A cortical mechanism linking saliency detection and motor reactivity in rhesus monkeys

: Sudden and surprising sensory events trigger neural processes that swiftly adjust behavior. To study the phylogenesis and the mechanism of this phenomenon, we trained two male rhesus monkeys to keep a cursor inside a visual target by exerting force on an isometric joystick. We examined the effect of surprising auditory stimuli on exerted force, scalp electroencephalographic (EEG) activity, and local field potentials (LFP) recorded from the dorso-lateral prefrontal cortex. Auditory stimuli elicited (1) a biphasic modulation of isometric force: a transient decrease followed by a corrective tonic increase, and (2) EEG and LFP deflections dominated by two large negative-positive waves (N70 and P130). The EEG potential was maximal at the scalp vertex, highly reminiscent of the human 'vertex potential'. Electrocortical potentials and force were tightly coupled: the P130 amplitude predicted the magnitude of the corrective force increase, particularly in the LFPs recorded from deep rather than superficial cortical layers. These results disclose a phylogenetically-preserved cortico-motor mechanism supporting adaptive behavior in response to salient sensory events.Significance Statement Survival in the natural world depends on an animal's capacity to adapt ongoing behavior to unexpected events. To study the neural mechanisms underlying this capacity, we trained monkeys to apply constant force on a joystick while we recorded their brain activity from the scalp and, invasively, from the prefrontal cortex contralateral to the hand holding the joystick. Unexpected auditory stimuli elicited a biphasic force modulation: a transient reduction followed by a corrective adjustment. The same stimuli also elicited EEG and LFP responses, dominated by a biphasic wave that predicted the magnitude of the behavioral adjustment. These results disclose a phylogenetically-preserved cortico-motor mechanism supporting adaptive behavior in response to unexpected events

Deletion of the BDNF receptor TrkB.T1 rescues hippocampal parvalbumin positive interneurons in a mouse model of Amyotrophic Lateral Sclerosis

In addition to motoneurons degeneration, Amyotrophic Lateral Sclerosis (ALS) patients have defects in brain regions primarily associated with cognitive functions, such as the hippocampus. These defects have also been confirmed in animal models of ALS. The report that transgenic mice expressing a mutant form of the human superoxide dismutase-1 (hSOD1) with a Gly93 → Ala substitution (G93A-hSOD1), causing familial ALS, have degeneration of a subsets of spinal interneurons (Mol Neurobiol. 2012, 45: 30-42) prompted us to investigate whether this phenotype extends to other CNS interneuron populations. The calcium-binding protein parvalbumin positive interneurons (PVi), constitute the largest class of hippocampal interneurons and play essential roles in hippocampus development and plasticity. Interestingly, we found that PVi are reduced in the hippocampus of presymptomatic G93A-hSOD1 mice compared to controls. Therefore, we decided to use the hippocampal PVi as a model system to identify pathways that may affect the survival of this neuronal population in neurodegenerative conditions. Recently we have shown that deletion of the BDNF receptor TrkB.T1 lacking the intracellular tyrosine kinase domain delays the onset of motoneuron degeneration in the G93A-hSOD1 mice (PLoS One. 2012, 7:e39946). Thus, we investigated hippocampal PVi in G93A-hSOD1/TrkB.T1 deficient mice, G93A-hSOD1 animals at the presymptomatic state and wild type mice as controls. Eight-week-old brains were processed to visualize PVi. After image acquisition, hippocampal slices stained for PV were analyzed with ImageJ. Surprisingly, we found that the number of hippocampal PVi was comparable between wild type and G93A-hSOD1/TrkB.T1-/-. Statistical analysis by ANOVA performed on raw data revealed highly significant differences among the three genotypes [F(2,137)=9.077, p=0.0002]. Post-hoc tests showed that G93A-hSOD1 mice had significantly less PVi (79.05±0.56) compared to wild type (93.84±0.93) and to G93A-hSOD1/TrkB.T1-/- mice (93.10±0.54). These data suggest that BDNF/TrkB.T1 signaling affects not only motoneurons but also hippocampal PVi survival. Moreover, they unveil a new function for TrkB.T1 in a cell population essential for normal hippocampal function and suggest the relevance of targeting this pathway in neurodegenerative conditions

Does gravity influence the timing of motion? A project study on isochronous repetitive movements in human healthy subjects

The ability to perform isochronous repetitive movements while listening to a paced auditory stimulus requires a flexible process that integrates timing information with movement. Our group has developed and studied an audio-motor and recall-motor integration paradigm in which sets of repeated isochronous wrist"s flexion-extensions (IWFEs) are performed under different sensory conditions while minimizing visual and tactile information. Data indicate that the listening alone to paced auditory stimuli does not improve the precision of an isochronous performance (Modulation of isochronous movements in a flexible environment: links between motion and auditory experience. Bravi et al., 2014, Exp Brain Res, DOI 10.1007/s00221-014-3845-9). Recently, using the same paradigm, we tried to get further insights into the domain of repetitive timed movements by introduction of an external perturbation of the motor peripheral (kinesiotaping), thus showing how the precision of isochronous performance is subject to peripheral contribution. In line with our previous studies we are investigating, by means of a synchronization-continuation paradigm under different audio conditions, whether and how the gravity vector influences the production of IWFEs. First, sets of IWFEs are performed with the forearm, supported on armrest, in pronated position. Second, sets of IWFEs are performed with the forearm internally rotated by 90 degrees. Kinematic parameters were evaluated during each session and temporal parameters of movements were analyzed. Preliminary results suggest that the gravity vector influences isochronous movements by altering their durations. Results provide further evidence for an adaptable control of timing in the audio-motor coupling for isochronous movements

Acetylcholine, GABA and neuronal networks: A working hypothesis for compensations in the dystrophic brain

Duchenne muscular dystrophy (DMD), a genetic disease arising from a mutation in the dystrophin gene, is characterized by muscle failure and is often associated with cognitive deficits. Studies of the dystrophic brain on the murine mdx model of DMD provide evidence of morphological and functional alterations in the central nervous system (CNS) possibly compatible with the cognitive impairment seen in DMD. However, while some of the alterations reported are a direct consequence of the absence of dystrophin, others seem to be associated only indirectly. In this review we reevaluate the literature in order to formulate a possible explanation for the cognitive impairments associated with DMD. We present a working hypothesis, demonstrated as an integrated neuronal network model, according to which within the cascade of events leading to cognitive impairments there are compensatory mechanisms aimed to maintain functional stability via perpetual adjustments of excitatory and inhibitory components. Such ongoing compensatory response creates continuous perturbations that disrupt neuronal functionality in terms of network efficiency. We have theorized that in this process acetylcholine and network oscillations play a central role. A better understating of these mechanisms could provide a useful diagnostic index of the disease's progression and, perhaps, the correct counterbalance of this process might help to prevent deterioration of the CNS in DMD. Furthermore, the involvement of compensatory mechanisms in the CNS could be extended beyond DMD and possibly help to clarify other physio-pathological processes of the CNS

A little elastic for a better performance: kinesiotaping of the motor effector modulates neural mechanisms for rhythmic movements

Background and Aim: A rhythmic motor performance is brought about by an integration of timing information with movements. We have recently demonstrated that the precision of an isochronous performance, defined as performance of repeated movements having a uniform duration, was insensible to auditory stimuli of various characteristics (Bravi et al. 2014). Such finding has led us to further investigate where do the determining factors of precision reside. Materials and Methods: For this purpose we used manipulation of cutaneous afferents by kinesiotaping (KT), an approach that was previously shown to improve some isokinetic performances (Kim and Lee 2013; Wong et al. 2012). Subjects, tested without KT and with KT, have participated in sessions in which sets of repeated isochronous wrist's flexion-extensions (IWFEs) were performed under various auditory conditions and during their recall. Kinematics was recorded and temporal parameters were extracted and analyzed. Results and Discussion: Various degrees of improvement in the isochronous performances were evident for the KT recordings especially in terms of temporal precision. Our results indicate that, in the precision of repetitive rhythmic movements, the manipulation of cutaneous afferents plays a significant role. Whether this increase in precision is achieved by augmentation of the efficiency in central or local neural mechanisms is to be determined, but what remains certain is that when it comes to precision, a little elastic makes the difference

Paced auditory stimuli with distinct characteristics affect differently the clock-like neural process?

In millisecond timing research, two forms of timing are distinguished: event-based and emergent timing (Spencer and Ivry, Brain Cogn, 2005, 58, 84-93). The essential difference between the two timing modes is considered to be consisting in the involvement or noninvolment of a clock-like neural process, i.e., an abstract effector-independent representation of the time intervals to be produced (Wing and Kristofferson, Percept Psycholphys, 1973, 14: 5-12). The character of movements in a rhythmic motor task is considered a key factor for eliciting a specific mode of timing. The class of discrete movements, defined as having a clear-cut beginning and end, shown to engage the involvement of clock-like neural process (Huys et al., 2008, PLoS Comput Biol, 4: e1000061.10.1371). Discrete movements are not the only ones favoring exploitation of the event-based timing. Recent studies have demonstrated that salient auditory markers, such as streams of clicks (Torre and Delignières, 2008, Biol Cyb, 99: 159-170) and tactile feedback (Studenka et al., 2012, Q J Exp Psychol 65, 1086-1100.10.1080), are also able to elicit the event-based timing. Here, we investigated whether simple and complex paced auditory stimuli, as streams of clicks and excerpts of music, influence differently the processes for temporal regulation. Particularly, we wanted to study if music, when compared with clicks, has a different power in encouraging the event-based timing. Also, since Zelaznik and Rosembaum (2010, J Exp Psychol H Percept Perfor, 36: 1565-1575) provided evidence that external auditory event representation of movement favors event-based timing, we decided to explore whether the recall of an auditory stimulus, where auditory imagery is involved and is simulating an internal auditory representation, might influence timing control processes. In order to answer to these questions, subjects have participated in a session in which sets of repeated isochronous wrist's flexion-extensions were performed under various auditory conditions and during their recall. Kinematics was recorded and temporal parameters were extracted and analyzed. Results indicate that streams of clicks and music do affect differently the timing processes, with music having only a minor role in provoking event-based timing, especially evident at high ranges of tempi. In addition, the auditory experience, constructed of components drawn from memory in the absence of direct sensory instigation of experience, favors the involvement of event-based timing

Increased anxiety-like behavior and selective learning impairments are concomitant to loss of hippocampal interneurons in the presymptomatic SOD1(G93A) ALS mouse model.

Amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease primarily characterized by motor neuron death, causes damages beyond motor-related areas. In particular, cognitive impairments and hippocampal damage have been reported in ALS patients. We investigated spatial navigation learning and hippocampal interneurons in a mutant SOD1(G93A) mouse (mSOD1) model of ALS. Behavioral tests were performed by using presymptomatic mSOD1 mice. General motor activity was comparable to that of wild-type mice in the open-field test, in which, however mSOD1 exhibited increased anxiety-like behavior. In the Barnes maze test, mSOD1 mice displayed a delay in learning, outperformed wild-type mice during the first probe trial, and exhibited impaired long-term memory. Stereological counts of parvalbumin-positive interneurons, which are crucial for hippocampal physiology and known to be altered in other central nervous system regions of mSOD1 mice, were also performed. At postnatal day (P) 56, the population of parvalbumin-positive interneurons in mSOD1 mice was already reduced in CA1 and in CA3, and at P90 the reduction extended to the dentate gyrus. Loss of parvalbumin-positive hippocampal interneurons occurred mostly during the presymptomatic stage. Western blot analysis showed that hippocampal parvalbumin expression levels were already reduced in mSOD1 mice at P56. The hippocampal alterations in mSOD1 mice could at least partly account for the increased anxiety-like behavior and deficits in spatial navigation learning. Our study provides evidence for cognitive alterations and damage to the \u3b3-aminobutyric acid (GABA)ergic system in the hippocampus of murine ALS, thereby revealing selective deficits antecedent to the onset of motor symptoms

Do different musics interfere differently with the timing of repetitive isochronic movements? A project study on human healthy subjects

Our group has previously developed an experimental paradigm based on performance of repetitive isochronous wrist flexion-extensions (IWFEs) not requiring explicit time representation. IWFEs have been coupled to time-based audio stimuli. We found that timed auditory stimuli, expecially those in the high range of bpm, influence the timing of IWFEs in conditions of recall. Recalls of previously listened music reduce the rate of isochronous movements while recalls of clicks result in an increased rate of movements. At present we are investigating the ability of different timed musics - acknowledged being familiar vs unfamiliar - to shape perception of time and, consequently, to influence subsequent production of IWFEs. Selected subject are neither musically-trained nor listeners of classical music repertoire. We tested the differential behaviour of IWFEs in the conditions of listening of auditory stimuli, both metronome clicks and timed musical excerpts (as familiar, from contemporary entertainment music; as unfamiliar, from classical repertoire), and in recall conditions. Preliminary results suggest that music aknowledged being familiar univocally influences the timing of IWFEs in the conditions of recall whereas unfamiliar music evokes an assorted palette of results, veritably reflecting the listening biography of the single subjects or their attitude toward the unknown music message. Specific influence of music on movement tends to vanish with unfamiliarity, merging eventually with the one elicited by listening to simple clicks

A little elastic for a better performance: kinesiotaping of the motor effector modulates neural mechanisms for rhythmic movements

A rhythmic motor performance is brought about by an integration of timing information with movements. Investigations on the millisecond time scale distinguish two forms of time control, event-based timing and emergent timing. While event-based timing asserts the existence of a central internal timekeeper for the control of repetitive movements, the emergent timing perspective claims that timing emerges from dynamic control of nontemporal movements parameters. We have recently demonstrated that the precision of an isochronous performance, defined as performance of repeated movements having a uniform duration, was insensible to auditory stimuli of various characteristics (Bravi et al., 2014). Such finding has led us to investigate whether the application of an elastic therapeutic tape (Kinesio® Tex taping; KTT) used for treating athletic injuries and a variety of physical disorders, is able to reduce the timing variability of repetitive rhythmic movement. Young healthy subjects, tested with and without KTT, have participated in sessions in which sets of repeated isochronous wrist’s flexion-extensions (IWFEs) were performed under various auditory conditions and during their recall. Kinematics was recorded and temporal parameters were extracted and analyzed. Our results show that the application of KTT decreases the variability of rhythmic movements by a 2-fold effect: on the one hand KTT provides extra proprioceptive information activating cutaneous mechanoreceptors, on the other KTT biases toward the emergent timing thus modulating the processes for rhythmic movements. Therefore, KTT appears able to render movements less audio dependent by relieving, at least partially, the central structures from time control and making available more resources for an augmented performance

The entorhino-hippocampal neurons of pre-symptomatic SOD1(G93A) mice

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease primarily characterized by degeneration of the motorneurons. Studies on animal models and ALS patients suggest the involvement of circuits not directly associated with motor control, such as those of the hippocampus, providing neurobiological bases for the cognitive impairments affecting a subpopulation of ALS patients. Also, the entorhino-hippocampal (EH) pathway is damaged in Alzheimer’s disease, a pathology having some etiopathogenic connections with ALS. Prompted by a lack of information on EH connections of the SOD1(G93A) mouse, we used a retrograde tract-tracing technique to investigate the morphology of EH projection neurons in these mice. Animals were anaesthetized and placed on stereotaxic frame. After opening of the skull and exposing the temporal region, animals received hippocampal pressure injections of a solution containing a retrograde tracer (10% biotinylated dextran amine; BDA), coinjected with NMDA, to promote tracer uptake. After 96h, mice were sacrified. Brains were dissected out and cut into 50 μm thick coronal sections. Selected sections were processed for immunofluorescence to visualize retrogradely labeled EH neurons. Sections containing the BDA injection points and the entorhinal cortex were collected. For each selected cell, optical sections were collected by Leica confocal microscope and imported into ImageJ (NIH) to perform the data analysis, conducted blind to genotype. Parameters investigated include: number of EH neurons, lengths of dendrite segments, and density of dendritic spines. The possible anomalies of EH neurons could provide relevant knowledge for the role of this circuitry as potential cause for cognitive impairment in ALS patients