Odysseas Papazachariadis

Cognitive control of movement in down syndrome

Inhibition of inappropriate responses allows to shape the motor behavior accordingly to the context in which a subject acts and is an essential executive function. Inhibition has been poorly investigated in Down Syndrome (DS) patients. We tested, using a countermanding task, the inhibitory control in a group of DS patients and in a group of patients with developmental disorders of non-genetic etiology, matched for mental age. We found that the duration of the stopping process, the stop signal reaction time (SSRT), was not statistically different in the two groups of patients. At the same time, the normalized inhibitory function resulted shallower in DS patients indicating a poor inhibitory control. We interpreted the results on the basis of the known anatomical differences in the brain of adult DS patients and more specifically in a possible altered dialogue between the fronto-striatal and fronto-cerebellar networks during motor control.

Early Visuomotor Integration Processes Induce LTP/LTD-Like Plasticity in the Human Motor Cortex

To investigate whether visuomotor integration processes induce long-term potentiation (LTP) and depression (LTD)-like plasticity in the primary motor cortex (M1), we designed a new paired associative stimulation (PAS) protocol coupling left primary visual area (V1) activation achieved by hemifield visual evoked potentials (VEPs) and transcranial magnetic stimulation (TMS) over the left M1, at specific interstimulus intervals (ISIs), delivered at 1 Hz (V-PAS). Before and after V-PAS, we measured motor evoked potentials (MEPs). To clarify the mechanisms underlying V-PAS, we tested the effect of 1-Hz repetitive TMS (rTMS), 0.25-Hz V-PAS and rTMS, and a shorter 0.25-Hz V-PAS protocol. To examine V-PAS with contralateral V1 activation, we delivered V-PAS activating the right V1. To clarify whether V-PAS increases V1 activity or parieto- and premotor-to-M1 connectivity, before and after V-PAS, we examined VEPs and MEPs evoked by paired-pulse techniques. V-PAS increased, decreased, or left MEPs unchanged according to the ISI used. After 1-Hz rTMS MEPs decreased. Although 0.25-Hz rTMS elicited no aftereffect, 0.25-Hz V-PAS modulated MEPs according to the ISI used. The short 0.25-Hz V-PAS protocol left MEPs unchanged. Contralateral V-PAS inhibited MEPs. After V-PAS, VEPs remained unchanged and the premotor-to-M1 inhibitory connections decreased. V-PAS induces M1 LTP/LTD-like plasticity by activating premotor-to-motor connections.

Do non-human primates cooperate? Evidences of motor coordination during a joint action task in macaque monkeys

Humans are intensively social primates, therefore many of their actions are dedicated to communication and interaction with other individuals. Despite the progress in understanding the cognitive and neural processes that allow humans to perform cooperative actions, in non-human primates only few studies have investigated the ability to interact with a partner in order to reach a common goal. These studies have shown that in naturalistic conditions animals engage in various types of social behavior that involve forms of mutual coordination and cooperation. However, little is known on the capacity of non-human primates to actively cooperate in a controlled experimental setting, which allows full characterization of the motor parameters underlying individual action and their change during motor cooperation. To this aim, we analyzed the behavior of three pairs of macaque monkeys trained to perform solo and joint-actions by exerting a force on an isometric joystick, as to move an individual or a common cursor toward visual targets on a screen. We found that during cooperation monkeys reciprocally adapt their behavior by changing the parameters that define the spatial and temporal aspects of their action, as to fine tune their joint effort, and maximize their common performance. Furthermore the results suggest that when acting together the movement parameters that specify each actors behavior are not only modulated during execution, but also during planning. These findings provide the first quantitative description of action coordination in non-human primates during the performance of a joint action task.

A differential color flicker test for detecting acquired color vision impairment in multiple sclerosis and diabetic retinopathy.

BACKGROUND Optic neuritis related to multiple sclerosis and diabetic retinopathy are relatively selective post-retinal and retinal vision disorders. Vision impairment in both conditions is reliably measured by testing critical fusion frequency (CFF). METHODS To examine color vision, we measured the CFF in response to red and blue stimuli, and tested CFF values in patients without evident vision impairment. To ensure that differences in CFF values in a given subject depended only on color perception we displayed red and blue flickering stimuli at equal luminance. CFF to red or blue stimuli were compared in patients with medical history of optic neuritis related to multiple sclerosis (post-retinal vision impairment), patients with diabetic retinopathy (retinal vision impairment) and healthy subjects. RESULTS The test procedure disclosed altered CFF values for red and blue stimuli in both groups of patients studied. The comparison between the two groups disclosed a prevalent CFF impairment for red stimuli in patients with optic neuritis related to multiple sclerosis and for blue stimuli in patients with diabetic retinopathy. CONCLUSIONS The differential color flicker test appears highly accurate in detecting color vision impairment. Comparison of the two color CFFs differentiates retinal from post-retinal visual disorders.

Posterior Parietal Cortex Encoding of Dynamic Hand Force Underlying Hand–Object Interaction

Major achievements of primate evolution are skilled hand–object interaction and tool use, both in part dependent on parietal cortex expansion. We recorded spiking activity from macaque inferior parietal cortex during directional manipulation of an isometric tool, which required the application of hand forces to control a cursors motion on a screen. In areas PFG/PF, the activity of ∼70% neurons was modulated by the hand force necessary to implement the desired target motion, reflecting an inverse model, rather than by the intended motion of the visual cursor (forward model). The population vector matched the direction and amplitude of the instantaneous force increments over time. When exposed to a new force condition, that obliged the monkey to change the force output to successfully bring the cursor to the final target, the activity of a consistent subpopulation of neurons changed in an orderly fashion and, at the end of a “Wash-out” session, retained memory of the new learned association, at the service of predictive control of force. Our findings suggest that areas PFG/PF represent a crucial node of the distributed control of hand force, by encoding instantaneous force variations and serving as a memory reservoir of hand dynamics required for object manipulation and tool use. This is coherent with previous studies in humans showing the following: (1) impaired adaptation to a new force field under TMS parietal perturbation; (2) defective control of direction of hand force after parietal lesion; and (3) fMRI activation of parietal cortex during object manipulation requiring control of fine hand forces. SIGNIFICANCE STATEMENT Skilled object manipulation and tool use are major achievements of primate evolution, both largely dependent on posterior parietal cortex (PPC) expansion. Neurophysiological and fMRI studies in macaque and humans had documented a crucial role of PPC in encoding the hand kinematics underlying these functions, leaving to premotor and motor areas the role of specifying the underlying hand forces. We recorded spiking activity from macaque PPC during manipulation of an isometric tool and found that population activity is not only modulated by the dynamic hand force and its change over time, but also retains memory of the exerted force, as a reservoir to guide of future hand action. This suggests parallel parietal encoding of hand dynamics and kinematics during object manipulation.

Alpha- and beta-band oscillations subserve different processes in reactive control of limb movements

The capacity to rapidly suppress a behavioral act in response to sudden instruction to stop is a key cognitive function. This function, called reactive control, is tested in experimental settings using the stop signal task, which requires subjects to generate a movement in response to a go signal or suppress it when a stop signal appears. The ability to inhibit this movement fluctuates over time: sometimes, subjects can stop their response, and at other times, they can not. To determine the neural basis of this fluctuation, we recorded local field potentials (LFPs) in the alpha (6–12 Hz) and beta (13–35 Hz) bands from the dorsal premotor cortex of two nonhuman primates that were performing the task. The ability to countermand a movement after a stop signal was predicted by the activity of both bands, each purportedly representing a distinct neural process. The beta band represents the level of movement preparation; higher beta power corresponds to a lower level of movement preparation, whereas the alpha band supports a proper phasic, reactive inhibitory response: movements are inhibited when alpha band power increases immediately after a stop signal. Our findings support the function of LFP bands in generating the signatures of various neural computations that are multiplexed in the brain.

iTBS-induced LTP-like plasticity parallels oscillatory activity changes in the primary sensory and motor areas of macaque monkeys.

Recently, neuromodulation techniques based on the use of repetitive transcranial magnetic stimulation (rTMS) have been proposed as a non-invasive and efficient method to induce in vivo long-term potentiation (LTP)-like aftereffects. However, the exact impact of rTMS-induced perturbations on the dynamics of neuronal population activity is not well understood. Here, in two monkeys, we examine changes in the oscillatory activity of the sensorimotor cortex following an intermittent theta burst stimulation (iTBS) protocol. We first probed iTBS modulatory effects by testing the iTBS-induced facilitation of somatosensory evoked potentials (SEP). Then, we examined the frequency information of the electrocorticographic signal, obtained using a custom-made miniaturised multi-electrode array for electrocorticography, after real or sham iTBS. We observed that iTBS induced facilitation of SEPs and influenced spectral components of the signal, in both animals. The latter effect was more prominent on the θ band (4–8 Hz) and the high γ band (55–90 Hz), de-potentiated and potentiated respectively. We additionally found that the multi-electrode array uniformity of β (13–26 Hz) and high γ bands were also afflicted by iTBS. Our study suggests that enhanced cortical excitability promoted by iTBS parallels a dynamic reorganisation of the interested neural network. The effect in the γ band suggests a transient local modulation, possibly at the level of synaptic strength in interneurons. The effect in the θ band suggests the disruption of temporal coordination on larger spatial scales.

Promoting endogenous associative plasticity in human primary motor cortex.

As predicted by the Hebbian rule for associative plasticity, the strength of synaptic efficacy increases or decreases according to the specific time interval between pre- and postsynaptic activity due to spike timing-dependent plasticity (STDP). In healthy humans, one way to elicit cortical associative plasticity due to STDP is by applying paired associative stimulation (PAS), which consists of transcranial magnetic stimulation (TMS) delivered over the primary motor cortex (M1) combined with electric stimulation of a mixed peripheral nerve. When repetitive TMS pulses are delivered at 25 ms together with time-locked electric nerve stimulation at the contralateral wrist (PAS25), motor evoked potentials (MEPs) increase in size for approximately 60 min, whereas at 10 ms (PAS10) MEPs decrease in size (Stefan et al. 2000). As PAS implies repetitive activation of sensorimotor circuits at specific interstimulus intervals (ISIs), PAS-induced long-term changes in MEP amplitude reflect mechanisms of an associative Hebbian form of STDP (Stefan et al. 2000). Several authors have recently developed new PAS protocols by coupling TMS over M1 with stimuli delivered over the contralateral M1 (Koganemaru et al. 2009; Rizzo et al. 2009), or targeting non-primary motor areas including the supplementary motor area (SMA) (Arai et al. 2011) and the ventral region of the premotor area (PMv) (Buch et al. 2011). More recently, we have developed a modified PAS protocol involving TMS paired with laser-induced nociceptive system activation (Laser-PAS). By delivering laser pulses that elicit laser evoked potentials (LEPs) over the skin, we found that when TMS follows laser stimulation at the specific ISI of the LEPs’ N1 component + 50 ms (Laser-PAS50), MEPs increase in size for approximately 60 min, reflecting cortical STDP arising from pain–motor integration processes (Suppa et al. 2012). Taken together, these studies demonstrate that Hebbian forms of associative plasticity operate in M1 as a general principle regardless of the nature of the specific stimuli coupled with TMS. In addition to PAS protocols involving two exogenous stimuli (i.e. TMS and electric peripheral nerve activation), several authors have elicited associative plasticity in M1 by pairing exogenous stimuli with endogenous neural activity contributing to movement related cortical potentials (MRCPs) (Thabit et al. 2010; Mrachacz-Kersting et al. 2012). MRCPs are commonly recorded in the form of contingent negative variation (CNV) and Bereitschaftspotential (BP). The CNV consists of a slow negative potential that occurs between a ‘warning’ signal and a ‘go’ signal and can be divided in an early component (CNV1), 1.5–0.5 s before the ‘go’ signal, and a late component (CNV2), 0.5 s or less before the ‘go’ signal. By contrast, the BP precedes a self-initiated movement and consists of an early component (BP1), 1.5–0.5 s before movement onset, and a late component (BP2), 0.5 s or less before movement onset. Although the CNV and BP reflect different forms of neural activity, i.e. externally triggered versus self-triggered movement preparation, the late component of both CNV2 and BP2 is believed to reflect neural activity in M1 (Jankelowitz & Colebatch, 2002). Recently, Thabit et al. (2010) developed a new PAS protocol by delivering TMS over M1 paired with a visual cued simple-reaction time task consisting of repetitive self-triggered thumb abductions. They found that MEPs increased or decreased significantly in size according to specific ISIs; when TMS preceded EMG onset at 50 ms, MEPs increased in size, whereas when TMS followed EMG onset at 100 ms, MEPs decreased in size, reflecting associative plasticity in M1. Although Thabit et al. (2010) did not record MRCPs, they speculated that associative plasticity occurred because M1 neural elements activated by TMS overlapped, at least in part, those generating the late motor component of MRCPs. They did not, therefore, clarify which MRCP component related to the self-triggered thumb abductions was specifically associated with TMS in inducing the observed associative plasticity. A recent study published in The Journal of Physiology (Mrachacz-Kersting et al. 2012) investigated the issue of associative plasticity elicited by pairing exogenous stimuli with endogenous neural activity contributing to MRCPs. Differently from Thabit et al. (2010), Mrachacz-Kersting et al. (2012) designed a new PAS protocol able to elicit changes in the amplitude of MEPs recorded from lower limb muscles by coupling CNV-related neural activity generated by imagined ankle dorsiflexion with electric stimulation of the common peroneal nerve. In their experimental protocol, after the ‘go’ signal, subjects were asked to imagine a ballistic right ankle dorsiflexion, to hold the imagined voluntary contraction for 2 s and then to release the imagined contraction. Electric stimulation of the right common peroneal nerve was delivered at specific ISIs before, during and after the CNV mean peak negativity. The authors (Mrachacz-Kersting et al. 2012) examined the effect of the associative protocol by measuring MEP amplitudes from the right tibialis anterior muscle before and after PAS. When peripheral electric stimuli were delivered during the CNV mean peak negativity, MEPs from the tibialis anterior muscle increased in size significantly, whereas the other ISIs left MEPs unchanged. Mrachacz-Kersting et al. (2012) concluded that MEP changes arose from associative plasticity in neural elements generating the late CNV (endogenous stimulus) and receiving afferent inputs from the common peroneal nerve activation (exogenous stimulus). The study of Mrachacz-Kersting et al. (2012) is interesting since the proposed PAS protocol combining CNV and peripheral electric nerve stimulation at specific ISIs provides novel information on mechanisms underlying associative plasticity in human motor cortex. However, as Mrachacz-Kersting et al. (2012) did not apply TMS during PAS, the exact location where associative plasticity occurred remains unclear. Brain activation patterns induced by the execution of a real movement differ significantly from those induced by the imagination of a motor act since the activation of M1 is less prominent during an imagined motor act than during motor execution (Jankelowitz & Colebatch, 2002). Hence, it is difficult to determine whether the associative plasticity reported by the authors (Mrachacz-Kersting et al. 2012) was indeed related to M1 intrinsic activity or whether it reflected, instead, enhanced functional connectivity between M1 and non-primary motor areas, including the dorsal premotor cortex. In addition, it remains unclear whether the LTP-like plasticity in M1 reported by Mrachacz-Kersting et al. (2012) reflected STDP or rather arose from a ‘gating effect’ of the afferent sensory input driven by motor imagery-induced neural activity (Ziemann & Siebner, 2008). Differently from STDP, which requires precise timing and specific associativity between stimuli (Stefan et al. 2000), LTP-like plasticity might be also driven from afferent sensory inputs gated by a transient and unspecific enhancement in M1 excitability due to motor imagery (Ziemann & Siebner, 2008). As associative plasticity due to STDP plays a crucial role in memory and learning processes, the various PAS protocols here reported might be helpful as a means of promoting functional recovery in patients with various types of motor disorders. In addition, it may in the future be possible to exploit PAS protocols that induce cortical associative plasticity in brain–computer interface (BCI) technologies to improve the quality of interaction with the surrounding environment in patients with severe motor disabilities.

Median nerve stimulation modulates extracellular signals in the primary motor area of a macaque monkey.

Aiming to better define the functional influence of somatosensory stimuli on the primary motor cortex (M1) of primates, we investigated changes in extracellular neural activity induced by repetitive median nerve stimulation (MNS). We described neural adaptation and signal integration in both the multiunit activity (MUA) and the local field potential (LFP). To identify integration of initial M1 activity in the MNS response, we tested the correlation between peak amplitude responses and band energy preceding the peaks. Most of the sites studied in the M1 resulted responsive to MNS. MUA response peak amplitude decreased significantly in time in all sites during repetitive MNS, LFP response peak amplitude instead resulted more variable. Similarly, correlation analysis with the initial activity revealed a significant influence when tested using MUA peak amplitude modulation and a less significant correlation when tested using LFP peak amplitude. Our findings improve current knowledge on mechanisms underlying early M1 changes consequent to afferent somatosensory stimuli.

Unraveling Acetylcholine Impact on Human Cortical Plasticity

In recent years, a growing number of studies on humans have used repetitive transcranial magnetic stimulation (rTMS) techniques to induce and examine plasticity in the primary motor cortex (M1). This plasticity is reflected by long-term changes in motor-evoked potential (MEP) amplitudes elicited by