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Ischemic injuries within the motor cortex result in functional deficits that may profoundly impact activities of daily living in patients. Current rehabilitation protocols achieve only limited recovery of motor abilities. The brain reorganizes spontaneously after injury, and it is believed that appropriately boosting these neuroplastic processes may restore function via recruitment of spared areas and pathways. Here I review studies on circuit reorganization, neuronal and glial plasticity and axonal sprouting following ischemic damage to the forelimb motor cortex, with a particular focus on rodent models. I discuss evidence pointing to compensatory take-over of lost functions by adjacent peri-lesional areas and the role of the contralesional hemisphere in recovery. One key issue is the need to distinguish “true” recovery (i.e. re-establishment of original movement patterns) from compensation in the assessment of post-stroke functional gains. I also consider the effects of physical rehabilitation, including robot-assisted therapy, and the potential mechanisms by which motor training induces recovery. Finally, I describe experimental approaches in which training is coupled with delivery of plasticizing drugs that render the remaining, undamaged pathways more sensitive to experience-dependent modifications. These combinatorial strategies hold promise for the definition of more effective rehabilitation paradigms that can be translated into clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Visual cortical areas in the two hemispheres interact via the corpus callosum, but the precise role of the callosal pathway in visual processing remains controversial. Here we have investigated the function of transcallosal projections in human primary visual cortex (V1). Visual evoked potentials (VEPs) triggered by grating stimuli of different contrasts were recorded before and after functional inactivation of the occipital cortex of one hemisphere via off-line low-frequency repetitive transcranial magnetic stimulation (rTMS; 0.5 Hz stimulation for 20 min). VEPs were recorded in V1 before (T0), immediately after (T1) and 45'' following the completion of rTMS (T2). We found that low-frequency rTMS had an inhibitory effect on VEPs amplitudes at all contrasts in the treated side. Remarkably, reduction of VEP amplitudes in the inhibited hemisphere at T1 was accompanied by an increase in VEP amplitudes in the contralateral side only at mid-high contrasts (50–90%). This disinhibitory effect was observed with both central and hemifield stimulation. No changes in VEP amplitudes were observed when rTMS was applied to a cortical site more anterior with respect to V1. These data provide the first evidence that a mechanism of transcallosal inhibition dampens neural responses at high contrasts in human visual cortex. [Copyright &y& Elsevier]

To investigate functional changes underlying photosensitivity, we studied the response of the visual cortex to low-frequency, inhibitory repetitive Transcranial Magnetic Stimulation (rTMS) in patients with photosensitive seizures and healthy volunteers. Visual evoked potentials (VEPs) triggered by grating stimuli of different contrasts were recorded in both hemispheres before and after functional inactivation of the occipital cortex of one side via low-frequency rTMS (0.5 Hz for 20 ′ ). VEPs were recorded before (T0), immediately after (T1) and 45 ′ following the completion of rTMS (T2). Baseline amplitudes of the early VEP components (N1 and P1) were enhanced in photosensitive subjects. At T1, rTMS produced an inhibitory effect on VEPs amplitudes at all contrasts in the targeted side, and a concurrent facilitation of responses in the contralateral hemisphere. While the relative variation with respect to pre-rTMS values was similar in photosensitive patients and controls at T1, robust changes appeared in the recovery phase (T2): visual responses recovered more quickly in the stimulated hemisphere, and disinhibition persisted in the contralateral side of photosensitive subjects. The rapid recovery of excitability and the persistent transcallosal disinhibition following perturbation of cortical activity may play a role in the pathophysiology of photosensitive epilepsy. [ABSTRACT FROM AUTHOR]

Objective To investigate functional changes underlying photosensitivity, we studied the response of the visual cortex to low-frequency, inhibitory repetitive transcranial magnetic stimulation (rTMS) in patients with photosensitive seizures and healthy volunteers. Methods Visual evoked potentials (VEPs) triggered by grating stimuli of different contrasts were recorded in both hemispheres before and after functional inactivation of the occipital cortex of one side via low-frequency rTMS (0.5 Hz for 20 ′ ). VEPs were recorded in before (T0), immediately after (T1) and 45 ′ following the completion of rTMS (T2). Results Baseline amplitudes of the early VEP components (N1 and P1) were enhanced in photosensitive subjects. At T1, rTMS produced an inhibitory effect on VEPs amplitudes at all contrasts in the targeted side, and a concurrent facilitation of responses in the contralateral hemisphere. While the relative variation with respect to pre-rTMS values was similar in photosensitive patients and controls at T1, robust changes appeared in the recovery phase (T2). Conclusion Visual responses recovered more quickly in the stimulated hemisphere, and disinhibition persisted in the contralateral side of photosensitive subjects. Key message The rapid recovery of excitability and the persistent transcallosal disinhibition following perturbation of cortical activity may play a role in the pathophysiology of photosensitive epilepsy. [ABSTRACT FROM AUTHOR]

A role for neurotrophins in regulating cortical developmental plasticity has clearly emerged in these last years. In this review we first present a summary of the early data on the action of NGF in visual cortical development and plasticity in the rat and of the actions of the other neurotrophins in the visual cortex of other mammals. In addition, in order to clarify the differerences in the results obtained with the various neurotrophins in different animal preparations we also report new data on the action of NGF, BDNF, NT3 and NT4 in the same preparation, namely the visual cortex of the rat. We discuss old and new results in a physiological model where different neurotrophins play different roles in regulating visual cortical development and plasticity by acting on different neural targets, such as LGN afferents, intracortical circuitry and subcortical afferents and propose a tentative scheme summarizing these actions. [ABSTRACT FROM AUTHOR]

Transcutaneous spinal Direct Current Stimulation (tsDCS) is a noninvasive technique based on the application of weak currents over spinal cord. We studied the effects of tsDCS on interhemispheric connectivity and visual processing by evaluating changes in ipsilateral Silent Period (iSP), Transcallosal Conduction Time (TCT) and hemifield Visual Evoked Potentials (hVEPs), before and at different intervals following sham, anodal and cathodal tsDCS (T10–T12 level, 2.0 mA, 20 ′ ). Motor Evoked Potentials (MEPs) were recorded from abductor pollicis brevis (APB), abductor hallucis (AH) and deltoid muscles. hVEPs were recorded bilaterally by reversal of a horizontal square wave grating. Anodal tsDCS increased TCT ( p < 0.001) and the interhemispheric delay for both the main VEP components (N1: p = 0.0003; P1: p < 0.0001), dampening iSP duration (APB: p < 0.0001; AH: p = 0.0005; deltoid: p < 0.0001), while cathodal stimulation elicited opposite effects ( p < 0.0001). tsDCS would be a promising therapeutic tool in managing a number of human diseases characterized by an impaired interhemispheric processing, with anodal stimulation leading to a functional disconnection between hemispheres. It could also be helpful as an early rehabilitation strategy in patients with acute brain lesions, when other non-invasive brain stimulation techniques are not indicated due to safety concerns. [ABSTRACT FROM AUTHOR]

In the present paper, we analyze local field potentials (LFPs) recorded from the secondary motor cortex (M2) and primary visual cortex (VI) of freely moving mice reared in environmental enrichment (EE) and standard condition (SC). We focus on the scaling properties of the signals by using an integrated approach combining three different techniques: the Higuchi method, detrended fluctuation analysis, and power spectrum. Each technique provides direct or indirect estimations of the Hurst exponent H and this prevents spurious identification of scaling properties in time-series analysis. It is well known that the power spectrum of an LFP signal scales as 1/fβ with ß > 0. Our results indicate the existence of a particular power spectrum scaling law 1/fβ with ß < 0 for low frequencies (f < 4 Hz) for both SC and EE rearing conditions. This type of scaling behavior is associated to the presence of anticorrelation in the corresponding LFP signals. Moreover, since EE is an experimental protocol based on the enhancement of sensorimotor stimulation, we study the possible effects of EE on the scaling properties of secondary motor cortex (M2) and primary visual cortex (VI). Notably, the difference between Hurst's exponents in EE and SC for individual cortical regions (M2) and (VI) is not statistically significant. On the other hand, using the detrended cross-correlation coefficient, we find that EE significantly reduces the functional coupling between secondary motor cortex (M2) and visual cortex (VI). [ABSTRACT FROM AUTHOR]

Highlights: [•] Otx2 overexpression results in an increased number of midbrain dopaminergic DA neurons. [•] Otx2-overexpressing mice show increased dopamine transporter expression and hypolocomotion. [•] Otx2-overexpressing mice show an increased number of parvalbumin-positive cells and a peculiar c-fos mRNA after KA seizures. [ABSTRACT FROM AUTHOR]

Abstract: In adult mammals, newborn neural precursor cells (NPCs) derived from either the subventricular zone (SVZ) or the subgranular zone (SGZ) migrate into the olfactory bulb and the dentate gyrus (DG), respectively, where some of them mature into excitatory and inhibitory neurons. There is increasing evidence that this neurogenesis process is important for some types of learning and synaptic plasticity and vice versa. Survivin, a member of the inhibitor-of-apoptosis protein (IAP) family, has been suggested to have a central role in the regulation of neurogenesis. The protein is abundantly expressed in nervous tissue during embryonic development while being restricted postnatally to proliferating and migrating NPCs in SVZ and SGZ. Here we examined adult SurvivinCamcre mice with a conditional deletion of the survivin gene in embryonic neurogenic regions. Although the deletion of survivin had no effect on basic excitability in DG and CA1-region, there was a marked impairment of long-term potentiation (LTP) in these areas. Our data support a function of survivin in hippocampal synaptic plasticity and learning and underline the importance of adult brain neurogenesis for proper operation of the hippocampal tri-synaptic circuit and the physiological functions that depend on it. [Copyright &y& Elsevier]

Abstract: Evidence indicates that accumulation of excitotoxic mediators, such as glutamate, contributes to neuronal damage after an ischaemic insult. It is not clear, however, whether this accumulation is due to excess synaptic release or to impaired uptake. To test a role for synaptic release, here we investigated the neuroprotective potential of the synaptic blocker botulinum neurotoxin E (BoNT/E), that prevents vesicle fusion via the cleavage of the SNARE (soluble NSF-attachment receptor) protein SNAP-25 (synaptosomal-associated protein of 25 kDa). Focal ischaemia was induced in vivo by infusing the potent vasoconstricting peptide endothelin-1 (ET-1) into the CA1 area of the hippocampus in adult rats; BoNT/E or vehicle were administered into the same site 20 min later. Injection of ET-1 was found to produce a transient and massive increase in glutamate release that was potently antagonized by BoNT/E. To assess whether blocking transmitter release translates into neuroprotection, the extent of the ischaemic damage was determined 24 h and 6 weeks after the insult. We found that BoNT/E administration consistently reduced the loss of CA1 pyramidal neurons at 24 h. The neuroprotective effect of BoNT/E, however, was no longer significant at 6 weeks. These data provide evidence that blockade of synaptic transmitter release delays neuronal cell death following focal brain ischaemia, and underline the importance of assessing long-term neuroprotection in experimental stroke studies. [Copyright &y& Elsevier]

• Robotic rehabilitation should be combined with neuromodulatory intervention. • Serotonin may support stroke recovery by inducing cortical disinhibition. • Combined treatment promoted recovery in general motor tests and manual dexterity. Despite recent progresses in robotic rehabilitation technologies, their efficacy for post-stroke motor recovery is still limited. Such limitations might stem from the insufficient enhancement of plasticity mechanisms, crucial for functional recovery. Here, we designed a clinically relevant strategy that combines robotic rehabilitation with chemogenetic stimulation of serotonin release to boost plasticity. These two approaches acted synergistically to enhance post-stroke motor performance. Indeed, mice treated with our combined therapy showed substantial functional gains that persisted beyond the treatment period and generalized to non-trained tasks. Motor recovery was associated with a reduction in electrophysiological and neuroanatomical markers of GABAergic neurotransmission, suggesting disinhibition in perilesional areas. To unveil the translational potentialities of our approach, we specifically targeted the serotonin 1A receptor by delivering Buspirone, a clinically approved drug, in stroke mice undergoing robotic rehabilitation. Administration of Buspirone restored motor impairments similarly to what observed with chemogenetic stimulation, showing the immediate translational potential of this combined approach to significantly improve motor recovery after stroke. [ABSTRACT FROM AUTHOR]

Glial-fibrillary-acidic-protein (GFAP) has recently drawn significant attention from the clinical environment as a promising biomarker. The pathologies which can be linked to the presence of GFAP in blood severely affect the human central nervous system. These pathologies are glioblastoma multiforme (GBM), traumatic brain injuries (TBIs), multiple sclerosis (MS), intracerebral hemorrhage (ICH), and neuromyelitis optica (NMO). Here, we develop three different detection strategies for GFAP, among the most popular in the biosensing field and never examined side by side within the experimental frame. We compare their capability of detecting GFAP in a clean-buffer and serum-matrix by using gold-coated quartz-crystal-microbalance (QCM) sensors. All the three detection strategies are based on antibodies, and each of them focuses on a key aspect of the biosensing process. The first is based on a polyethylene glycol (PEG) chain for antifouling, the second on a protein-G linker for controlling antibody-orientation, and the third on antibody-splitting and direct surface immobilization for high-surface coverage. Then, we select the best-performing protocol and validate its detection performance with an ultra-high-frequency (UHF) surface-acoustic-wave (SAW) based lab-on-chip (LoC). GFAP successful detection is demonstrated in a clean-buffer and serum-matrix at a concentration of 35 pM. This GFAP level is compatible with clinical diagnostics. This result suggests the use of our technology for the realization of a point-of-care biosensing platform for the detection of multiple brain-pathology biomarkers. • GFAP is linked to severe pathologies of the human central nervous system. • GFAP is a promising biomarker that can be found in circulating blood. • Three functionalization approaches for detecting GFAP with biosensors are developed. • The functionalization capability of detecting GFAP is firstly evaluated by QCM. • A new SAW biosensor is used for detecting diagnostic GFAP levels in serum-matrix. [ABSTRACT FROM AUTHOR]

Epilepsy is characterized by substantial network rearrangements leading to spontaneous seizures and little is known on how an epileptogenic focus impacts on neural activity in the contralateral hemisphere. Here, we used a model of unilateral epilepsy induced by injection of the synaptic blocker tetanus neurotoxin (TeNT) in the mouse primary visual cortex (V1). Local field potential (LFP) signals were simultaneously recorded from both hemispheres of each mouse in acute phase (peak of toxin action) and chronic condition (completion of TeNT effects). To characterize the neural electrical activities the corresponding LFP signals were analyzed with several methods of time series analysis. For the epileptic mice, the spectral analysis showed that TeNT determines a power redistribution among the different neurophysiological bands in both acute and chronic phases. Using linear and nonlinear interdependence measures in both time and frequency domains, it was found in the acute phase that TeNT injection promotes a reduction of the interhemispheric coupling for high frequencies (12-30 Hz) and small time lag (<20 ms), whereas an increase of the coupling is present for low frequencies (0.5-4 Hz) and long time lag (>40 ms). On the other hand, the chronic period is characterized by a partial or complete recovery of the interhemispheric interdependence level. Granger causality test and symbolic transfer entropy indicate a greater driving influence of the TeNT-injected side on activity in the contralateral hemisphere in the chronic phase. Lastly, based on experimental observations, we built a computational model of LFPs to investigate the role of the ipsilateral inhibition and exicitatory interhemispheric connections in the dampening of the interhemispheric coupling. The time evolution of the interhemispheric coupling in such a relevant model of epilepsy has been addressed here. [ABSTRACT FROM AUTHOR]

Photosensitive epilepsy (PE) is a form of epileptic seizure induced by several powerful visual stimuli. Cortical mechanisms underlying paroxysmal activity have been widely studied in several ways. Here, we employed rTMS in an attempt to disclose the role of callosal input in modulating cortical visual excitability in both healthy subjects and PE patients. We enrolled 10 healthy subjects (5 males and 5 females; mean age 16.8 ± 3.4 yrs) and 5 patients (15.9 ± 4.2 yrs). Visual evoked potentials (VEPs) triggered by grating stimuli of different contrasts were recorded before and after functional inactivation of the occipital cortex of one hemisphere via off-line low-frequency repetitive transcranial magnetic stimulation (rTMS; 0.5 Hz stimulation for 20 min). VEPs were recorded in V1 before (T0), immediately after (T1) and 45′ following the end of rTMS (T2). We found that low-frequency rTMS had an inhibitory effect on VEP amplitudes at all contrasts in the treated side in controls and patients. Reduction of VEP amplitudes in the inhibited hemisphere at T1 was accompanied by an increase in VEP amplitudes in the contralateral side at mid-high contrasts (50–90%) in healthy subjects ( p < 0.05). This disinhibitory effect was observed with both central and hemifield stimulation; in PE patients, we showed both a larger potentiating of VEPs amplitudes at T1 ( p < 0.01) and a persistence of the disinhibitory effect at T2 ( p < 0.01). No changes in VEP amplitudes were observed when rTMS was applied to a cortical site more anterior than V1. In patients with photosensitive epilepsy VEPs amplitude increases progressively when contrast rises; consequently there is no saturation of evoked responses. That could suggest an impairment of transcallosal inhibitory loops, underlying the phenomenon of contrast gain control. In fact, some forms of photosensitivity tend to improve spontaneously around 18 years age, the time at which is completed the maturation of trancallosal projections. [ABSTRACT FROM AUTHOR]