension of one hand. The first two experiments showed that the observation of a one‐hand movement always evoked a bimanual resonant response independent of which hand was observed and that these bilateral responses were consistently phase‐linked. H‐reflexes simultaneously recorded in right and left flexor carpi radialis muscles were always modulated ‘in‐phase’ with each other. The goal of the third experiment was to define the role of primary motor cortex in the bilateral resonant response. Bilateral H‐reflexes were recorded during a temporary inactivation induced by transcranial magnetic stimulation over the left cortical hand motor area of observers. The finding that such cortical depression abolished the H‐reflex modulation of only the right flexor carpi radialis motoneurones, leaving it unchanged on the left side, suggested that both primary motor areas were activated by the premotor cortex and transmit the resonant activation through crossed corticospinal pathways. The data provide further evidence that the subliminal activation of motor pathways induced by movement observation is organized according to general rules shared with the control of voluntary movement.

The shape of motor resonance: Right- or left-handed?

The human mirror neuron system is a fronto-parietal neural pathway which, when activated by action observation, gives rise to an internal simulation of the observed action (motor resonance). Here we demonstrate how handedness shapes the resonant response, by engaging right-handed (RH) and left-handed (LH) subjects in observation and execution of actions preferentially performed by the dominant hand. We hypothesize that since motor resonance reproduces subliminally the specific motor program for the observed action, it should be subject to motor constraints, such as handedness. A conjunction analysis for observed and executed actions revealed that handedness determines a lateralized activation of the areas engaged in motor resonance. Premotor-BA6 and parietal-BA40 are strongly left lateralized in RH subjects observing or moving their right hand, and to a lesser degree their left hand. Extremely LH subjects show a similar pattern of lateralization on the right, while more ambidextrous LH subjects show a more bilateral activation. The activation of a cortical network outside the mirror neuron system is also discussed.

Mirroring avatars: Dissociation of action and intention in human motor resonance

Observation of others’ actions induces a subliminal activation of motor pathways (motor resonance) that is mediated by the mirror neuron system and reflects the motor program encoding the observed action. Whether motor resonance represents the movements composing an action or also its motor intention remains of debate, as natural actions implicitly contain their motor intentions. Here, action and intention are dissociated using a natural and an impossible action with the same grasping intention: subjects observe an avatar grasping a ball using either a natural hand action (‘palmar’ finger flexion) or an impossible hand action (‘dorsal’ finger flexion). Motor‐evoked potentials (MEPs), elicited by single transcranial magnetic stimulation of the hand area in the primary motor cortex, were used to measure the excitability modulation of motor pathways during observation of the two different hand actions. MEPs were recorded from the opponens pollicis (OP), abductor digiti minimi (ADM) and extensor carpi radialis (ECR) muscles. A significant MEP facilitation was found in the OP, during observation of the grasping phase of the natural action; MEPs in the ADM were facilitated during observation of the hand opening phase of the natural action and of both opening and grasping phases of the impossible action. MEPs in the ECR were not affected. As different resonant responses are elicited by the observation of the two different actions, despite their identical intention, we conclude that the mirror neuron system cannot utilize the observer’s subliminal motor program in the primary motor cortex to encode action intentions.

The Mirror Neuron System and The Strange Case of Broca's Area

Mirror neurons, originally described in the monkey premotor area F5, are embedded in a frontoparietal network for action execution and observation. A similar Mirror Neuron System (MNS) exists in humans, including precentral gyrus, inferior parietal lobule, and superior temporal sulcus. Controversial is the inclusion of Brocas area, as homologous to F5, a relevant issue in light of the mirror hypothesis of language evolution, which postulates a key role of Brocas area in action/speech perception/production. We assess “mirror” properties of this area by combining neuroimaging and intraoperative neurophysiological techniques. Our results show that Brocas area is minimally involved in action observation and has no motor output on hand or phonoarticulatory muscles, challenging its inclusion in the MNS. The presence of these functions in premotor BA6 makes this area the likely homologue of F5 suggesting that the MNS may be involved in the representation of articulatory rather than semantic components of speech. Hum Brain Mapp 36:1010–1027, 2015.

What you see is what you get: motor resonance in peripheral vision

Observation of others’ actions evokes a subliminal motor resonant response, which reflects the motor program encoding observed actions. The possibility that actions located in the peripheral field of vision may also activate motor resonant responses has not been investigated. We examine the excitability modulation of motor pathways in response to grasping actions viewed in near peripheral vision; results are directly compared to responses to the same actions viewed in central vision (Borroni et al. in Eur J Neurosci 34:662–669, 2011. doi:10.1111/j.1460-9568.2011.07779.x). We hypothesize that actions observed in peripheral vision are effective in modulating the excitability of motor pathways, but that responses have a low kinematic specificity. While the neural resources of central vision provide the most accurate perception of biological motion, the decreased visual acuity in periphery may be sufficient to discriminate only general aspects of movement and perhaps to recognize the gist of visual scenes. Right-handed subjects observed a video of two grasping actions at 10° eccentricity in the horizontal plane. Motor-evoked potentials were elicited in the right OP and ADM muscles by TMS of the left primary motor cortex at different delays during the observed actions. Results show that actions viewed in near peripheral vision are effective in modulating the subliminal activation of motor circuits, but that responses are rough and inaccurate, and do not reflect the motor program encoding the observed action or its goal. We suggest that due to their limited kinematic accuracy, these subliminal motor responses may provide information about the general aspects of observed actions, rather than their specific execution.