Modulation Of Neuroplasticity Research Articles

Possibilities of non-invasive neuromodulation in rehabilitation

This article describes the physical basis and clinical capabilities of various non-invasive neuromodulatory techniques in the rehabilitation of patients. Neuromodulatory techniques can improve the patient’s recovery by influencing the processes of neuroplasticity. Modern non-invasive neuromodulation includes TES therapy, magnetic therapy, TCMP, EHF therapy, as well as one of the most promising methods — rhythmic transcranial magnetic stimulation (rTMS). It is assumed that TMS has a modulating effect on the regulation of the functions of the autonomic nervous system, cerebral vascular reactivity, activity of the immune system, in addition to affecting the electrophysiological parameters of neurons, also affects the facilitation of sprinting, neurogenesis. In addition, TMS causes inhibition in nociceptive trigeminothalamic neurons. The methods of non-invasive modulation of neuroplasticity are based on neurophysiological processes of activation and inhibition in the central and peripheral nervous system, as well as the possibility of their regulation by various components of electromagnetic effects. Non-invasive methods of neuromodulation can be combined with other methods of therapy (drug, physiotherapy, reflexology, massage, manual therapy, etc.). Features of non-invasive neuromodulation methods, their safety and ease of use allow for differentiated use in the clinic of rehabilitation treatment and become an important component of active drug and non-drug rehabilitation of patients. Key words neuroplasticity, non-invasive neuromodulation; non-drug rehabilitation, transcranial magnetic stimulation

Lithography Processable Ta2O5 Barrier-Layered Chitosan Electric Double Layer Synaptic Transistors.

We proposed a synaptic transistor gated using a Ta2O5 barrier-layered organic chitosan electric double layer (EDL) applicable to a micro-neural architecture system. In most of the previous studies, a single layer of chitosan electrolyte was unable to perform lithography processes due to poor mechanical/chemical resistance. To overcome this limitation, we laminated a high-k Ta2O5 thin film on chitosan electrolyte to ensure high mechanical/chemical stability to perform a lithographic process for micropattern formation. Artificial synaptic behaviors were realized by protonic mobile ion polarization in chitosan electrolytes. In addition, neuroplasticity modulation in the amorphous In–Ga–Zn-oxide (a-IGZO) channel was implemented by presynaptic stimulation. We also demonstrated synaptic weight changes through proton polarization, excitatory postsynaptic current modulations, and paired-pulse facilitation. According to the presynaptic stimulations, the magnitude of mobile proton polarization and the amount of weight change were quantified. Subsequently, the stable conductance modulation through repetitive potential and depression pulse was confirmed. Finally, we consider that proposed synaptic transistor is suitable for advanced micro-neural architecture because it overcomes the instability caused when using a single organic chitosan layer.

Photoperiodic changes in hippocampal neurogenesis and plasma metabolomic profiles in relation to depression-like behavior in mice

Photoperiod alters affective behaviors and brain neuroplasticity in several mammalian species. We addressed whether neurogenesis and signaling pathways of insulin-like growth factor-I (IGF-I), a key modulator of neuroplasticity, are regulated by photoperiod in C57BL/6 J mice, a putative model of seasonal affective disorder. We also examined the effects of photoperiod on plasma metabolomic profiles in relation to depression-like behavior to understand a possible linkage between peripheral metabolism and behavior. Mice that were maintained under long-day conditions (LD) exhibited a higher number of 5-bromo-2′-deoxyuridine-positive cells and higher levels of astrocyte marker in the dentate gyrus of the hippocampus compared to that of mice under short-day conditions (SD). Plasma IGF-I levels and levels/expression of IGF-I signaling molecules in the hippocampus (Brn-4, NeuroD1, and phospho-Akt) involved in neuronal proliferation and differentiation were higher in the mice under LD. Metabolome analysis using plasma of the mice under LD and SD identified several metabolites that were highly correlated with immobility in the forced swim test, a depression-like behavior. Negative correlations with behavior occurred in the levels of 23 metabolites, including metabolites related to neurogenesis and antidepressant-like effects of exercise, metabolites in the biosynthesis of arginine, and the occurrence of branched chain amino acids. Three metabolites had positive correlations with the behavior, including guanidinosuccinic acid, a neurotoxin. Taken together, photoperiodic responses of neurogenesis and neuro-glial organization in the hippocampus may be involved in photoperiodic alteration of depression-like behavior, mediated through multiple pathways, including IGF-I and peripheral metabolites.

The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects.

Matrix metalloproteinases (MMPs) are synthesized by neurons and glia and released into the extracellular space, where they act as modulators of neuroplasticity and neuroinflammatory agents. Development of epilepsy (epileptogenesis) is associated with increased expression of MMPs, and therefore, they may represent potential therapeutic drug targets. Using quantitative PCR (qPCR) and immunohistochemistry, we studied the expression of MMPs and their endogenous inhibitors tissue inhibitors of metalloproteinases (TIMPs) in patients with status epilepticus (SE) or temporal lobe epilepsy (TLE) and in a rat TLE model. Furthermore, we tested the MMP2/9 inhibitor IPR-179 in the rapid-kindling rat model and in the intrahippocampal kainic acid mouse model. In both human and experimental epilepsy, MMP and TIMP expression were persistently dysregulated in the hippocampus compared with in controls. IPR-179 treatment reduced seizure severity in the rapid-kindling model and reduced the number of spontaneous seizures in the kainic acid model (during and up to 7 weeks after delivery) without side effects while improving cognitive behavior. Moreover, our data suggest that IPR-179 prevented an MMP2/9-dependent switch-off normally restraining network excitability during the activity period. Since increased MMP expression is a prominent hallmark of the human epileptogenic brain and the MMP inhibitor IPR-179 exhibits antiseizure and antiepileptogenic effects in rodent epilepsy models and attenuates seizure-induced cognitive decline, it deserves further investigation in clinical trials.

Feasibility of Cerebellar Transcranial Direct Current Stimulation to Facilitate Goal-Directed Weight Shifting in Chronic Post-Stroke Hemiplegics.

Neurological disorder such as stroke can adversely affect one's weight-bearing symmetry leading to dysfunctional postural control. Recovery after stroke is facilitated through functionally-relevant neuroplastic modulation. Functionally-relevant cerebellum coordinates voluntary movements. Specifically, the dentate nuclei and lower limb representations (lobules VII-IX) of the cerebellum are involved in error-correction, crucial for postural control. It is postulated that cerebellar transcranial direct current stimulation (ctDCS) of the dentate nuclei and lobules VII-IX can modulate postural control in chronic stroke survivors. The objectives of this work were to (1) present a refined Virtual Reality (VR)-based balance training platform (VBaT) that can measure Center of Pressure (CoP) and (2) carry out a study to understand the implication of ctDCS stimulating the dentate nuclei (PhaseD) and lobules VII-IX (PhaseL) on the postural control of chronic stroke patients when they interacted with VBaT. Also, we investigated whether hemiplegic patients (with intact cerebellum) having Basal Ganglia (BG) infarction had any differential abilities to correct postural sway from those with no BG infarction (while shifting weight to the Affected side). Results of a single-session single-blind crossover study on randomized PhaseD and PhaseL stimulation (with an intermediate resting state bipolar bilateral ctDCS) on 12 chronic hemiplegic patients on separate days indicated differentiated findings (post stimulation) on CoP-related indices. We observed an incremental effect on one's postural control during PhaseD and inhibitory effect on the dentate nuclei during PhaseL. Clustering analysis showed that those with BG infarction demonstrated poor postural control and deficit in error correction ability irrespective of the ctDCS Phase.

Correlation of brain-derived neurotrophic factor with severity of depression and treatment response

BackgroundBrain-derived neurotrophic factor (BDNF) is a modulator of neuroplasticity in the brain. It plays an important role in the pathophysiology of depression through the stress pathway. The information about correlation of BDNF levels with depression severity and treatment response in Indian population is scarce. MethodsConsecutive 60 never treated cases with depression reporting to a large tertiary care psychiatry unit and 60 healthy matched controls from 01 January 2016 to 31 December 2016 were enrolled for study. Sociodemographic data were collected. Diagnosis of depression was carried out as per International Classification of Diseases-10th revision (ICD-10) diagnostic criteria for research. The Hamilton Rating Scale for Depression (HRSD) was administered and accordingly scored. Venous blood for BDNF levels was collected from all cases and controls. Cases were reassessed after 04 weeks of treatment with HRSD and BDNF levels. ResultsThe mean level of serum BDNF among cases (18.56 ng/ml) was found to be reduced significantly as compared with healthy controls (32.41 ng/ml). The mean serum BDNF level (18.56 ng/ml) in never treated cases was significantly negatively correlated with the median clinical HRSD score (18.5). There was a significant increase in the mean level of serum BDNF after antidepressant treatment. ConclusionThe study has revealed statistically significant low levels of serum BDNF in cases not exposed to treatment with depression compared with healthy controls. There was significant negative correlation of levels of serum BDNF with depression severity. The levels of serum BDNF significantly increased after four weeks of treatment.

Interhemispheric Functional Reorganization and its Structural Base After BCI-Guided Upper-Limb Training in Chronic Stroke.

Brain-computer interface (BCI)-guided robot-assisted upper-limb training has been increasingly applied to stroke rehabilitation. However, the induced long-term neuroplasticity modulation still needs to be further characterized. This study investigated the functional reorganization and its structural base after BCI-guided robot-assisted training using resting-state fMRI, task-based fMRI, and diffusion tensor imaging (DTI) data. The clinical improvement and the neurological changes before, immediately after, and six months after 20-session BCI-guided robot hand training were explored in 14 chronic stroke subjects. The structural base of the induced functional reorganization and motor improvement were also investigated using DTI. Repeated measure ANOVA indicated long-term motor improvement was found (F[2, 26] = 6.367, p = 0.006). Significantly modulated functional connectivity (FC) was observed between ipsilesional motor regions (M1 and SMA) and some contralesional areas (SMA, PMd, SPL) in the seed-based analysis. Modulated FC with ipsilesional M1 was significantly correlated with motor function improvement (r = 0.6455, p = 0.0276). Besides, increased interhemispheric FC among the sensorimotor area from resting-state data and increased laterality index from task-based data together indicated the re-balance of the two hemispheres during the recovery. Multiple linear regression models suggested that both motor function improvement and the functional change between ipsilesional M1 and contralesional premotor area were significantly associated with the ipsilesional corticospinal tract integrity. The results in the current study provided solid support for stroke recovery mechanism in terms of interhemispheric interaction and its structural substrates, which could further enhance the understanding of BCI training in stroke rehabilitation. This study was registered at https://clinicaltrials.gov (NCT02323061).

Enrichment Environment Positively Influences Depression- and Anxiety-Like Behavior in Serotonin Transporter Knockout Rats through the Modulation of Neuroplasticity, Spine, and GABAergic Markers.

The serotonin transporter (5-HTT in humans, SERT in rodents) is the main regulator of serotonergic transmission in the brain. The short allelic variant of the 5-HTT gene is in humans associated with psychopathologies and may enhance the vulnerability to develop depression after exposure to stressful events. Interestingly, the short allele also increases the sensitivity to a positive environment, which may buffer the vulnerability to depression. Since this polymorphism does not exist in rodents, male SERT knockout (SERT−/−) rats were tested to explore the molecular mechanisms based on this increased predisposition. This article investigates the influences of a positive manipulation, namely, enriched environment (EE), on the depressive-like behavior observed in SERT−/− rats. We found that one month of EE exposure normalized the anhedonic and anxious-like phenotype characteristics of this animal model. Moreover, we observed that EE exposure also restored the molecular alterations in the prefrontal cortex by positively modulating the expression of the neurotrophin Bdnf, and of spines and gamma-aminobutyric acid (GABA)ergic markers. Overall, our data confirm the depression-like phenotype of SERT−/− rats and highlight the ability of EE to restore behavioral and molecular alterations, thus promoting the opportunity to use EE as a supporting non-pharmacological approach to treat mood disorders.

Characterising the influence of cerebellum on the neuroplastic modulation of intracortical motor circuits.

The cerebellum (CB) has extensive connections with both cortical and subcortical areas of the brain, and is known to strongly influence function in areas it projects to. In particular, research using non-invasive brain stimulation (NIBS) has shown that CB projections to primary motor cortex (M1) are likely important for facilitating the learning of new motor skills, and that this process may involve modulation of late indirect (I) wave inputs in M1. However, the nature of this relationship remains unclear, particularly in regards to how CB influences the contribution of the I-wave circuits to neuroplastic changes in M1. Within the proposed research, we will therefore investigate how CB effects neuroplasticity of the I-wave generating circuits. This will be achieved by downregulating CB excitability while concurrently applying a neuroplastic intervention that specifically targets the I-wave circuitry. The outcomes of this study will provide valuable neurophysiological insight into key aspects of the motor network, and may inform the development of optimized interventions for modifying motor learning in a targeted way.

Nonlinear Effects of Dopamine D1 Receptor Activation on Visuomotor Coordination Task Performance

Dopamine plays an important role in the modulation of neuroplasticity, which serves as the physiological basis of cognition. The physiological effects of dopamine depend on receptor subtypes, and the D1 receptor is critically involved in learning and memory formation. Evidence from both animal and human studies shows a dose-dependent impact of D1 activity on performance. However, the direct association between physiology and behavior in humans remains unclear. In this study, four groups of healthy participants were recruited, and each group received placebo or medication inducing a low, medium, or high amount of D1 activation via the combination of levodopa and a D2 antagonist. After medication, fMRI was conducted during a visuomotor learning task. The behavioral results revealed an inverted U-shaped effect of D1 activation on task performance, where medium-dose D1 activation led to superior learning effects, as compared to placebo as well as low- and high-dose groups. A respective dose-dependent D1 modulation was also observed for cortical activity revealed by fMRI. Further analysis demonstrated a positive correlation between task performance and cortical activation at the left primary motor cortex. Our results indicate a nonlinear curve of D1 modulation on motor learning in humans and the respective physiological correlates in corresponding brain areas.

Auditory cognitive training improves prepulse inhibition in serine racemase mutant mice.

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.

Memory and Cognition-Related Neuroplasticity Enhancement by Transcranial Direct Current Stimulation in Rodents: A Systematic Review.

Brain stimulation techniques, including transcranial direct current stimulation (tDCS), were identified as promising therapeutic tools to modulate synaptic plasticity abnormalities and minimize memory and learning deficits in many neuropsychiatric diseases. Here, we revised the effect of tDCS on the modulation of neuroplasticity and cognition in several animal disease models of brain diseases affecting plasticity and cognition. Studies included in this review were searched following the terms (“transcranial direct current stimulation”) AND (mice OR mouse OR animal) and according to the PRISMA statement requirements. Overall, the studies collected suggest that tDCS was able to modulate brain plasticity due to synaptic modifications within the stimulated area. Changes in plasticity-related mechanisms were achieved through induction of long-term potentiation (LTP) and upregulation of neuroplasticity-related proteins, such as c-fos, brain-derived neurotrophic factor (BDNF), or N-methyl-D-aspartate receptors (NMDARs). Taken into account all revised studies, tDCS is a safe, easy, and noninvasive brain stimulation technique, therapeutically reliable, and with promising potential to promote cognitive enhancement and neuroplasticity. Since the use of tDCS has increased as a novel therapeutic approach in humans, animal studies are important to better understand its mechanisms as well as to help improve the stimulation protocols and their potential role in different neuropathologies.

Brain Connectivity Modulation After Exoskeleton-Assisted Gait in Chronic Hemiplegic Stroke Survivors: A Pilot Study.

The aim of this study was to investigate electroencephalographic (EEG) connectivity short-term changes, quantified by node strength and betweenness centrality, induced by a single trial of exoskeleton-assisted gait in chronic stroke survivors. Study design was randomized crossover. Electroencephalographic data (64-channel system) were recorded before gait (baseline) and after unassisted overground walking and overground exoskeleton-assisted walking. Coherence was estimated for alpha1, alpha2, and beta frequency ranges. Graph analysis assessed network model properties: node strength and betweenness centrality. Nine participants were included in the final analysis. In the group (four participants) with a left-hemisphere stroke lesion (dominant hemisphere), over the vertex, node strength increased in alpha1, alpha2, and beta bands, and betweenness centrality decreased in alpha2 both after unassisted overground walking and exoskeleton-assisted walking. In the group (five participants) with a right-hemisphere lesion (nondominant hemisphere), node strength increased in alpha1 and alpha2 over the contralesional sensorimotor area and ipsilesional prefrontal area after overground exoskeleton-assisted walking, compared with baseline and unassisted overground walking. A single session of exoskeleton training provides short-term neuroplastic modulation in chronic stroke. In participants with a nondominant hemisphere lesion, exoskeleton training induces activations similar to those observed in able-bodied participants, suggesting a role of lesion lateralization in networks' reorganization.

TTC9A deficiency induces estradiol-mediated changes in hippocampus and amygdala neuroplasticity-related gene expressions in female mice

The involvement of tetratricopeptide repeat domain 9A (TTC9A) deficiency in anxiety-like responses and behavioral despair through estradiol action on the serotonergic system has been reported. Emerging evidence suggests that estradiol is a potent modulator of neuroplasticity. As estradiol and neuroplasticity changes are both implicated in mood regulation, and estradiol activity is negatively regulated by TTC9A, we hypothesized that the behavioral changes induced by Ttc9a-/- is also mediated by neuroplasticity-related mechanisms. To understand the effects of TTC9A and estradiol modulation on neuroplasticity functions, we performed a behavioral analysis of tail suspension immobility and neuroplasticity-related gene expression study of brain samples collected in a previous study involving ovariectomized (OVX) Ttc9a-/- mice with estradiol or vehicle treatment. We observed that OVX-Ttc9a-/- mice had significantly reduced the tail suspension immobility compared to OVX-Ttc9a-/- estradiol-treated mice. Interestingly, there was an upregulation in gene expression of tropomyosin receptor kinase B (Trkb) in the ventral hippocampus, as well as brain-derived neurotrophic factor (Bdnf) and postsynaptic density protein-95 (Psd-95) in the amygdala of OVX-Ttc9a-/- mice compared to those treated with estradiol. These findings indicate that estradiol plays an inhibitory role in neuroplasticity in Ttc9a-/- mice. These observations were not found in the wildtype mice, as the presence of TTC9A suppressed the effects of estradiol. Our data suggest the behavioral alterations in Ttc9a-/- mice were mediated by estradiol regulation involving neuroplasticity-related mechanisms in both the hippocampus and amygdala regions.

O-08 Brain connectivity modulation after exoskeleton gait in chronic stroke survivors: a pilot study

Background Restoration of independent gait after stroke is a principal goal of survivors. Exoskeleton overground gait training provides trunk support and inter-limb coordination based on fine-tuning of the robot control parameters. The aim of our study was to identify short-term plasticity based on electroencephalography (EEG) data induced by a single trial of exoskeleton gait training in unilateral hemiplegic stroke survivors. Material and methods 64-channel EEG was recorded before gait (T0), after overground walking (T1) and after overground exoskeleton (EksoGT) gait training (T2) in 9 stroke survivors. Relative power and coherence were estimated for alpha1 (8–10 Hz), alpha2 (10.5–12.5 Hz) and beta (13–30 Hz) frequency ranges. Graph analysis assessed network model properties: node strength (S) and betweenness centrality (BC). Results Left-hemisphere stroke subjects showed S decrease over anterior and posterior cortex in alpha1, alpha2 and beta at T1 and T2. BC decreased at vertex at T1 and T2 in alpha2 and beta. Right-hemisphere stroke subjects displayed power decrease after exoskeleton walking in alpha2 over CPZ and CP2, and in beta over left contralateral sensorimotor cortex (cSM) and right ipsilateral prefrontal cortex (iPFC). S increased in alpha1 and alpha2 over cSM and iPFC at T2; BC decreased in alpha2 over iPFC at T2 compared to T1. Conclusions A single session of tailored exoskeleton training provides short-term neuroplastic modulation in chronic stroke. Right-hemisphere stroke subjects re-establish a more physiological activation network; a similar reorganization does not take place in left-hemisphere stroke subjects, supporting the role of lateralization in limb control and stroke recovery.

Distribution of brain derived neurotrophic factor (BDNF) immunostaining along the C2–C5 spinal cord in adult rats

BDNF is a powerful modulator of neuroplasticity and can be found across the rostral‐caudal extent of the spinal neuroaxis in neurons, astrocytes and microglia. BDNF is necessary and sufficient to drive plasticity in the phrenic motor system, likely through either pre‐ and/or post‐synaptic actions on phrenic motoneurons. To our knowledge, the relative distribution of BDNF expression across this region of the mid‐cervical spinal cord has not been systematically “mapped”. Accordingly, in ongoing experiments, we are quantitatively evaluating the distribution of BDNF positive neurons in the C2–C5 spinal cord in adult Sprague‐Dawley rats. The guiding hypothesis is that BDNF will be most prevalent in the C3‐5 ventral horn in the region of the phrenic motor nucleus. Tissues were harvested from adult male rats and processed with standard immunochemistry methods using a BDNF antibody (Alomone, 1:500 dilution). Control experiments showed an absence of spinal cord staining when tissues were incubated without the primary antibody and while keeping all other aspects constant. A custom MATLAB code was used to quantify the number of BDNF positive cells throughout C2–C5. Specifically, BDNF expressing soma were identified as areas with fluorescent intensity above a common threshold. To separate putative neurons, identified regions were sorted by size and only regions with an area of 250–1500 μm2 were included for further analysis. We observed BDNF expression within neurons in laminae I, II, VII, VIII, and IX across the mid‐cervical spinal cord. Further, the number of BDNF positive neurons increased in a rostral to caudal manner from C2 to C5 (P<0.05). There were more BDNF expressing neurons located in the ventral horn when compared to the dorsal horn across C2–C5 (p< 0.01). Finally, smaller BDNF positive cells were evident throughout the gray and white matter which is consistent with microglial distribution in the spinal cord, however, this staining has not been verified at this time. These initial results suggest that naturally occurring levels of BDNF vary across the cervical spinal cord, and are greatest in the region of the phrenic motor nucleus.Support or Funding Information1R01HL139708‐01A1 (DDF), T32‐HD043730 (MDS).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

7-Chloro-4-(Phenylselanyl) Quinoline with Memory Enhancer Action in Aging Rats: Modulation of Neuroplasticity, Acetylcholinesterase Activity, and Cholesterol Levels.

This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) to restore the cognitive impairment caused by aging in male Wistar rats. Moreover, modulation of neuroplasticity markers, acetylcholinesterase (AChE) activity, and cholesterol levels was performed. Aged rats were intragastrically treated with 4-PSQ (5mg/kg) for 7days. Animals were tested in behavioral tasks, and then plasma (to determine cholesterol levels), hippocampus, and cerebral cortex (to determine neural cell adhesion molecule (NCAM) and polysialyltransferase (PST) levels, and AChE activity) were removed. Our findings demonstrated that treatment of aged rats with 4-PSQ restored short-term and long-term memories in the object recognition tests. 4-PSQ treatment did not restore exploratory activity (rearings) but partially restored locomotor activity (crossings) reduced by aging in the open-field test. Moreover, the compound restored the reduction in the NCAM and PST levels, and AChE activity in cerebral structures, as well as the increase in the plasma cholesterol levels, caused by aging in rats. In conclusion, 4-PSQ restored cognitive impairment caused by aging in rats by modulating synaptic plasticity, cholinergic system, and cholesterol levels.

BDNF genotype and tDCS interaction in aphasia treatment

BackgroundSeveral studies, including a randomized controlled trial by our group, support applying anodal tDCS (A-tDCS) to the left hemisphere during behavioral aphasia treatment to improve outcomes. A clear mechanism explaining A-tDCS's efficacy has not been established, but modulation of neuroplasticity may be involved. Objective/hypothesisThe brain-derived neurotrophic factor (BDNF) gene influences neuroplasticity and may modulate the effects of tDCS. Utilizing data from our recently completed trial, we conducted a planned test of whether aphasia treatment outcome is influenced by interaction between A-tDCS and a single-nucleotide polymorphism of the BDNF gene, rs6265. MethodsSeventy-four individuals with chronic stroke-induced aphasia completed 15 language therapy sessions and were randomized to receive 1 mA A-tDCS or sham tDCS (S-tDCS) to the intact left temporoparietal region for the first 20 min of each session. BDNF genotype was available for 67 participants: 37 participants had the typical val/val genotype. The remaining 30 participants had atypical BDNF genotype (Met allele carriers). The primary outcome factor was improvement in object naming at 1 week after treatment completion. Maintenance of treatment effects was evaluated at 4 and 24 weeks. ResultsAn interaction was revealed between tDCS condition and genotype for treatment-related naming improvement (F = 4.97, p = 0.03). Participants with val/val genotype who received A-tDCS showed greater response to aphasia treatment than val/val participants who received S-tDCS, as well as the Met allele carriers, regardless of tDCS condition. ConclusionIndividuals with the val/val BDNF genotype are more likely to benefit from A-tDCS during aphasia treatment.

Neurobiology of cognitive remediation in schizophrenia: Effects of EAAT2 polymorphism

Cognitive deficits represent core features of schizophrenia, affecting quality of life and functioning. The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate reuptake and its activity is crucial for glutamatergic neurotransmission, prevention of excitotoxic damage and cerebral metabolism. Different studies reported that EAAT2 rs4354668 (−181 T/G) influences cognitive functions and brain structures in patients with schizophrenia. Specifically, the G allele, linked to lower EAAT2 expression, was associated with impaired prefrontal cognitive performance and reduced grey matter volumes. Cognitive remediation therapy (CRT) is one of the best available tool to treat cognitive deficits in schizophrenia, able to induce a neuroplastic modulation of cognitive functions. The present study aims to investigate the effects of rs4354668 on CRT outcome, also considering possible genotype interaction with antipsychotic (AP) treatment, since EAAT2 expression is negatively influenced by clozapine.We examined rs4354668 in 88 clinically stabilized patients with schizophrenia, treated with CRT and assessed at enrolment, at the end of CRT and after 3 months. We observed greater working memory improvements among patients carrying the T/T genotype, regardless of AP treatment. Moreover, we reported a significant interaction between pharmacological treatment and rs4354668 on executive functions, with greater improvements among T/T patients treated with APs other than clozapine.These observations suggest that impaired EAAT2 expression may attenuate CRT outcome. Moreover, our results indicate the possibility that rs4354668 could also differentially influence the response to CRT depending on the AP treatment.

Circadian modulation of neuroplasticity by melatonin: a target in the treatment of depression.

Mood disorders are a spectrum of neuropsychiatric disorders characterized by changes in the emotional state. In particular, major depressive disorder is expected to have a worldwide prevalence of 20% in 2020, representing a huge socio-economic burden. Currently used antidepressant drugs have poor efficacy with only 30% of the patients in remission after the first line of treatment. Importantly, mood disorder patients present uncoupling of circadian rhythms. In this regard, melatonin (5-methoxy-N-acetyltryptamine), an indolamine synthesized by the pineal gland during the night, contributes to synchronization of body rhythms with the environmental light/dark cycle. In this review, we describe evidence supporting antidepressant-like actions of melatonin related to the circadian modulation of neuroplastic changes in the hippocampus. We also present evidence for the role of melatonin receptors and their signalling pathways underlying modulatory effects in neuroplasticity. Finally, we briefly discuss the detrimental consequences of circadian disruption on neuroplasticity and mood disorders, due to the modern human lifestyle. Together, data suggest that melatonin's stimulation of neurogenesis and neuronal differentiation is beneficial to patients with mood disorders. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.