Secondary somatosensory and posterior insular cortices: a somatomotor hub for object prehension and manipulation movements.

The secondary somatosensory cortex (SII) and posterior insular cortex (pIC) are recognized for processing touch and movement information during hand manipulation in humans and non-human primates. However, their involvement in three-dimensional (3D) object manipulation remains unclear. To investigate neural activity related to hand manipulation in the SII/pIC, we trained two macaque monkeys to grasp three objects (a cone, a plate, and a ring) and engage in visual fixation on the object. Our results revealed that 19.4% (n = 50/257) of the task-related neurons in SII/pIC were active during hand manipulations, but did not respond to passive somatosensory stimuli. Among these neurons, 44% fired before hand-object contact (reaching to grasping neurons), 30% maintained tonic activity after contact (holding neurons), and 26% showed continuous discharge before and after contact (non-selective neurons). Object grasping-selectivity varied and was weak among these neurons, with only 24% responding to fixation of a 3D object (visuo-motor neurons). Even neurons unresponsive to passive visual stimuli showed responses to set-related activity before the onset of movement (42%, n = 21/50). Our findings suggest that somatomotor integration within SII/pIC is probably integral to all prehension sequences, including reaching, grasping, and object manipulation movements. Moreover, the existence of a set-related activity within SII/pIC may play a role in directing somatomotor attention during object prehension-manipulation in the absence of vision. Overall, SII/pIC may play a role as a somatomotor hub within the lateral grasping network that supports the generation of intentional hand actions based on haptic information.

Nicotinic acetylcholine receptors and epilepsy.

Despite recent advances in understanding the causes of epilepsy, especially the genetic, comprehending the biological mechanisms that lead to the epileptic phenotype remains difficult. A paradigmatic case is constituted by the epilepsies caused by altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions in mature as well as developing brain. The ascending cholinergic projections exert potent control of forebrain excitability, and wide evidence implicates nAChR dysregulation as both cause and effect of epileptiform activity. First, tonic-clonic seizures are triggered by administration of high doses of nicotinic agonists, whereas non-convulsive doses have kindling effects. Second, sleep-related epilepsy can be caused by mutations on genes encoding nAChR subunits widely expressed in the forebrain (CHRNA4, CHRNB2, CHRNA2). Third, in animal models of acquired epilepsy, complex time-dependent alterations in cholinergic innervation are observed following repeated seizures. Heteromeric nAChRs are central players in epileptogenesis. Evidence is wide for autosomal dominant sleep-related hypermotor epilepsy (ADSHE). Studies of ADSHE-linked nAChR subunits in expression systems suggest that the epileptogenic process is promoted by overactive receptors. Investigation in animal models of ADSHE indicates that expression of mutant nAChRs can lead to lifelong hyperexcitability by altering i) the function of GABAergic populations in the mature neocortex and thalamus, ii) synaptic architecture during synaptogenesis. Understanding the balance of the epileptogenic effects in adult and developing networks is essential to plan rational therapy at different ages. Combining this knowledge with a deeper understanding of the functional and pharmacological properties of individual mutations will advance precision and personalized medicine in nAChR-dependent epilepsy.

Close facial emotions enhance physiological responses and facilitate perceptual discrimination.

Accumulating evidence indicates that the peripersonal space (PPS) constitutes a privileged area for efficient processing of proximal stimuli, allowing to flexibly adapt our behavior both to the physical and social environment. Whether and how behavioral and physiological signatures of PPS relate to each other in emotional contexts remains, though, elusive. Here, we addressed this question by having participants to discriminate male from female faces depicting different emotions (happiness, anger or neutral) and presented at different distances (50 cm-300 cm) while we measured the reaction time and accuracy of their responses, as well as pupillary diameter, heart rate and heart rate variability. Results showed facilitation of participants' performances (i.e., faster response time) when faces were presented close compared to far from the participants, even when controlling for retinal size across distances. These behavioral effects were accompanied by significant modulation of participants' physiological indexes when faces were presented in PPS. Interestingly, both PPS representation and physiological signals were affected by features of the seen faces such as the emotional valence, its sex and the participants' sex, revealing the profound impact of social context onto the autonomic state and behavior within PPS. Together, these findings suggest that both external and internal signals contribute in shaping PPS representation.

Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology.

Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic focal seizures, mainly arising in the neocortex during non-rapid eye movements (NREM) sleep. The familial form is autosomal dominant SHE (ADSHE), which can be caused by mutations in genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR), Na+-gated K+ channels, as well as non-channel signaling proteins, such as components of the gap activity toward rags 1 (GATOR1) macromolecular complex. The causative genes may have different roles in developing and mature brains. Under this respect, nicotinic receptors are paradigmatic, as different pathophysiological roles are exerted by distinct nAChR subunits in adult and developing brains. The widest evidence concerns α4 and ß2 subunits. These participate in heteromeric nAChRs that are major modulators of excitability in mature neocortical circuits as well as regulate postnatal synaptogenesis. However, growing evidence implicates mutant α2 subunits in ADSHE, which poses interpretive difficulties as very little is known about the function of α2-containing (α2*) nAChRs in the human brain. Planning rational therapy must consider that pharmacological treatment could have different effects on synaptic maturation and adult excitability. We discuss recent attempts towards precision medicine in the mature brain and possible approaches to target developmental stages. These issues have general relevance in epilepsy treatment, as the pathogenesis of genetic epilepsies is increasingly recognized to involve developmental alterations.

Acute and Chronic Dopaminergic Depletion Differently Affect Motor Thalamic Function.

The motor thalamus (MTh) plays a crucial role in the basal ganglia (BG)-cortical loop in motor information codification. Despite this, there is limited evidence of MTh functionality in normal and Parkinsonian conditions. To shed light on the functional properties of the MTh, we examined the effects of acute and chronic dopamine (DA) depletion on the neuronal firing of MTh neurons, cortical/MTh interplay and MTh extracellular concentrations of glutamate (GLU) and gamma-aminobutyric acid (GABA) in two states of DA depletion: acute depletion induced by the tetrodotoxin (TTX) and chronic denervation obtained by 6-hydroxydopamine (6-OHDA), both infused into the medial forebrain bundle (MFB) in anesthetized rats. The acute TTX DA depletion caused a clear-cut reduction in MTh neuronal activity without changes in burst content, whereas the chronic 6-OHDA depletion did not modify the firing rate but increased the burst firing. The phase correlation analysis underscored that the 6-OHDA chronic DA depletion affected the MTh-cortical activity coupling compared to the acute TTX-induced DA depletion state. The TTX acute DA depletion caused a clear-cut increase of the MTh GABA concentration and no change of GLU levels. On the other hand, the 6-OHDA-induced chronic DA depletion led to a significant reduction of local GABA and an increase of GLU levels in the MTh. These data show that MTh is affected by DA depletion and support the hypothesis that a rebalancing of MTh in the chronic condition counterbalances the profound alteration arising after acute DA depletion state.

Deep brain stimulation of the pedunculopontine nucleus modulates subthalamic pathological oscillations.

Low frequency deep brain stimulation (DBS) of the pedunculopontine nucleus area (PPNa) has been proposed as a novel surgical target for gait dysfunction in the late stage of Parkinson's disease (PD). Since the mid-2000s, we have shown that intrasurgical delivery of stimulation in the pontine tegmentum affects the firing activity in the subthalamic nucleus (STN), but its effect on STN oscillatory rhythms has not been studied. Neuronal oscillations detected by local field potential (LFPs) have great importance, since they express complex movement-related behavior such as locomotion. Therefore, we examined the effect of three PPNa-DBS stimulation protocols (at 10, 25 and 80 Hz) on the STN oscillatory activity of PD patients. We focused on the anti-kinetic beta (ß, 15-30 Hz), the pro-kinetic gamma (γ, 60-90 Hz) and "gait-related" alpha (α, 7-12 Hz) bands. We hypothesized that modulation of STN oscillations might have clinical relevance in the PPNa-mediated effects. PPNa stimulation at 25 and 80 Hz decreased the power of the STN ß band by 33.94 and 40.22%, respectively. PPNa-DBS did not affect the other two bands with a tendency to suppress α power, while γ oscillation increased. Our results suggest that the anti-kinetic ß band is the oscillation most sensitive to PPNa-DBS despite the negligible clinical efficacy on bradykinesia. However, how these changes interact reciprocally with the cortex or are counterbalanced by lower brainstem/spinal pathways remain to be elucidated. Our observation might turn out to be helpful in new protocols designed with adaptive DBS supporting the addition of PPN implantation in PD patients experiencing declining efficacy of STN-DBS.

Reprint of "Animal models of early-stage Parkinson's disease and acute dopamine deficiency to study compensatory neurodegenerative mechanisms".

Parkinson's disease is a common neurodegenerative disease characterized by a widely variety of motor and non-motor symptoms. While the motor deficits are only visible following a severe dopamine depletion, neurodegenerative process and some non-motor symptoms are manifested years before the motor deficits. Importantly, chronic degeneration of dopaminergic neurons leads to the development of compensatory mechanisms that play roles in the progression of the disease and the response to anti-parkinsonian therapies. The identification of these mechanisms will be of great importance for improving our understanding of factors with important contributions to the disease course and the underlying adaptive process. To date, most of the data obtained from animal models reflect the late, chronic, dopamine-depleted states, when compensatory mechanisms have already been established. Thus, adequate animal models with which researchers are able to dissect early- and late-phase mechanisms are necessary. Here, we reviewed the literature related to animal models of early-stage PD and pharmacological treatments capable of inducing acute dopamine impairments and/or depletion, such as reserpine, haloperidol and tetrodotoxin. We highlighted the advantages, limitations and the future prospective uses of these models, as well as their applications in the identification of novel agents for treating this neurological disorder.

Animal models of early-stage Parkinson's disease and acute dopamine deficiency to study compensatory neurodegenerative mechanisms.

Parkinson's disease is a common neurodegenerative disease characterized by a widely variety of motor and non-motor symptoms. While the motor deficits are only visible following a severe dopamine depletion, neurodegenerative process and some non-motor symptoms are manifested years before the motor deficits. Importantly, chronic degeneration of dopaminergic neurons leads to the development of compensatory mechanisms that play roles in the progression of the disease and the response to anti-parkinsonian therapies. The identification of these mechanisms will be of great importance for improving our understanding of factors with important contributions to the disease course and the underlying adaptive process. To date, most of the data obtained from animal models reflect the late, chronic, dopamine-depleted states, when compensatory mechanisms have already been established. Thus, adequate animal models with which researchers are able to dissect early- and late-phase mechanisms are necessary. Here, we reviewed the literature related to animal models of early-stage PD and pharmacological treatments capable of inducing acute dopamine impairments and/or depletion, such as reserpine, haloperidol and tetrodotoxin. We highlighted the advantages, limitations and the future prospective uses of these models, as well as their applications in the identification of novel agents for treating this neurological disorder.

Data on thermal infrared imaging in laboratory non-human primates: Pleasant touch determines an increase in nasal skin temperature without affecting that of the eye lachrymal sites.

The data described here relate to the article entitled "The effect of pleasant touch on nose skin temperature, heart rate and heart rate variability: preliminary results in a male laboratory rhesus monkey" (Grandi and Heinzl, 2016) [1]. The cited paper and article here present additional material which represents the first evidence of the effect of pleasant touch in non-human primates in terms of skin temperature change, as recorded by means of infrared thermography. The sweep is considered a pleasant touch for monkeys. Here we forward preliminary evidence concerning the modulation of the eye lachrymal site temperature while a monkey received sweeps to the back from a familiar experimenter, and at different speeds (Grandi and Heinzl, 2016) [1].

Single Neurons in the Insular Cortex of a Macaque Monkey Respond to Skin Brushing: Preliminary Data of the Possible Representation of Pleasant Touch.

Pleasant touch may serve as a foundation for affiliative behavior, providing a mechanism for the formation and maintenance of social bonds among conspecifics. In humans, this touch is usually referred to as the caress. Dynamic caressing performed on the hairy skin with a velocity of 1-10 cm/s is perceived as being pleasant and determines positive cardio-physiological effects. Furthermore, imaging human studies show that affiliative touch activates the posterior insular cortex (pIC). Recently, it was demonstrated that pleasant touch in monkeys (i.e., sweeping in a grooming-like manner) is performed with velocities similar to those characteristics of human caress (9.31 cm/s), and causes similarly positive autonomic effects, if performed with velocity of 5 cm/s and 10 cm/s, but not lower or higher. Due to similarities between the human caress and non-human primate sweeping, we investigated for the first time whether single neurons of the perisylvian regions (secondary somatosensory cortex [SII] and pIC) of a rhesus monkey can process sweeping touch differently depending on the stimulus speed. We applied stimulation with two speeds: one that optimally induces positive cardio-physiological effects in the monkey who receives it, and includes the real speed of sweep (5-15 cm/s, sweep fast), and a non-optimal speed (1-5 cm/s, sweep slow). The results show that single neurons of insular cortex differently encode the stimulus speed. In particular, even the majority of recorded somatosensory neurons (82.96%) did not discriminate the two speeds, a small set of neurons (16.59%) were modulated just during the sweep fast. These findings represent the first evidence that single neurons of the non-human primates insular cortex can code affiliative touch, highlighting the similarity between human and non-human primates' social touch systems. This study constitutes an important starting point to carry out deeper investigation on neuronal processing of pleasant sweeping in the central nervous system.

How good is this food? A study on dogs' emotional responses to a potentially pleasant event using infrared thermography.

Understanding how animals express positive emotions is becoming an interesting and promising area of research in the study of animal emotions and affective experiences. In the present study, we used infrared thermography in combination with behavioral measures, heart rate (HR) and heart rate variability (HRV), to investigate dogs' emotional responses to a potentially pleasant event: receiving palatable food from the owner. Nineteen adult pet dogs, 8 females and 11 males, were tested and their eye temperature, HR, HRV and behavior were recorded during a 30-minutestestconsisting of three 10-minute consecutive phases: Baseline (Phase 1), positive stimulation through the administration of palatable treats (Feeding, Phase 2) and Post-feeding condition following the positive stimulation (Phase 3). Dogs' eye temperature and mean HR significantly increased during the positive stimulation phase compared with both Baseline and Post-feeding phases. During the positive stimulation with food (Phase 2), dogs engaged in behaviors indicating a positive emotional state and a high arousal, being focused on food treats and increasing tail wagging. However, there was no evidence of an increase in HRV during Phase 2 compared to the Phase 1, with SDNN significantly increasing only in Phase 3, after the positive stimulation occurred. Overall results point out that IRT may be a useful tool in assessing emotional states in dogs in terms of arousal but fails to discriminate emotional valence, whose interpretation cannot disregard behavioral indexes.

The Physiological Effect of Human Grooming on the Heart Rate and the Heart Rate Variability of Laboratory Non-Human Primates: A Pilot Study in Male Rhesus Monkeys.

Grooming is a widespread, essential, and complex behavior with social and affiliative valence in the non-human primate world. Its impact at the autonomous nervous system level has been studied during allogrooming among monkeys living in a semi-naturalistic environment. For the first time, we investigated the effect of human grooming to monkey in a typical experimental situation inside laboratory. We analyzed the autonomic response of male monkeys groomed by a familiar human (experimenter), in terms of the heart rate (HR) and heart rate variability (HRV) at different body parts. We considered the HRV in both the time (SDNN, RMSSD, and RMSSD/SDNN) and the frequency domain (HF, LF, and LF/HF). For this purpose, we recorded the electrocardiogram of two male rhesus monkeys seated in a primate chair while the experimenter groomed their mouth, chest, or arm. We demonstrated that (1) the grooming carried out by a familiar human determined a decrement of the HR and an increment of the HRV; (2) there was a difference in relation to the groomed body part. In particular, during grooming the mouth the HRV was higher than during grooming the arm and the chest. Taken together, the results represent the first evidence that grooming carried out by a familiar human on experimental monkeys has the comparable positive physiological effect of allogrooming between conspecifics. Moreover, since the results underlined the positive modulation of both HR and HRV, the present study could be a starting point to improve the well-being of non-human primates in experimental condition by means of grooming by a familiar person.

Predictive coding accounts of shared representations in parieto-insular networks.

The discovery of mirror neurons in the ventral premotor cortex (area F5) and inferior parietal cortex (area PFG) in the macaque monkey brain has provided the physiological evidence for direct matching of the intrinsic motor representations of the self and the visual image of the actions of others. The existence of mirror neurons implies that the brain has mechanisms reflecting shared self and other action representations. This may further imply that the neural basis self-body representations may also incorporate components that are shared with other-body representations. It is likely that such a mechanism is also involved in predicting other's touch sensations and emotions. However, the neural basis of shared body representations has remained unclear. Here, we propose a neural basis of body representation of the self and of others in both human and non-human primates. We review a series of behavioral and physiological findings which together paint a picture that the systems underlying such shared representations require integration of conscious exteroception and interoception subserved by a cortical sensory-motor network involving parieto-inner perisylvian circuits (the ventral intraparietal area [VIP]/inferior parietal area [PFG]-secondary somatosensory cortex [SII]/posterior insular cortex [pIC]/anterior insular cortex [aIC]). Based on these findings, we propose a computational mechanism of the shared body representation in the predictive coding (PC) framework. Our mechanism proposes that processes emerging from generative models embedded in these specific neuronal circuits play a pivotal role in distinguishing a self-specific body representation from a shared one. The model successfully accounts for normal and abnormal shared body phenomena such as mirror-touch synesthesia and somatoparaphrenia. In addition, it generates a set of testable experimental predictions.

Somato-motor haptic processing in posterior inner perisylvian region (SII/pIC) of the macaque monkey.

The posterior inner perisylvian region including the secondary somatosensory cortex (area SII) and the adjacent region of posterior insular cortex (pIC) has been implicated in haptic processing by integrating somato-motor information during hand-manipulation, both in humans and in non-human primates. However, motor-related properties during hand-manipulation are still largely unknown. To investigate a motor-related activity in the hand region of SII/pIC, two macaque monkeys were trained to perform a hand-manipulation task, requiring 3 different grip types (precision grip, finger exploration, side grip) both in light and in dark conditions. Our results showed that 70% (n = 33/48) of task related neurons within SII/pIC were only activated during monkeys' active hand-manipulation. Of those 33 neurons, 15 (45%) began to discharge before hand-target contact, while the remaining neurons were tonically active after contact. Thirty-percent (n = 15/48) of studied neurons responded to both passive somatosensory stimulation and to the motor task. A consistent percentage of task-related neurons in SII/pIC was selectively activated during finger exploration (FE) and precision grasping (PG) execution, suggesting they play a pivotal role in control skilled finger movements. Furthermore, hand-manipulation-related neurons also responded when visual feedback was absent in the dark. Altogether, our results suggest that somato-motor neurons in SII/pIC likely contribute to haptic processing from the initial to the final phase of grasping and object manipulation. Such motor-related activity could also provide the somato-motor binding principle enabling the translation of diachronic somatosensory inputs into a coherent image of the explored object.