Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex for Phantom Limb Pain.

BACKGROUND: Phantom limb pain (PLP) is a prevalent and distressing occurrence in 60-80% of individuals who have undergone amputations. Recent research underscores the significance of maladaptive cortical plasticity in the genesis of PLP, emphasizing the importance of targeting cortical areas for therapeutic interventions. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive tool for cortical stimulation, demonstrates effectiveness in treating various chronic pain conditions of neuropathic origin. Nevertheless, there exists a limited body of research investigating the application of rTMS as a therapeutic intervention specifically for managing PLP. Notably, the dorsolateral prefrontal cortex (DLPFC) plays a crucial role in central pain processing, suggesting its potential as a key therapeutic target in PLP treatment. There is a lack of adequate data regarding the effectiveness of DLPFC-targeting rTMS in alleviating the pain experienced by PLP patients. OBJECTIVE: In this study, our aim was to investigate the impact of 10 sessions of DLPFC-targeting rTMS on the pain status of individuals experiencing PLP. STUDY DESIGN: Randomized controlled trial. SETTING: Traumatic amputees reporting to the tertiary care center with PLP. METHODS: The study was approved by the Institute Ethics Committee (IECPG-299/27.04.2022) and registered in the Clinical Trials Registry of India (CTRI/2022/07/043938). Nineteen patients suffering from PLP were recruited and randomized into real or sham rTMS groups. In the real rTMS group, patients received 10 sessions of rTMS at the DLPFC contralateral to the amputation site. The rTMS, administered at 90% of the resting motor threshold (RMT), was delivered as 8 trains of 150 pulses per train at the rate of one Hz and an inter-train interval of 60 seconds. The total number of pulses per session was 1,200. The sham group received 10 sessions of sham rTMS through the perpendicular placement of an rTMS coil over the DLPFC. These sessions lasted for the same duration and included the same sounds as the real group but involved no active stimulation. The patients' pain status was evaluated using the Visual Analog Scale (VAS) at baseline, at the end of each session of real or sham rTMS and at the 15th, 30th, and 60th day after the the completion of real or sham therapy. RESULTS: A significant decrease in VAS scores was noted after 10 sessions of real rTMS that targeted the DLPFC, in contrast to the sham rTMS group. The real rTMS group's reduction in VAS scores also persisted during the follow-up. LIMITATIONS: A few patients had to drop out due to physical restrictions and financial constraints. Consequently, only a small number of individuals were able to complete the study protocol successfully. CONCLUSION: A regimen of 10 sessions of real rTMS of the DLPFC was associated with significant pain relief in patients with PLP, and the effects were sustained for 2 months. Therefore, the present study shows that rTMS of the DLPFC has potential as an effective therapeutic intervention for sustained pain relief in PLP patients.

Neurophysiological markers of motor compensatory mechanisms in early Parkinson's disease.

Compensatory mechanisms in Parkinson's disease are defined as the changes that the brain uses to adapt to neurodegeneration and progressive dopamine reduction. Motor compensation in early Parkinson's disease could, in part, be responsible for a unilateral onset of clinical motor signs despite the presence of bilateral nigrostriatal degeneration. Although several mechanisms have been proposed for compensatory adaptations in Parkinson's disease, the underlying pathophysiology is unclear. Here, we investigate motor compensation in Parkinson's disease by investigating the relationship between clinical signs, dopamine transporter imaging data and neurophysiological measures of the primary motor cortex (M1), using transcranial magnetic stimulation in presymptomatic and symptomatic hemispheres of patients. In this cross-sectional, multicentre study, we screened 82 individuals with Parkinson's disease. Patients were evaluated clinically in their medication OFF state using standardized scales. Sixteen Parkinson's disease patients with bilateral dopamine transporter deficit in the putamina but unilateral symptoms were included. Twenty-eight sex- and age-matched healthy controls were also investigated. In all participants, we tested cortical excitability using single- and paired-pulse techniques, interhemispheric inhibition and cortical plasticity with paired associative stimulation. Data were analysed with ANOVAs, multiple linear regression and logistic regression models. Individual coefficients of motor compensation were defined in patients based on clinical and imaging data, i.e. the motor compensation coefficient. The motor compensation coefficient includes an asymmetry score to balance motor and dopamine transporter data between the two hemispheres, in addition to a hemispheric ratio accounting for the relative mismatch between the magnitude of motor signs and dopaminergic deficit. In patients, corticospinal excitability and plasticity were higher in the presymptomatic compared with the symptomatic M1. Also, interhemispheric inhibition from the presymptomatic to the symptomatic M1 was reduced. Lower putamen binding was associated with higher plasticity and reduced interhemispheric inhibition in the presymptomatic hemisphere. The motor compensation coefficient distinguished the presymptomatic from the symptomatic hemisphere. Finally, in the presymptomatic hemisphere, a higher motor compensation coefficient was associated with lower corticospinal excitability and interhemispheric inhibition and with higher plasticity. In conclusion, the present study suggests that motor compensation involves M1-striatal networks and intercortical connections becoming more effective with progressive loss of dopaminergic terminals in the putamen. The balance between these motor networks seems to be driven by cortical plasticity.

The importance of brain mapping for rehabilitation in birth nonprogressive neuromuscular diseases.

While motor mapping has been extensively studied in acquired motor conditions, a lack has been observed in terms of research on neurological disorders present since birth, with damage to the spinal cord and peripheral nerves (hence, defined in this study as nonprogressive neuromuscular diseases). Despite an injury at the level below the brain, the subsequent changes in the motor system involve cortical reorganization. In the scientific community, the need for a comprehensive approach targeting the brain is increasingly recognized for greater motor recovery in these patients. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) are the most utilized techniques for motor mapping. The knowledge obtained through motor mapping may be used to develop effective individual neuromodulation therapy that helps in functional motor recovery. This brief review compares the results of the brain mapping of a few existing studies in individuals with nonprogressive motor disorders of nonbrain origin present at birth to the brain mapping of individuals with similar acquired motor conditions. The review reveals some particular features in terms of central adaptation in individuals with birth conditions compared to their acquired counterparts, such as the nonsomatotopic presentation of involved muscles in the sensorimotor cortex and nonadjacent cortical areas. This topic is undoubtedly intriguing, justifying further research in the field. This review also discusses the benefits these patients can obtain from neuromodulation therapy addressed to the central nervous system and the importance of individual neurophysiological assessment in designing rehabilitation therapy for children with birth motor disorders.

Orbitofrontal cortex modulates auditory cortical sensitivity and sound perception in Mongolian gerbils.

Sensory perception is dynamic, quickly adapting to sudden shifts in environmental or behavioral context. Although decades of work have established that these dynamics are mediated by rapid fluctuations in sensory cortical activity, we have a limited understanding of the brain regions and pathways that orchestrate these changes. Neurons in the orbitofrontal cortex (OFC) encode contextual information, and recent data suggest that some of these signals are transmitted to sensory cortices. Whether and how these signals shape sensory encoding and perceptual sensitivity remain uncertain. Here, we asked whether the OFC mediates context-dependent changes in auditory cortical sensitivity and sound perception by monitoring and manipulating OFC activity in freely moving Mongolian gerbils of both sexes under two behavioral contexts: passive sound exposure and engagement in an amplitude modulation (AM) detection task. We found that the majority of OFC neurons, including the specific subset that innervates the auditory cortex, were strongly modulated by task engagement. Pharmacological inactivation of the OFC prevented rapid context-dependent changes in auditory cortical firing and significantly impaired behavioral AM detection. Our findings suggest that contextual information from the OFC mediates rapid plasticity in the auditory cortex and facilitates the perception of behaviorally relevant sounds.

Abnormal Global Cortical Responses in Drug-Naïve Patients With Schizophrenia Following Orbitofrontal Cortex Stimulation: A Concurrent Transcranial Magnetic Stimulation-Electroencephalography Study.

BACKGROUND: Abnormalities in cortical excitability and plasticity have been considered to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) can provide a direct evaluation of cortical responses to TMS. Here, we employed TMS-EEG to investigate cortical responses to orbitofrontal cortex (OFC) stimulation in schizophrenia. METHODS: In total, we recruited 92 drug-naïve patients with first-episode schizophrenia and 51 age- and sex-matched healthy individuals. For each participant, one session of 1-Hz repetitive TMS (rTMS) was delivered to the right OFC, and TMS-EEG data were obtained to explore the change in cortical-evoked activities before and immediately after rTMS during the eyes-closed state. The MATRICS Consensus Cognitive Battery was used to assess neurocognitive performance. RESULTS: The cortical responses indexed by global mean field amplitudes (i.e., P30, N45, and P60) were larger in patients with schizophrenia than in healthy control participants at baseline. Furthermore, after one session of 1-Hz rTMS over the right OFC, the N100 amplitude was significantly reduced in the healthy control group but not in the schizophrenia group. In the healthy control participants, there was a significant correlation between modulation of P60 amplitude by rTMS and working memory; however, this correlation was absent in patients with schizophrenia. CONCLUSIONS: Aberrant global cortical responses following right OFC stimulation were found in patients with drug-naïve first-episode schizophrenia, supporting its significance in the primary pathophysiology of schizophrenia.

Motor function in multiple sclerosis assessed by navigated transcranial magnetic stimulation mapping.

INTRODUCTION: Impaired motor function is a major cause of disability in multiple sclerosis (MS), involving various neuroplasticity processes typically assessed by neuroimaging. This study aimed to determine whether navigated transcranial magnetic stimulation (nTMS) could also provide biomarkers of motor cortex plasticity in patients with MS (pwMS). METHODS: nTMS motor mapping was performed for hand and leg muscles bilaterally. nTMS variables included the amplitude and latency of motor evoked potentials (MEPs), corticospinal excitability measures, and the size of cortical motor maps (CMMs). Clinical assessment included disability (Expanded Disability Status Scale, EDSS), strength (MRC scale, pinch and grip), and dexterity (9-hole Pegboard Test). RESULTS: nTMS motor mapping was performed in 68 pwMS. PwMS with high disability (EDSS ≥ 3) had enlarged CMMs with less dense distribution of MEPs and various MEP parameter changes compared to pwMS with low disability (EDSS < 3). Patients with progressive MS had also various MEP parameter changes compared to pwMS with relapsing remitting form. MRC score correlated positively with MEP amplitude and negatively with MEP latency, pinch strength correlated negatively with CMM volume and dexterity with MEP latency. CONCLUSIONS: This is the first study to perform 4-limb cortical motor mapping in pwMS using a dedicated nTMS procedure. By quantifying the cortical surface representation of a given muscle and the variability of MEP within this representation, nTMS can provide new biomarkers of motor function impairment in pwMS. Our study opens perspectives for the use of nTMS as an objective method for assessing pwMS disability in clinical practice.

Changes in visually and auditory attended audiovisual speech processing in cochlear implant users: A longitudinal ERP study.

Limited auditory input, whether caused by hearing loss or by electrical stimulation through a cochlear implant (CI), can be compensated by the remaining senses. Specifically for CI users, previous studies reported not only improved visual skills, but also altered cortical processing of unisensory visual and auditory stimuli. However, in multisensory scenarios, it is still unclear how auditory deprivation (before implantation) and electrical hearing experience (after implantation) affect cortical audiovisual speech processing. Here, we present a prospective longitudinal electroencephalography (EEG) study which systematically examined the deprivation- and CI-induced alterations of cortical processing of audiovisual words by comparing event-related potentials (ERPs) in postlingually deafened CI users before and after implantation (five weeks and six months of CI use). A group of matched normal-hearing (NH) listeners served as controls. The participants performed a word-identification task with congruent and incongruent audiovisual words, focusing their attention on either the visual (lip movement) or the auditory speech signal. This allowed us to study the (top-down) attention effect on the (bottom-up) sensory cortical processing of audiovisual speech. When compared to the NH listeners, the CI candidates (before implantation) and the CI users (after implantation) exhibited enhanced lipreading abilities and an altered cortical response at the N1 latency range (90-150 ms) that was characterized by a decreased theta oscillation power (4-8 Hz) and a smaller amplitude in the auditory cortex. After implantation, however, the auditory-cortex response gradually increased and developed a stronger intra-modal connectivity. Nevertheless, task efficiency and activation in the visual cortex was significantly modulated in both groups by focusing attention on the visual as compared to the auditory speech signal, with the NH listeners additionally showing an attention-dependent decrease in beta oscillation power (13-30 Hz). In sum, these results suggest remarkable deprivation effects on audiovisual speech processing in the auditory cortex, which partially reverse after implantation. Although even experienced CI users still show distinct audiovisual speech processing compared to NH listeners, pronounced effects of (top-down) direction of attention on (bottom-up) audiovisual processing can be observed in both groups. However, NH listeners but not CI users appear to show enhanced allocation of cognitive resources in visually as compared to auditory attended audiovisual speech conditions, which supports our behavioural observations of poorer lipreading abilities and reduced visual influence on audition in NH listeners as compared to CI users.

Predicting interindividual response to theta burst stimulation in the lower limb motor cortex using machine learning.

Using theta burst stimulation (TBS) to induce neural plasticity has played an important role in improving the treatment of neurological disorders. However, the variability of TBS-induced synaptic plasticity in the primary motor cortex prevents its clinical application. Thus, factors associated with this variability should be explored to enable the creation of a predictive model. Statistical approaches, such as regression analysis, have been used to predict the effects of TBS. Machine learning may potentially uncover previously unexplored predictive factors due to its increased capacity for capturing nonlinear changes. In this study, we used our prior dataset (Katagiri et al., 2020) to determine the factors that predict variability in TBS-induced synaptic plasticity in the lower limb motor cortex for both intermittent (iTBS) and continuous (cTBS) TBS using machine learning. Validation of the created model showed an area under the curve (AUC) of 0.85 and 0.69 and positive predictive values of 77.7 and 70.0% for iTBS and cTBS, respectively; the negative predictive value was 75.5% for both patterns. Additionally, the accuracy was 0.76 and 0.72, precision was 0.82 and 0.67, recall was 0.82 and 0.67, and F1 scores were 0.82 and 0.67 for iTBS and cTBS, respectively. The most important predictor of iTBS was the motor evoked potential amplitude, whereas it was the intracortical facilitation for cTBS. Our results provide additional insights into the prediction of the effects of TBS variability according to baseline neurophysiological factors.

Potential of focal cortical dysplasia in migraine pathogenesis.

Focal cortical dysplasias are abnormalities of the cerebral cortex associated with an elevated risk of neurological disturbances. Cortical spreading depolarization/depression is a correlate of migraine aura/headache and a trigger of migraine pain mechanisms. However, cortical spreading depolarization/depression is associated with cortical structural changes, which can be classified as transient focal cortical dysplasias. Migraine is reported to be associated with changes in various brain structures, including malformations and lesions in the cortex. Such malformations may be related to focal cortical dysplasias, which may play a role in migraine pathogenesis. Results obtained so far suggest that focal cortical dysplasias may belong to the causes and consequences of migraine. Certain focal cortical dysplasias may lower the threshold of cortical excitability and facilitate the action of migraine triggers. Migraine prevalence in epileptic patients is higher than in the general population, and focal cortical dysplasias are an established element of epilepsy pathogenesis. In this narrative/hypothesis review, we present mainly information on cortical structural changes in migraine, but studies on structural alterations in deep white matter and other brain regions are also presented. We develop the hypothesis that focal cortical dysplasias may be causally associated with migraine and link pathogeneses of migraine and epilepsy.

Long-term training alters response dynamics in the aging auditory cortex.

Age-related auditory dysfunction, presbycusis, is caused in part by functional changes in the auditory cortex (ACtx) such as altered response dynamics and increased population correlations. Given the ability of cortical function to be altered by training, we tested if performing auditory tasks might benefit auditory function in old age. We examined this by training adult mice on a low-effort tone-detection task for at least six months and then investigated functional responses in ACtx at an older age (∼18 months). Task performance remained stable well into old age. Comparing sound-evoked responses of thousands of ACtx neurons using in vivo 2-photon Ca2+ imaging, we found that many aspects of youthful neuronal activity, including low activity correlations, lower neural excitability, and a greater proportion of suppressed responses, were preserved in trained old animals as compared to passively-exposed old animals. Thus, consistent training on a low-effort task can benefit age-related functional changes in ACtx and may preserve many aspects of auditory function.

Sound-evoked adenosine release in cooperation with neuromodulatory circuits permits auditory cortical plasticity and perceptual learning.

Meaningful auditory memories are formed in adults when acoustic information is delivered to the auditory cortex during heightened states of attention, vigilance, or alertness, as mediated by neuromodulatory circuits. Here, we identify that, in awake mice, acoustic stimulation triggers auditory thalamocortical projections to release adenosine, which prevents cortical plasticity (i.e., selective expansion of neural representation of behaviorally relevant acoustic stimuli) and perceptual learning (i.e., experience-dependent improvement in frequency discrimination ability). This sound-evoked adenosine release (SEAR) becomes reduced within seconds when acoustic stimuli are tightly paired with the activation of neuromodulatory (cholinergic or dopaminergic) circuits or periods of attentive wakefulness. If thalamic adenosine production is enhanced, then SEAR elevates further, the neuromodulatory circuits are unable to sufficiently reduce SEAR, and associative cortical plasticity and perceptual learning are blocked. This suggests that transient low-adenosine periods triggered by neuromodulatory circuits permit associative cortical plasticity and auditory perceptual learning in adults to occur.

Strengthening of alpha synchronization is a neural correlate of cognitive transfer.

Cognitive training can lead to improvements in both task-specific strategies and general capacities, such as visuo-spatial working memory (VSWM). The latter emerge slowly and linearly throughout training, in contrast to strategy where changes typically occur within the first days of training. Changes in strategy and capacity have not been separated in prior neuroimaging studies. Here, we used a within-participants design with dense temporal sampling to capture the time dynamics of neural mechanisms associated with change in capacity. In four participants, neural activity was recorded with magnetoencephalography on seven occasions over two months of visuo-spatial working memory training. During scanning, the participants performed a trained visuo-spatial working memory task, a transfer task, and a control task. First, we extracted an individual visuo-spatial working memory-load-dependent synchronization network for each participant. Next, we identified linear changes over time in the network, congruent with the temporal dynamics of capacity change. Three out of four participants showed a gradual strengthening of alpha synchronization. Strengthening of the same connections was also found in the transfer task but not in the control task. This suggests that cognitive transfer occurs through slow, gradual strengthening of alpha synchronization between cortical regions that are vital for both the trained task and the transfer task.

Drawing improves memory in patients with hippocampal damage.

The hippocampus plays a critical role in the formation of declarative memories, and hippocampal damage leads to significant impairments in new memory formation. Drawing can serve as a form of multi-modal encoding that improves declarative memory performance relative to other multimodal encoding strategies such as writing. We examined whether, and to what extent, patients with hippocampal damage could benefit from the mnemonic strategy of drawing. Three patients with focal hippocampal damage, and one patient with both hippocampal and cortical lesions, in addition to 22 age-, sex-, and education-matched controls, were shown a list of words one at a time during encoding and instructed to either draw a picture or repeatedly write each word for 40 s. Following a brief filled delay, free recall and recognition memory for words from both encoding trial types were assessed. Controls showed enhanced recall and recognition memory for words drawn versus those that were written, an effect that was even more pronounced in patients with focal hippocampal damage. By contrast, the patient with both hippocampal and cortical lesions showed no drawing-mediated boost in either recall or recognition memory. These findings demonstrate that drawing is an effective encoding strategy, likely accruing from the engagement of extra-hippocampal processes including the integration of cortical-based motor, visual, and semantic processing, enabling more elaborative encoding.

Induction of excitatory brain state governs plastic functional changes in visual cortical topology.

Adult visual plasticity underlying local remodeling of the cortical circuitry in vivo appears to be associated with a spatiotemporal pattern of strongly increased spontaneous and evoked activity of populations of cells. Here we review and discuss pioneering work by us and others about principles of plasticity in the adult visual cortex, starting with our study which showed that a confined lesion in the cat retina causes increased excitability in the affected region in the primary visual cortex accompanied by fine-tuned restructuring of neuronal function. The underlying remodeling processes was further visualized with voltage-sensitive dye (VSD) imaging that allowed a direct tracking of retinal lesion-induced reorganization across horizontal cortical circuitries. Nowadays, application of noninvasive stimulation methods pursues the idea further of increased cortical excitability along with decreased inhibition as key factors for the induction of adult cortical plasticity. We used high-frequency transcranial magnetic stimulation (TMS), for the first time in combination with VSD optical imaging, and provided evidence that TMS-amplified excitability across large pools of neurons forms the basis for noninvasively targeting reorganization of orientation maps in the visual cortex. Our review has been compiled on the basis of these four own studies, which we discuss in the context of historical developments in the field of visual cortical plasticity and the current state of the literature. Overall, we suggest markers of LTP-like cortical changes at mesoscopic population level as a main driving force for the induction of visual plasticity in the adult. Elevations in excitability that predispose towards cortical plasticity are most likely a common property of all cortical modalities. Thus, interventions that increase cortical excitability are a promising starting point to drive perceptual and potentially motor learning in therapeutic applications.

The importance of pyramidal tract integrity for cortical plasticity and related functionality in patients with multiple sclerosis.

Background: Cortical plasticity induced by quadripulse stimulation (QPS) has been shown to correlate with cognitive functions in patients with relapsing-remitting multiple sclerosis (RRMS) and to not be reduced compared to healthy controls (HCs). Objective: This study aimed to compare the degree of QPS-induced plasticity between different subtypes of multiple sclerosis (MS) and HCs and to investigate the association of the degree of plasticity with motor and cognitive functions. We expected lower levels of plasticity in patients with progressive MS (PMS) but not RRMS compared to HCs. Furthermore, we expected to find positive correlations with cognitive and motor performance in patients with MS. Methods: QPS-induced plasticity was compared between 34 patients with PMS, 30 patients with RRMS, and 30 HCs using linear mixed-effects models. The degree of QPS-induced cortical plasticity was correlated with various motor and cognitive outcomes. Results: There were no differences regarding the degree of QPS-induced cortical plasticity between HCs and patients with RRMS (p = 0.86) and PMS (p = 0.18). However, we only found correlations between the level of induced plasticity and both motor and cognitive functions in patients with intact corticospinal tract integrity. Exploratory analysis revealed significantly reduced QPS-induced plasticity in patients with damage compared to intact corticospinal tract integrity (p < 0.001). Conclusion: Our study supports the notion of pyramidal tract integrity being of more relevance for QPS-induced cortical plasticity in MS and related functional significance than the type of disease.

Functional to structural plasticity in unilateral sudden sensorineural hearing loss: neuroimaging evidence.

A cortical plasticity after long-duration single side deafness (SSD) is advocated with neuroimaging evidence while little is known about the short-duration SSDs. In this case-cohort study, we recruited unilateral sudden sensorineural hearing loss (SSNHL) patients and age-, gender-matched health controls (HC), followed by comprehensive neuroimaging analyses. The primary outcome measures were temporal alterations of varied dynamic functional network connectivity (dFNC) states, neurovascular coupling (NVC) and brain region volume at different stages of SSNHL. The secondary outcome measures were pure-tone audiograms of SSNHL patients before and after treatment. A total of 38 SSNHL patients (21 [55%] male; mean [standard deviation] age, 45.05 [15.83] years) and 44 HC (28 [64%] male; mean [standard deviation] age, 43.55 [12.80] years) were enrolled. SSNHL patients were categorized into subgroups based on the time from disease onset to the initial magnetic resonance imaging scan: early- (n = 16; 1-6 days), intermediate- (n = 9; 7-13 days), and late- stage (n = 13; 14-30 days) groups. We first identified slow state transitions between varied dFNC states at early-stage SSNHL, then revealed the decreased NVC restricted to the auditory cortex at the intermediate- and late-stage SSNHL. Finally, a significantly decreased volume of the left medial superior frontal gyrus (SFGmed) was observed only in the late-stage SSNHL cohort. Furthermore, the volume of the left SFGmed is robustly correlated with both disease duration and patient prognosis. Our study offered neuroimaging evidence for the evolvement from functional to structural brain alterations of SSNHL patients with disease duration less than 1 month, which may explain, from a neuroimaging perspective, why early-stage SSNHL patients have better therapeutic responses and hearing recovery.

Representational drift in barrel cortex is receptive field dependent.

Cortical populations often exhibit changes in activity even when behavior is stable. How behavioral stability is maintained in the face of such 'representational drift' remains unclear. One possibility is that some neurons are stable despite broader instability. We examine whisker touch responses in superficial layers of primary vibrissal somatosensory cortex (vS1) over several weeks in mice stably performing an object detection task with two whiskers. While the number of touch neurons remained constant, individual neurons changed with time. Touch-responsive neurons with broad receptive fields were more stable than narrowly tuned neurons. Transitions between functional types were non-random: before becoming broadly tuned neurons, unresponsive neurons first pass through a period of narrower tuning. Broadly tuned neurons with higher pairwise correlations to other touch neurons were more stable than neurons with lower correlations. Thus, a small population of broadly tuned and synchronously active touch neurons exhibit elevated stability and may be particularly important for downstream readout.

Case report: Neural timing deficits prevalent in developmental disorders, aging, and concussions remediated rapidly by movement discrimination exercises.

Background: The substantial evidence that neural timing deficits are prevalent in developmental disorders, aging, and concussions resulting from a Traumatic Brain Injury (TBI) is presented. Objective: When these timing deficits are remediated using low-level movement-discrimination training, then high-level cognitive skills, including reading, attention, processing speed, problem solving, and working memory improve rapidly and effectively. Methods: In addition to the substantial evidence published previously, new evidence based on a neural correlate, MagnetoEncephalography physiological recordings, on an adult dyslexic, and neuropsychological tests on this dyslexic subject and an older adult were measured before and after 8-weeks of contrast sensitivity-based left-right movement-discrimination exercises were completed. Results: The neuropsychological tests found large improvements in reading, selective and sustained attention, processing speed, working memory, and problem-solving skills, never before found after such a short period of training. Moreover, these improvements were found 4 years later for older adult. Substantial MEG signal increases in visual Motion, Attention, and Memory/Executive Control Networks were observed following training on contrast sensitivity-based left-right movement-discrimination. Improving the function of magnocells using figure/ground movement-discrimination at both low and high levels in dorsal stream: (1) improved both feedforward and feedback pathways to modulate attention by enhancing coupled theta/gamma and alpha/gamma oscillations, (2) is adaptive, and (3) incorporated cycles of feedback and reward at multiple levels. Conclusion: What emerges from multiple studies is the essential role of timing deficits in the dorsal stream that are prevalent in developmental disorders like dyslexia, in aging, and following a TBI. Training visual dorsal stream function at low levels significantly improved high-level cognitive functions, including processing speed, selective and sustained attention, both auditory and visual working memory, problem solving, and reading fluency. A paradigm shift for treating cognitive impairments in developmental disorders, aging, and concussions is crucial. Remediating the neural timing deficits of low-level dorsal pathways, thereby improving both feedforward and feedback pathways, before cognitive exercises to improve specific cognitive skills provides the most rapid and effective methods to improve cognitive skills. Moreover, this adaptive training with substantial feedback shows cognitive transfer to tasks not trained on, significantly improving a person's quality of life rapidly and effectively.

Activation of p38 MAPK hinders the reactivation of visual cortical plasticity in adult amblyopic mice.

OBJECTIVE: To investigate the impact of p38 mitogen-activated protein kinase (MAPK) signaling on reactivating visual cortical plasticity in adult amblyopic mice. MATERIALS AND METHODS: Reverse suture (RS), environment enrichment (EE), and combined with left intracerebroventricular injection of p38 MAPK inhibitor (SB203580, SB) or p38 MAPK agonist (dehydrocorydaline hydrochloride, DHC) were utilized to treat adult amblyopic mice with monocular deprivation (MD). The visual water task, visual cliff test, and Flash visual-evoked potential were used to measure the visual function. Then, Golgi staining and transmission electron microscopy were used to assess the reactivation of structural plasticity in adult amblyopic mice. Western blot and immunohistochemistry detected the expression of ATF2, PSD-95, p38 MAPK, and phospho-p38 MAPK in the left visual cortex. RESULTS: No statistically significant difference was observed in the visual function in each pre-intervention group. Compared to pre-intervention, the visual acuity of deprived eyes was improved significantly, the impairment of visual depth perception was alleviated, and the P wave amplitude and C/I ratio were increased in the EE + RS, the EE + RS + SB, and the EE + RS + DMSO groups, but no significant difference was detected in the EE + RS + DHC group. Compared to EE + RS + DHC group, the density of dendritic spines was significantly higher, the synaptic density of the left visual cortex increased significantly, the length of the active synaptic zone increased, and the thickness of post-synaptic density (PSD) thickened in the left visual cortex of EE + RS, EE + RS + SB, and EE + RS + DMSO groups. And that, the protein expression of p-p38 MAPK increased while that of PSD-95 and ATF2 decreased significantly in the left visual cortex of the EE + RS + DHC group mice. CONCLUSION: RS and EE intervention improved the visual function and synaptic plasticity of the visual cortex in adult amblyopic mice. However, activating p38 MAPK hinders the recovery of visual function by upregulating the phosphorylation of p38 MAPK and decreasing the ATF2 protein expression.

Impaired long-term potentiation-like motor cortical plasticity in progressive supranuclear palsy.

OBJECTIVE: To elucidate long-term potentiation (LTP)-like effects on the primary motor cortical (M1) in progressive supranuclear palsy (PSP) and its relationships with clinical features. METHODS: Participants were 18 probable/possible PSP Richardson syndrome (PSP-RS) patients and 17 healthy controls (HC). We used quadripulse stimulation (QPS) over the M1 with an interstimulus interval of 5 ms (QPS-5) to induce LTP-like effect and analyzed the correlations between the degree of LTP-like effect and clinical features. We also evaluated cortical excitability using short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF) in 15 PSP patients and 17 HC. RESULTS: LTP-like effect after QPS in PSP was smaller than HC and negatively correlated with Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score, especially bradykinesia, but not with either age or any scores of cognitive functions. The SICI was abnormally reduced in PSP, but neither ICF nor SICF differed from those of normal subjects. None of these cortical excitability parameters correlated with any clinical features. CONCLUSIONS: LTP induction was impaired in PSP. The degree of LTP could reflect the severity of bradykinesia. The bradykinesia may partly relate with the motor cortical dysfunction. SIGNIFICANCE: The degree of motor cortical LTP could relate with the severity of motor symptoms in PSP.