Spatiotemporal dynamics of selective attention and visual conflict monitoring using a Stroop task.

Selective attention and conflict monitoring are daily human phenomena, yet the spatial and temporal neurological underpinnings of these processes are not fully understood. Current literature suggests these executive functions occur via diverse and highly interconnected neural networks, including top-down, bottom-up, and conflict-control loops. To investigate the spatiotemporal activity of these processes, we collected neuromagnetic data using magnetoencephalography (MEG) in 28 healthy adults (age 19-36), while they performed a computerized Stroop task based on color naming. We focused on low-frequency oscillations in the context of top-down control and hypothesized that conflict monitoring-related activity would first be observed in the left anterior cingulate cortex, followed by the left dorsolateral prefrontal cortex, and subsequently in the parietal and temporal lobes. Significant activity between 600-1000 ms post-stimulus onset was found for incongruent vs. congruent/neutral contrasts. Interestingly, spatiotemporal analysis did not provide evidence for a top-down pattern of activation, instead revealing a simultaneous pattern of activation in the frontal and temporal lobes. Most notable is the involvement of the left posterior inferior temporal cortex (pITC) and the left temporoparietal junction (TPJ), which have not conventionally been considered active players in attentional control. These results may be largely driven by alpha and beta oscillations from our sample population. Our findings challenge early theoretical models of top-down processing in the context of cognitive control from an attention perspective and also suggest a need to investigate attentional centers in the temporal lobe. Furthermore, the study highlights the valuable temporal data provided by MEG, which has been missing from previous studies.

An integrated full-head OPM-MEG system based on 128 zero-field sensors.

Compact optically-pumped magnetometers (OPMs) are now commercially available with noise floors reaching 10 fT/Hz1/2. However, to be used effectively for magnetoencephalography (MEG), dense arrays of these sensors are required to operate as an integrated turn-key system. In this study, we present the HEDscan, a 128-sensor OPM MEG system by FieldLine Medical, and evaluate its sensor performance with regard to bandwidth, linearity, and crosstalk. We report results from cross-validation studies with conventional cryogenic MEG, the Magnes 3,600 WH Biomagnetometer by 4-D Neuroimaging. Our results show high signal amplitudes captured by the OPM-MEG system during a standard auditory paradigm, where short tones at 1000 Hz were presented to the left ear of six healthy adult volunteers. We validate these findings through an event-related beamformer analysis, which is in line with existing literature results.

Hippocampal, basal ganglia and olfactory connectivity contribute to cognitive impairments in Parkinson's disease.

Cognitive impairment is increasingly recognized as a characteristic feature of Parkinson's disease (PD), yet relatively little is known about its underlying neurobiology. Previous investigations suggest that dementia in PD is associated with subcortical atrophy, but similar studies in PD with mild cognitive impairment have been mixed. Variability in cognitive phenotypes and diversity of PD symptoms suggest that a common neuropathological origin results in a multitude of impacts within the brain. These direct and indirect impacts of disease pathology can be investigated using network analysis. Functional connectivity, for instance, may be more sensitive than atrophy to decline in specific cognitive domains in the PD population. Fifty-eight participants with PD underwent a neuropsychological test battery and scanning with structural and resting state functional MRI in a comprehensive whole-brain association analysis. To investigate atrophy as a potential marker of impairment, structural gray matter atrophy was associated with cognitive scores in each cognitive domain using voxel-based morphometry. To investigate connectivity, large-scale networks were correlated with voxel time series and associated with cognitive scores using distance covariance. Structural atrophy was not associated with any cognitive domain, with the exception of visuospatial measures in primary sensory and motor cortices. In contrast, functional connectivity was associated with attention, executive function, language, learning and memory, visuospatial, and global cognition in the bilateral hippocampus, left putamen, olfactory cortex, and bilateral anterior temporal poles. These preliminary results suggest that cognitive domain-specific networks in PD are distinct from each other and could provide a network signature for different cognitive phenotypes.

Finger dexterity measured by the Grooved Pegboard test indexes Parkinson's motor severity in a tremor-independent manner.

Fine motor impairments are frequent complaints in people with Parkinson's disease (PD). While they may develop at an early stage of the disease, they become more problematic as the disease progresses. Tremors and fine motor symptoms may seem related, but evidence suggests two distinct phenomena. The purpose of our study was to investigate the relationships between fine motor skills and clinical characteristics of PD patients. We hypothesized worse fine motor skills to be associated with greater motor severity that is independent of tremor. We measured fine motor abilities using the Grooved Pegboard test (GPT) in each hand separately and collected clinical and demographics data in a cohort of 82 persons with PD. We performed regression analyses between GPT scores and a range of outcomes: motor severity, time from diagnosis, age and tremors. We also explored similar associations using finger and hand dexterity scores from a standardized PD rating scale. Our results indicate that scores on the GPT for each hand, as measures of manual dexterity, are associated with motor severity and time from diagnosis. The presence of tremors was not a confounding factor, as hypothesized, but age was associated with GPT scores for the dominant hand. Motor severity was also associated with hand and finger dexterity as measured by single items from the clinical Parkinson's rating scale. These findings suggest that the GPT to be useful tool for motor severity assessments of people with PD.

Does Prefrontal Glutamate Index Cognitive Changes in Parkinson's Disease?

Introduction: Cognitive impairment is a highly prevalent non-motor feature of Parkinson's disease (PD). A better understanding of the underlying pathophysiology may help in identifying therapeutic targets to prevent or treat dementia. This study sought to identify metabolic alterations in the prefrontal cortex (PFC), a key region for cognitive functioning that has been implicated in cognitive dysfunction in PD. Methods: Proton Magnetic Resonance Spectroscopy was used to investigate metabolic changes in the PFC of a cohort of cognitively normal individuals without PD (CTL), as well as PD participants with either normal cognition (PD-NC), mild cognitive impairment (PD-MCI), or dementia (PDD). Ratios to Creatine (Cre) resonance were obtained for glutamate (Glu), glutamine and glutamate combined (Glx), N-acetylaspartate (NAA), myoinositol (mI), and total choline (Cho), and correlated with cognitive scores across multiple domains (executive function, learning and memory, language, attention, visuospatial function, and global cognition) administered to the PD participants only. Results: When individuals retain cognitive capabilities, the presence of Parkinson's disease does not create metabolic disturbances in the PFC. However, when cognitive symptoms are present, PFC Glu/Cre ratios decrease with significant differences between the PD-NC and PPD groups. In addition, Glu/Cre ratios and memory scores were marginally associated, but not after Bonferroni correction. Conclusion: These preliminary findings indicate that fluctuations in prefrontal glutamate may constitute a biomarker for the progression of cognitive impairments in PD. We caution for larger MRS investigations of carefully defined PD groups.

Profiling Parkinson's disease cognitive phenotypes via resting-state magnetoencephalography.

Aberrant brain oscillations are a hallmark of Parkinson's disease (PD) pathophysiology and may be related to both motor and nonmotor symptoms. Mild cognitive impairment (MCI) affects many people with PD even at the time of diagnosis and conversion risks to PD dementia (PDD) are very high. Unfortunately, pharmacotherapies are not addressing cognitive symptoms in PD. Profiling PD cognitive phenotypes (e.g., MCI, PDD, etc.) may therefore help inform future treatments. Neurophysiological methods, such as magnetoencephalography (MEG), offer the advantage of observing oscillatory patterns, whose regional and temporal profiles may elucidate how cognitive changes relate to neural mechanisms. We conducted a resting-state MEG cross-sectional study of 89 persons with PD stratified into three phenotypic groups: normal cognition, MCI, and PDD, to identify brain regions and frequencies most associated with each cognitive profile. In addition, a neuropsychological battery was administered to assess each domain of cognition. Our data showed higher power in lower frequency bands (delta and theta) observed along with more severe cognitive impairment and associated with memory, language, attention, and global cognition. Of the total 119 brain parcels assessed during source analysis, widespread group differences were found in the beta band, with significant changes mostly occurring between the normal cognition and MCI groups. Moreover, bilateral frontal and left-hemispheric regions were particularly affected in the other frequencies as cognitive decline becomes more pronounced. Our results suggest that MCI and PDD may be qualitatively distinct cognitive phenotypes, and most dramatic changes seem to have happened when the PD brain shows mild cognitive decline.NEW & NOTEWORTHY Can we better stage cognitive decline in patients with Parkinson's disease (PD)? Here, we provide evidence that mild cognitive impairment, rather than being simply a milder form of dementia, may be a qualitatively distinct phase in its development. We suggest that the most dramatic neurophysiological changes may occur during the time the PD brain transitions from normal cognition to MCI, then compensatory changes further occur as the brain "switches" to a dementia state.

A Study Protocol for an Open-Label Feasibility Treatment Trial of Visual Snow Syndrome With Transcranial Magnetic Stimulation.

Background: Visual Snow (VS) syndrome is believed to be due to aberrant central visual processing. Positron Emission Tomography (PET) brain imaging and visual evoked potential studies provide evidence for excessive neuronal activity in the medial temporal lobe, specifically the lingual gyrus, and suggest the VS syndrome is a hyperexcitability syndrome. These data provide the basis for consideration of repetitive transcranial magnetic stimulation (rTMS) as a potential treatment for the VS syndrome. Objective: To publish the study protocol for a pilot study underway at the University of Colorado School of Medicine to investigate the use of rTMS intervention to improve symptoms and visual dysfunction associated with VS. The study aims to determine the adverse events and drop-out rate, evaluate performance of outcome measures, including a novel VS symptom scale, and describe changes in outcomes associated with treatment. Methods and Design: Up to 10 participants meeting criteria for VS syndrome, age 19-65 years, will undergo an open-label intervention consisting of 10 rTMS sessions, occurring 5 days a week over a 2-week period. Participants will complete pre-treatment and post-treatment assessments that include: the Colorado Visual Snow Scale (CVSS), the National Eye Institute Visual Functional Questionnaire-25 (VFQ-25), the General Anxiety Disorder-7 scale (GAD-7), and three psychophysical visual processing tasks. Discussion: Knowledge gained from this pilot study will inform future study planning and provide valuable lessons for future investigation of rTMS for the VS syndrome. An overview of study proceedings thus far demonstrates recruitment challenges associated with the COVID-19 pandemic, and additional challenges that are unique to the VS syndrome and to treatment schedules associated with TMS. Registration: This study has been approved by the Colorado Multiple Institutional Review Board. ClinicalTrials.gov Identifier: NCT04925232.

A novel approach to understanding Parkinsonian cognitive decline using minimum spanning trees, edge cutting, and magnetoencephalography.

Graph theory-based approaches are efficient tools for detecting clustering and group-wise differences in high-dimensional data across a wide range of fields, such as gene expression analysis and neural connectivity. Here, we examine data from a cross-sectional, resting-state magnetoencephalography study of 89 Parkinson's disease patients, and use minimum-spanning tree (MST) methods to relate severity of Parkinsonian cognitive impairment to neural connectivity changes. In particular, we implement the two-sample multivariate-runs test of Friedman and Rafsky (Ann Stat 7(4):697-717, 1979) and find it to be a powerful paradigm for distinguishing highly significant deviations from the null distribution in high-dimensional data. We also generalize this test for use with greater than two classes, and show its ability to localize significance to particular sub-classes. We observe multiple indications of altered connectivity in Parkinsonian dementia that may be of future use in diagnosis and prediction.

Randomized controlled trial of neurologic music therapy in Parkinson's disease: research rehabilitation protocols for mechanistic and clinical investigations.

BACKGROUND: Presently available medications and surgical treatments for Parkinson's disease have limited effects on fine motor problems and often leave patients with significant fine motor disability. Standard of care occupational therapy (OT) yields low efficacy, potentially due to a lack of standard protocols. Neurologic music therapy (NMT) techniques, especially rhythmic auditory stimulation which relies on interaction between rhythm and movement, have shown to be effective in PD gait rehabilitation possibly through their reliance on neural pathways that are not affected by PD. Therapeutic instrumental music performance (TIMP) is one other NMT technique that holds promise but which mode of action and efficacy has not been investigated in PD yet. METHODS: One hundred PD participants will be randomly assigned to receive 15 sessions of either TIMP with rhythm or TIMP without rhythm, standard of care OT, or to be waitlisted (control) over 5 consecutive weeks. Brain oscillatory responses will be collected using magnetoencephalography during an auditory-motor task to understand the underlying mechanisms. The Grooved Pegboard, the UPDRS III finger tap, and the finger-thumb opposition will be assessed to investigate clinical changes related to fine motor function. This project will also serve to confirm or refute our pilot data findings suggesting NMT relies on compensatory brain networks utilized by the PD brain to bypass the dysfunctional basal ganglia. DISCUSSION: This study aims to use standardized TIMP and OT research protocols for investigating the neuronal pathways utilized by each intervention and possibly study their efficacy with respect to fine motor rehabilitation via a randomized control trial in the PD population. TRIAL REGISTRATION: ClinicalTrials.gov NCT03049033 . Registered on September 29, 2020.

The emergent relationship between temporoparietal junction and anosognosia in Alzheimer's disease.

Anosognosia and impairment of insight are characteristic features of Alzheimer's disease (AD), which can lead to delays in appropriate medical care and significant family discord. The default mode network (DMN), a distributed but highly connected network of brain regions more active during rest than during task, is integrally involved in awareness. DMN dysfunction is common in AD, and disrupted communication between memory-related and self-related DMN networks is associated with anosognosia in AD patients. In addition, the temporoparietal junction (TPJ) is a key region of the "social brain" and also contributes to representations of the self. The exact classification of the TPJ within the DMN is unclear, though connections between the TPJ and DMN have been highlighted in multiple avenues of research. Here we discuss the relationship between the TPJ, DMN, and AD, as well as the potential involvement of the TPJ in anosognosia in AD. We review past and present findings to raise attention to the TPJ, with a specific emphasis on neuroimaging technologies which suggest a pivotal role of the TPJ within large-scale brain networks linked to anosognosia in AD.

Transcranial Magnetic Stimulation as Treatment for Mal de Debarquement Syndrome: Case Report and Literature Review.

This manuscript presents the case of an adult, male patient with mal de debarquement syndrome (MdDS); results from his experimental treatment with repetitive transcranial magnetic stimulation (rTMS) are also provided. Additionally, we included a review of literature related to the neurophysiology of MdDS and its treatment with rTMS. A 41-year-old man had been experiencing symptoms of MdDS, which initially emerged following a car ride, for 11 to 12 years. Pharmacologic approaches had failed to provide symptom relief; thus, we investigated an intervention using low-frequency (1 Hz) rTMS unilaterally for 2 consecutive weeks. The outcome measures included a standardized, computerized dynamic posturography test to quantify the patient's balance and identify abnormalities in his use of the sensory systems contributing to postural control, as well as the Hospital Anxiety and Depression Scale (HADS) to measure his anxiety and depression. An rTMS treatment log was created to document any adverse events. Following rTMS, the patient's balance scores improved significantly; these improvements were mostly related to the patient's increased reliance on the visual and vestibular systems. Our patient's HADS Anxiety and Depression subscores also showed improvement post-rTMS. The presented case study provides preliminary evidence that rTMS may be a noninvasive treatment option for improving balance, specifically in individuals with MdDS. This evidence can be used to further therapeutic research on, and provide strategies for treating, MdDS.

Auditory entrainment of motor responses in older adults with and without Parkinson's disease: An MEG study.

Medical therapies applied to Parkinson's disease (PD) have advanced tremendously since the 1960's based on advances in our understanding of the underlying neurophysiology. Behavioral therapies, such as rhythmic auditory stimulation (RAS), have been developed more recently and demonstrated efficacy. However, the neural mechanisms of RAS are only vaguely understood. In this study, we examined the neurophysiology of RAS using magnetoencephalography (MEG) in a sample of older adults with (21 people) and without PD (23 participants). All participants underwent high-density MEG during a beat-based cued tapping task with rhythmic and non-rhythmic patterns, and the resulting data were analyzed using a Bayesian image reconstruction method. Complex wavelet based time-frequency decomposition was used to compute inter-trial phase locking factor (PLF) to auditory stimuli for left and right signal space projection vectors. Tapping with a rhythm compared to a non-rhythmic sequence resulted in differential brain activity in each group: (i) a greater activation of temporal, motor and parietal areas was found in healthy adults; (ii) a greater reliance on parietal and frontal gyri was found in PD participants. During rhythmic tapping, older adults without PD had significantly stronger neural activity in bilateral frontal, supplementary and primary motor areas compared to those with PD. Conversely, older adults with PD exhibited significantly stronger activity in the bilateral parietal regions, as well as the rolandic operculum and bilateral supramarginal gyri, relative to their healthy peers. These data suggest that RAS mobilizes diverse oscillatory networks; Healthy controls may shift to frontal areas mobilization whereas PD patients rely on parietal areas to a greater extent, which may reflect frontal network dysfunction with compensation in PD, and could serve as specific regions of interest for further RAS studies.

Preliminary Neurophysiological Evidence of Altered Cortical Activity and Connectivity With Neurologic Music Therapy in Parkinson's Disease.

Neurologic Music Therapy (NMT) is a novel impairment-focused behavioral intervention system whose techniques are based on the clinical neuroscience of music perception, cognition, and production. Auditory Stimulation (RAS) is one of the NMT techniques, which aims to develop and maintain a physiological rhythmic motor activity through rhythmic auditory cues. In a series of breakthrough studies beginning in the mid-nineties, we discovered that RAS durably improves gait velocity, stride length, and cadence in Parkinson's disease (PD). No study to date reports the neurophysiological evidence of auditory-motor frequency entrainment after a NMT intervention in the Parkinson's community. We hypothesized that NMT-related motor improvements in PD are due to entrainment-related coupling between auditory and motor activity resulting from an increased functional communication between the auditory and the motor cortices. Spectral analysis in the primary motor and auditory cortices during a cued finger tapping task showed a simultaneous increase in evoked power in the beta-range along with an increased functional connectivity after a course of NMT in a small sample of three older adults with PD. This case study provides preliminary evidence that NMT-based motor rehabilitation may enhance cortical activation in the auditory and motor areas in a synergic manner. With a lack of both control subjects and control conditions, this neuroimaging case-proof of concept series of visible changes suggests potential mechanisms and offers further education on the clinical applications of musical interventions for motor impairments.

Rhythmic auditory cues shape neural network recruitment in Parkinson's disease during repetitive motor behavior.

It is well established clinically that rhythmic auditory cues can improve gait and other motor behaviors in Parkinson's disease (PD) and other disorders. However, the neural systems underlying this therapeutic effect are largely unknown. To investigate this question we scanned people with PD and age-matched healthy controls using functional magnetic resonance imaging (fMRI). All subjects performed a rhythmic motor behavior (right hand finger tapping) with and without simultaneous auditory rhythmic cues at two different speeds (1 and 4 Hz). We used spatial independent component analysis (ICA) and regression to identify task-related functional connectivity networks and assessed differences between groups in intra- and inter-network connectivity. Overall, the control group showed greater intra-network connectivity in perceptual and motor related networks during motor tapping both with and without rhythmic cues. The PD group showed greater inter-network connectivity between the auditory network and the executive control network, and between the executive control network and the motor/cerebellar network associated with the motor task performance. We interpret our results as indicating that the temporal rhythmic auditory information may assist compensatory mechanisms through network-level effects, reflected in increased interaction between auditory and executive networks that in turn modulate activity in cortico-cerebellar networks.

Central Visual Oscillopsia: Case Report and Review of the Literature.

Here we present a patient with persistent central visual oscillopsia, review the literature on this condition, and report results from an experimental intervention using repetitive transcranial magnetic stimulation. A 57-year-old man reported persistent visual oscillopsia after a traumatic brain injury suffered 20 years earlier. Symptoms were presumed to be of cortical origin given his normal eye movements, eye stability, and peripheral vestibular function. Furthermore, he reported oscillopsia with visual imagery during eye closure. Occipital lesions damaging white matter connections identified on magnetic resonance imaging were suspected to be the cause of his symptoms. Repetitive transcranial magnetic stimulation was applied to the left extrastriate visual motion area V5/MT, to bilateral V5/MT, and to bilateral striate visual area V1. The primary outcome measure was dynamic visual acuity. Secondary outcome measures were gaze stabilization testing and subjective improvement as noted by interviews of the patient. Gaze stabilization and dynamic visual acuity testing revealed no difference between pre- and post-intervention with repetitive transcranial magnetic stimulation. The patient reported symptomatic improvement in large-amplitude oscillations that persisted for at least 12 months, but stated that smaller-amplitude oscillations were unchanged. Pathologies associated with central oscillopsia in the literature include neuromyelitis optica spectrum disorder, stroke, migraine without infarction, and psychological trauma. The patient's reported improvement in large- but not small-amplitude oscillopsia suggests that these symptoms may result from different neurophysiological mechanisms. Repetitive transcranial magnetic stimulation did not result in clinically significant improvement, suggesting a need for other strategies to treat this condition.

Safety of Transcranial Magnetic Stimulation in Children: A Systematic Review of the Literature.

BACKGROUND: Data and best practice recommendations for transcranial magnetic stimulation (TMS) use in adults are largely available. Although there are fewer data in pediatric populations and no published guidelines, its practice in children continues to grow. METHODS: We performed a literature search through PubMed to review all TMS studies from 1985 to 2016 involving children and documented any adverse events. Crude risks were calculated per session. RESULTS: Following data screening we identified 42 single-pulse and/or paired-pulse TMS studies involving 639 healthy children, 482 children with central nervous system disorders, and 84 children with epilepsy. Adverse events occurred at rates of 3.42%, 5.97%, and 4.55% respective to population and number of sessions. We also report 23 repetitive TMS studies involving 230 central nervous system and 24 children with epilepsy with adverse event rates of 3.78% and 0.0%, respectively. We finally identified three theta-burst stimulation studies involving 90 healthy children, 40 children with central nervous system disorder, and no epileptic children, with adverse event rates of 9.78% and 10.11%, respectively. Three seizures were found to have occurred in central nervous system disorder individuals during repetitive TMS, with a risk of 0.14% per session. There was no significant difference in frequency of adverse events by group (P = 0.988) or modality (P = 0.928). CONCLUSIONS: Available data suggest that risk from TMS/theta-burst stimulation in children is similar to adults. We recommend that TMS users in this population follow the most recent adult safety guidelines until sufficient data are available for pediatric specific guidelines. We also encourage continued surveillance through surveys and assessments on a session basis.

Relevance of neuronal and glial NPC1 for synaptic input to cerebellar Purkinje cells.

Niemann-Pick type C disease is a rare and ultimately fatal lysosomal storage disorder with variable neurologic symptoms. The disease-causing mutations concern NPC1 or NPC2, whose dysfunction entails accumulation of cholesterol in the endosomal-lysosomal system and the selective death of specific neurons, namely cerebellar Purkinje cells. Here, we investigated whether neurodegeneration is preceded by an imbalance of synaptic input to Purkinje cells and whether neuronal or glial absence of NPC1 has different impacts on synapses. To this end, we prepared primary cerebellar cultures from wildtype or NPC1-deficient mice that are glia-free and highly enriched with Purkinje cells. We report that lack of NPC1 in either neurons or glial cells did not affect the excitability of Purkinje cells, the formation of dendrites or their excitatory synaptic activity. However, simultaneous absence of NPC1 from neuronal and glial cells impaired the presynaptic input to Purkinje cells suggesting a cooperative effect of neuronal and glial NPC1 on synapses.

Autonomous CaMKII requires further stimulation by Ca2+/calmodulin for enhancing synaptic strength.

A hallmark feature of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is generation of autonomous (Ca(2+)-independent) activity by T286 autophosphorylation. Biochemical studies have shown that "autonomous" CaMKII is ∼5-fold further stimulated by Ca(2+)/CaM, but demonstration of a physiological function for such regulation within cells has remained elusive. In this study, CaMKII-induced enhancement of synaptic strength in rat hippocampal neurons required both autonomous activity and further stimulation. Synaptic strength was decreased by CaMKIIα knockdown and rescued by reexpression, but not by mutants impaired for autonomy (T286A) or binding to NMDA-type glutamate receptor subunit 2B (GluN2B; formerly NR2B; I205K). Full rescue was seen with constitutively autonomous mutants (T286D), but only if they could be further stimulated (additional T305/306A mutation), and not with two other mutations that additionally impair Ca(2+)/CaM binding. Compared to rescue with wild-type CaMKII, the CaM-binding-impaired mutants even had reduced synaptic strength. One of these mutants (T305/306D) mimicked an inhibitory autophosphorylation of CaMKII, whereas the other one (Δstim) abolished CaM binding without introducing charged residues. Inhibitory T305/306 autophosphorylation also reduced GluN2B binding, but this effect was independent of reduced Ca(2+)/CaM binding and was not mimicked by T305/306D mutation. Thus, even autonomous CaMKII activity must be further stimulated by Ca(2+)/CaM for enhancement of synaptic strength.