Effects of chronic iTBS‐rTMS and enriched environment on visual cortex early critical period and visual pattern discrimination in dark‐reared rats

Early cortical critical period resembles a state of enhanced neuronal plasticity enabling the establishment of specific neuronal connections during first sensory experience. Visual performance with regard to pattern discrimination is impaired if the cortex is deprived from visual input during the critical period. We wondered how unspecific activation of the visual cortex before closure of the critical period using repetitive transcranial magnetic stimulation (rTMS) could affect the critical period and the visual performance of the experimental animals. Would it cause premature closure of the plastic state and thus worsen experience‐dependent visual performance, or would it be able to preserve plasticity? Effects of intermittent theta‐burst stimulation (iTBS) were compared with those of an enriched environment (EE) during dark‐rearing (DR) from birth. Rats dark‐reared in a standard cage showed poor improvement in a visual pattern discrimination task, while rats housed in EE or treated with iTBS showed a performance indistinguishable from rats reared in normal light/dark cycle. The behavioral effects were accompanied by correlated changes in the expression of brain‐derived neurotrophic factor (BDNF) and atypical PKC (PKCζ/PKMζ), two factors controlling stabilization of synaptic potentiation. It appears that not only nonvisual sensory activity and exercise but also cortical activation induced by rTMS has the potential to alleviate the effects of DR on cortical development, most likely due to stimulation of BDNF synthesis and release. As we showed previously, iTBS reduced the expression of parvalbumin in inhibitory cortical interneurons, indicating that modulation of the activity of fast‐spiking interneurons contributes to the observed effects of iTBS. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 19–33, 2016     

Interaction of Motor Training and Intermittent Theta Burst Stimulation in Modulating Motor Cortical Plasticity: Influence of BDNF Val66Met Polymorphism

Cortical physiology in human motor cortex is influenced by behavioral motor training (MT) as well as repetitive transcranial magnetic stimulation protocol such as intermittent theta burst stimulation (iTBS). This study aimed to test whether MT and iTBS can interact with each other to produce additive changes in motor cortical physiology. We hypothesized that potential interaction between MT and iTBS would be dependent on BDNF Val66Met polymorphism, which is known to affect neuroplasticity in the human motor cortex. Eighty two healthy volunteers were genotyped for BDNF polymorphism. Thirty subjects were assigned for MT alone, 23 for iTBS alone, and 29 for MT + iTBS paradigms. TMS indices for cortical excitability and motor map areas were measured prior to and after each paradigm. MT alone significantly increased the motor cortical excitability and expanded the motor map areas. The iTBS alone paradigm also enhanced excitability and increased the motor map areas to a slightly greater extent than MT alone. A combination of MT and iTBS resulted in the largest increases in the cortical excitability, and the representational motor map expansion of MT + iTBS was significantly greater than MT or iTBS alone only in Val/Val genotype. As a result, the additive interaction between MT and iTBS was highly dependent on BDNF Val66Met polymorphism. Our results may have clinical relevance in designing rehabilitative strategies that combine therapeutic cortical stimulation and physical exercise for patients with motor disabilities.     

Pulsed electromagnetic fields induced femoral metaphyseal bone thickness changes in the rat

The effect of 1 Hz, 30 mT pulsed magnetic fields on young adult rat femoral metaphyseal bone thickness was assessed. Ten same litter, female Wistar rats were studied; five of them underwent 30 min magnetic stimulation sessions for 20 consecutive days. The anterior and posterior cortical, as well as trabecular bone transverse thicknesses were measured. The results obtained under clear field microscopy in stimulated and control histological cuts were (in microm) 398 +/- 32 versus 260 +/- 22 (P = 0.002), 380 +/- 68 versus 252 +/- 21 (P = 0.03), and 168 +/- 11 versus 112 +/- 11 (P = 0.002), respectively. The transcranial magnetic stimulation system, approved for human therapy, generates pulsed electromagnetic fields, which induce a significant thickness increase in cortical and trabecular in vivo stimulated bone tissues. This is the first time this effect in healthy animals is shown.     

Gender differences in changes of motor cortex excitability during elevated blood lactate levels

Gender differences in cortical excitability have been detected by using transcranial magnetic stimulation (TMS). The present study was carried out to compare the effects of high blood lactate levels, induced by performing a maximal exhausting exercise, on the excitability of the primary motor cortex in young male and female athletes. The study was carried out on 21 young males and 20 females from the Middle Distance Track Team of our university. Before the exercise, at the end, as well as 5 and 10 min after the conclusion, venous blood lactate and glucose were measured and excitability of the motor cortex was evaluated by using TMS. We observed a similar enhancement of excitability of primary motor cortex, concomitantly with an increase of blood lactate, in both young male and female athletes. However, the improvement was significantly higher (p < 0.05) in women (37.4% ± 3.97) than in men (42.0% ± 6.43), suggesting a greater sensitiveness of female cerebral cortex to blood lactate.     

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.     

Dyskinesia in Parkinson's disease: mechanisms and current non‐pharmacological interventions

Dopamine replacement therapy in Parkinson's disease is associated with several unwanted effects, of which dyskinesia is the most disabling. The development of new therapeutic interventions to reduce the impact of dyskinesia in Parkinson's disease is therefore a priority need. This review summarizes the key molecular mechanisms that underlie dyskinesia. The role of dopamine receptors and their associated signaling mechanisms including dopamine‐cAMP‐regulated neuronal phosphoprotein, extracellular signal‐regulated kinase, mammalian target of rapamycin, mitogen and stress‐activated kinase‐1 and Histone H3 are summarized, along with an evaluation of the role of cannabinoid and nicotinic acetylcholine receptors. The role of synaptic plasticity and animal behavioral results on dyskinesia are also evaluated. The most recent therapeutic advances to treat Parkinson's disease are discussed, with emphasis on the possibilities and limitations of non‐pharmacological interventions such as physical activity, deep brain stimulation, transcranial magnetic field stimulation and cell replacement therapy. The review suggests new prospects for the management of Parkinson's disease‐associated motor symptoms, especially the development of dyskinesia.

     

Unilateral lesion of the nigrostriatal pathway decreases the response of fast-spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat

5-Hydroxytryptamine_1A (5-HT_1A) receptors are expressed in the prefrontal cortical interneurons. Among these interneurons, calcium-binding protein parvalbumin (PV)-positive fast spiking (FS) interneurons play an important role in regulatory function of the prefrontal cortex. In the present study, the response of medial prefrontal cortex (mPFC) FS interneurons to the selective 5-HT_1A receptor agonist 8-OH-DPAT and change in expression of 5-HT_1A receptor on PV-positive neurons were examined in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (SNc) by using extracellular recording and double-labeling immunofluorescence histochemistry. Systemic administration of 8-OH-DPAT (1-243 μg/kg, i.v.) dose-dependently inhibited the mean firing rate of the FS interneurons in sham-operated and the lesioned rats, respectively. The cumulative doses producing inhibition in the lesioned rats (243 μg/kg) was significantly higher than that of sham-operated rats (27 μg/kg). Furthermore, the local application of 8-OH-DPAT (0.01 μg) in the mPFC inhibited the FS interneurons in sham-operated rats, while having no effect on firing rate of the FS interneurons in the lesioned rats. In contrast to sham-operated rats, the lesion of the SNc in rats did not cause the change of PV-positive neurons in the prelimbic prefrontal cortex, a subregion of the mPFC, whereas the lesion of the SNc markedly reduced in percentage of PV-positive neurons expressing 5-HT_1A receptors. Our results indicate that degeneration of the nigrostriatal pathway results in the decreased response of FS interneurons in the mPFC to 5-HT_1A receptor stimulation, which attributes to down-regulation of 5-HT_1A receptor expression in these interneurons.     

Relationship between blood lactate and cortical excitability between taekwondo athletes and non-athletes after hand-grip exercise

Objectives: In taekwondo competitions, fatigue has a large influence on performance. Recent studies have reported that the excitability in the primary hand motor cortex, investigated with transcranial magnetic stimulation (TMS), is enhanced at the end of a maximal exercise and that this improvement correlates with blood lactate. The aim of the present study was to investigate the relationship between blood lactate and cortical excitability in taekwondo athletes and non-athletes.

Methods: The excitability of the primary motor cortex was measured before and after fatiguing hand-grip exercise by TMS. Capillary blood lactate was measured at rest (pre-test), at the end (0?min), and at 3 and 10?min after the exercise by using a “Lactate Pro” portable lactate analyzer.

Results: Significant differences in cortical excitability between the two groups were found after the exercise (p?p?Conclusion: The present findings showed changes in the excitability in the athletes group and also in the non-athletes group. However, blood lactate seems to have the greater effect in trained subjects compared to untrained subjects. In fact, it appears that, during extremely intensive exercise in taekwondo athletes, lactate may delay the onset of fatigue not only by maintaining the excitability of muscle, but also by increasing the excitability of the primary motor cortex more than in non-athletes.     

Do changes in spinal reflex excitability elicited by transcranial magnetic stimulation differ based on the site of cerebellar stimulation?

Abstract

Purpose: The present study aimed to investigate whether spinal reflex excitability is influenced by the site of cerebellar transcranial magnetic stimulation (C-TMS).

Materials and methods: Fourteen healthy volunteers (mean age: 24.6?±?6.6?years [11 men]) participated. Participants lay on a bed in the prone position, with both ankle joints fixed to prevent unwanted movement. Right tibial nerve stimulation was provided to elicit the H-reflex in the right soleus muscle. Conditioning transcranial magnetic stimulation (TMS) was delivered at one of the following sites 110?ms prior to tibial stimulation: right, central, or left cerebellum; midline parietal (Pz) region; or sham stimulation. A total of 10 test trials were included for each condition, in random order. The unconditioned and conditioned H-reflexes were measured during random inter-test trials, and the cerebellar spinal facilitation (CSpF) ratios for each site were calculated (the ratio of conditioned to unconditioned H-reflexes). CSpF ratios were compared among TMS sites.

Results: CSpF ratios were significantly higher at cerebellar sites than at the Pz site or during sham stimulation. However, there was no significant difference in CSpF ratio among cerebellar sites.

Conclusions: TMS conditioning over any part of the cerebellum facilitated the excitability of the spinal motoneuron pool. Facilitation of the H-reflex due to C-TMS may involve the effects of the bilateral descending tract of the spinal cord on the spinal motoneuron pool. Alternatively, direct brainstem stimulation may have activated portions of the bilateral descending tract of the spinal cord.     

Sleep deprivation in depression stabilizing antidepressant effects by repetitive transcranial magnetic stimulation

Partial sleep deprivation (PSD) has a profound and rapid effect on depressed mood. However, the transient antidepressant effect of PSD - most patients relapse after one night of recovery sleep - is limiting the clinical use of this method. Using a controlled, balanced parallel design we studied, whether repetitive transcranial magnetic stimulation (rTMS) applied in the morning after PSD is able to prevent this relapse. 20 PSD responders were randomly assigned to receive either active or sham stimulation during the following 4 days after PSD. Active stimulation prolonged significantly (p < 0.001) the antidepressant effect of PSD up to 4 days. This finding indicates that rTMS is an efficacious method to prevent relapse after PSD.     

Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons

An understanding of the diversity of cortical GABAergic interneurons is critical to understand the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+-binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for ～40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents ～30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layerIV. The 5HT3aR group, which also accounts for ～30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that do not express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests that they might be involved in shaping cortical circuits during specific brain states and behavioral contexts.     

Fgfr1 Inactivation in the Mouse Telencephalon Results in Impaired Maturation of Interneurons Expressing Parvalbumin

Fibroblast growth factors (Fgfs) and their receptors (Fgfr) are expressed in the developing and adult CNS. Previous studies demonstrated a decrease in cortical interneurons and locomotor hyperactivity in mice with a conditional Fgfr1 deletion generated in radial glial cells during midneurogenesis (Fgfr1^f/f;hGfapCre+). Here, we report earlier and more extensive inactivation of Fgfr1 in neuroepithelial cells of the CNS (Fgfr1^f/f;NesCre+). Similar to findings in Fgfr1^f/f;hGfapCre+ mice, parvalbumin positive (PV+) cortical interneurons are also decreased in the neocortex of Fgfr1f/f;NesCre+ mice when compared to control littermates (Fgfr1f/f). Fgfr1f/f;NesCre+ embryos do not differ from controls in the initial specification of GABAergic cells in the ganglionic eminence (GE) as assessed by in situ hybridization for Dlx2, Mash1 and Nkx2. Equal numbers of GABAergic neuron precursors genetically labeled with green fluorescent protein (GFP) were observed at P0 in Fgfr1^f/f;hGfapCre+;Gad1-GFP mutant mice. However, fewer GFP+ and GFP+/PV+ interneurons were observed in these mutants at adulthood, indicating that a decrease in cortical interneuron markers is occurring postnatally. Fgfr1 is expressed in cortical astrocytes in the postnatal brain. To test whether the astrocytes of mice lacking Fgfr1 are less capable of supporting interneurons, we co-cultured wild type Gad1-GFP+ interneuron precursors isolated from the medial GE (MGE) with astrocytes from Fgfr1f/f control or Fgfr1^f/f;hGfapCre+ mice. Interneurons grown on Fgfr1 deficient astrocytes had small soma size and fewer neurites per cell, but no differences in cell survival. Decreased soma size of Gad67 immunopositive interneurons was also observed in the cortex of adult Fgfr1^f/f;NesCre+ mice. Our data indicate that astrocytes from Fgfr1 mutants are impaired in supporting the maturation of cortical GABAergic neurons in the postnatal period. This model may elucidate potential mechanisms of impaired PV interneuron maturation relevant to neuropsychiatric disorders that develop in childhood and adolescence.     

Sociability development in mice with cell‐specific deletion of the NMDA receptor NR1 subunit gene

Social affiliative behavior is an important component of everyday life in many species and is likely to be disrupted in disabling ways in various neurodevelopmental and neuropsychiatric disorders. Therefore, determining the mechanisms involved in these processes is crucial. A link between N‐methyl‐d ‐aspartate (NMDA) receptor function and social behaviors has been clearly established. The cell types in which NMDA receptors are critical for social affiliative behavior, however, remain unclear. Here, we use mice carrying a conditional allele of the NMDA R1 subunit to address this question. Mice bearing a floxed NMDAR1 (NR1) allele were crossed with transgenic calcium/calmodulin‐dependent kinase IIα (CaMKIIα)‐Cre mice or parvalbumin (PV)‐Cre mice targeting postnatal excitatory forebrain or PV‐expressing interneurons, respectively, and assessed using the three‐chambered Social Approach Test. We found that deletion of NR1 in PV‐positive interneurons had no effect on social sniffing, but deletion of NR1 in glutamatergic pyramidal cells resulted in a significant increase in social approach behavior, regardless of age or sex. Therefore, forebrain excitatory neurons expressing NR1 play an important role in regulating social affiliative behavior.     

Effects of high frequency electromagnetic field (EMF) emitted by mobile phones on the human motor cortex

We investigated whether the pulsed high frequency electromagnetic field (EMF) emitted by a mobile phone has short term effects on the human motor cortex. We measured motor evoked potentials (MEPs) elicited by single pulse transcranial magnetic stimulation (TMS), before and after mobile phone exposure (active and sham) in 10 normal volunteers. Three sites were stimulated (motor cortex (CTX), brainstem (BST) and spinal nerve (Sp)). The short interval intracortical inhibition (SICI) of the motor cortex reflecting GABAergic interneuronal function was also studied by paired pulse TMS method. MEPs to single pulse TMS were also recorded in two patients with multiple sclerosis showing temperature dependent neurological symptoms (hot bath effect). Neither MEPs to single pulse TMS nor the SICI was affected by 30 min of EMF exposure from mobile phones or sham exposure. In two MS patients, mobile phone exposure had no effect on any parameters of MEPs even though conduction block occurred at the corticospinal tracts after taking a bath. As far as available methods are concerned, we did not detect any short-term effects of 30 min mobile phone exposure on the human motor cortical output neurons or interneurons even though we can not exclude the possibility that we failed to detect some mild effects due to a small sample size in the present study. This is the first study of MEPs after electromagnetic exposure from a mobile phone in neurological patients.     

Therapeutic staff exposure to magnetic field pulses during TMS/rTMS treatments

Transcranial magnetic stimulation or repetitive transcranial magnetic stimulation (TMS/rTMS) is currently being used in treatments of the central nervous system diseases, for instance, depressive states. The principles of localized magnetic stimulation are summarized and the risk and level of occupational field exposure of the therapeutic staff is analyzed with reference to ICNIRP guidelines for pulses below 100 kHz. Measurements and analysis of the occupational exposure to magnetic fields of the staff working with TMS/rTMS are presented.     

Enhancement of spike-timing precision by autaptic transmission in neocortical inhibitory interneurons

In vivo studies suggest that precise firing of neurons is important for correct sensory representation. Principal neocortical neurons fire imprecisely when repeatedly activated by fixed sensory stimuli or current depolarizations. Here we show that in contrast to pyramidal neurons, firing in neocortical GABAergic fast-spiking (FS) interneurons is quite precise. FS interneurons are self-innervated by powerful GABAergic autaptic connections reliably activated after each spike, suggesting that autapses strongly regulate FS-cell spike timing. Indeed, blockade of autaptic transmission degraded temporal precision in multiple ways. Under these conditions, realistic dynamic-clamp hyperpolarizing autapses restored precision of spike timing, even in the presence of synaptic noise. Furthermore, firing precision was increased in pyramidal neurons by artificial GABAergic autaptic conductances, suggesting that tightly coupled synaptic feedback inhibition regulates spike timing in principal cells. Thus, well-timed inhibition, whether autaptic or synaptic, facilitates precise spike timing and promotes synchronized cortical network oscillations relevant to several behaviors.     

Perineuronal nets play a role in regulating striatal function in the mouse

The striatum is the primary input nucleus of the basal ganglia, a collection of nuclei that play important roles in motor control and associative learning. We have previously reported that perineuronal nets (PNNs), aggregations of chondroitin-sulfate proteoglycans (CSPGs), form in the matrix compartment of the mouse striatum during the second postnatal week. This period overlaps with important developmental changes, including the attainment of an adult-like gait. Here, we investigate the identity of the cells encapsulated by PNNs, characterize their topographical distribution and determine their function by assessing the impact of enzymatic digestion of PNNs on two striatum-dependent behaviors: ambulation and goal-directed spatial learning. We show PNNs are more numerous caudally, and that a substantial fraction (41%) of these structures surrounds parvalbumin positive (PV+) interneurons, while approximately 51% of PV+ cells are ensheathed by PNNs. The colocalization of these structures is greatest in dorsal, lateral and caudal regions of the striatum. Bilateral digestion of striatal PNNs led to an increase in both the width and variability of hind limb gait. Intriguingly, this also resulted in an improvement in the acquisition rate of the Morris water maze. Together, these data show that PNNs are associated with specific elements of striatal circuits and play a key role in regulating the function of this important structure in the mouse.     

The neuropsychology of face perception: beyond simple dissociations and functional selectivity

Face processing relies on a distributed, patchy network of cortical regions in the temporal and frontal lobes that respond disproportionately to face stimuli, other cortical regions that are not even primarily visual (such as somatosensory cortex), and subcortical structures such as the amygdala. Higher-level face perception abilities, such as judging identity, emotion and trustworthiness, appear to rely on an intact face-processing network that includes the occipital face area (OFA), whereas lower-level face categorization abilities, such as discriminating faces from objects, can be achieved without OFA, perhaps via the direct connections to the fusiform face area (FFA) from several extrastriate cortical areas. Some lesion, transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) findings argue against a strict feed-forward hierarchical model of face perception, in which the OFA is the principal and common source of input for other visual and non-visual cortical regions involved in face perception, including the FFA, face-selective superior temporal sulcus and somatosensory cortex. Instead, these findings point to a more interactive model in which higher-level face perception abilities depend on the interplay between several functionally and anatomically distinct neural regions. Furthermore, the nature of these interactions may depend on the particular demands of the task. We review the lesion and TMS literature on this topic and highlight the dynamic and distributed nature of face processing.     

Development of NMDA NR2 subunits and their roles in critical period maturation of neocortical GABAergic interneurons

The goals of this research are to (1) determine the changes in the composition of NMDA receptor (NMDAR) subunits in GABAergic interneurons during critical period (CP); and (2) test the effect of chronic blockage of specific NR2 subunits on the maturation of specific GABAergic interneurons. Our data demonstrate that: (1) The amplitude of NMDAR mediated EPSCs (EPSCs(NMDAR) ) was significantly larger in the postCP group. (2) The coefficient of variation (CV), τ(decay) and half-width of EPSCs(NMDAR) were significantly larger in the preCP group. (3) A leftward shift in the half-activation voltages in the postCP vs. preCP group. (4) Using subunit-specific antagonists, we found a postnatal shift in NR2 composition towards more NR2A mediated EPSCs(NMDAR) . These changes occurred within a two-day narrow window of CP and were similar between fast-spiking (FS) and regular spiking (RSNP) interneurons. (5) Chronic blockage of NR2A, but not NR2B, decreased the expression of parvalbumin (PV), but not other calcium binding proteins in layer 2/3 and 4 of barrel cortex. (6) Chronic blockage of NR2A selectively affected the maturation of IPSCs mediated by FS cells. In summary, we have reported, for the first time, developmental changes in the molecular composition of NMDA NR2 subunits in interneurons during CP, and the effects of chronic blockage of NR2A but not NR2B on PV expression and inhibitory synaptic transmission from FS cells. These results support an important role of NR2A subunits in developmental plasticity of fast-spiking GABAergic circuits during CP.