TDP-43-Immunoreactive pathology in frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) with and without associated motor neuron disease

A proportion of patients with motor neuron disease (MND) exhibit frontotemporal dementia (FTD) and some patients with FTD develop the clinical features of MND. Frontotemporal lobar degeneration (FTLD) is the pathological substrate of FTD and some forms of this disease (referred to as FTLD-U) share with MND the common feature of ubiquitin-immunoreactive, tau-negative cellular inclusions in the cerebral cortex and hippocampus. Recently, the transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) has been found to be a major protein of the inclusions of FTLD-U with or without MND and these cases are referred to as FTLD with TDP-43 proteinopathy (FTLD-TDP). To clarify the relationship between MND and FTLD-TDP, TDP-43 pathology was studied in nine cases of FTLD-MND and compared with cases of familial and sporadic FTLD–TDP without associated MND. A principal components analysis (PCA) of the nine FTLD-MND cases suggested that variations in the density of surviving neurons in the frontal cortex and neuronal cytoplasmic inclusions (NCI) in the dentate gyrus (DG) were the major histological differences between cases. The density of surviving neurons in FTLD-MND was significantly less than in FTLD-TDP cases without MND, and there were greater densities of NCI but fewer neuronal intranuclear inclusions (NII) in some brain regions in FTLD-MND. A PCA of all FTLD-TDP cases, based on TDP-43 pathology alone, suggested that neuropathological heterogeneity was essentially continuously distributed. The FTLD-MND cases exhibited consistently high loadings on PC2 and overlapped with subtypes 2 and 3 of FTLD-TDP. The data suggest: (1) FTLD-MND cases have a consistent pathology, variations in the density of NCI in the DG being the major TDP-43-immunoreactive difference between cases, (2) there are considerable similarities in the neuropathology of FTLD-TDP with and without MND, but with greater neuronal loss in FTLD-MND, and (3) FTLD-MND cases are part of the FTLD-TDP ‘continuum’ overlapping with FTLD-TDP disease subtypes 2 and 3.

TDP-43-immunoreactive pathology in frontotemporal lobar degeneration with TDP proteinopathy (FTLD-TDP) with and without associated motor neuron disease (MND)

A proportion of patients with motor neuron disease (MND) exhibit frontotemporal dementia (FTD) and some patients with FTD develop the clinical features of MND. Frontotemporal lobar degeneration (FTLD) is the pathological substrate of FTD and some forms of this disease (referred to as FTLD-U) share with MND the common feature of ubiquitin-immunoreactive, tau-negative cellular inclusions in the cerebral cortex and hippocampus. Recently, the transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) has been found to be a major protein of the inclusions of FTLD-U with or without MND and these cases are referred to as FTLD with TDP-43 proteinopathy (FTLD-TDP). To clarify the relationship between MND and FTLD-TDP, TDP-43 pathology was studied in nine cases of FTLD-MND and compared with cases of familial and sporadic FTLD-TDP without associated MND. A principal components analysis (PCA) of the nine FTLD-MND cases suggested that variations in the density of surviving neurons in the frontal cortex and neuronal cytoplasmic inclusions (NCI) in the dentate gyrus (DG) were the major histological differences between cases. The density of surviving neurons in FTLD-MND was significantly less than in FTLD-TDP cases without MND, and there were greater densities of NCI but fewer neuronal intranuclear inclusions (NII) in some brain regions in FTLD-MND. A PCA of all FTLD-TDP cases, based on TDP-43 pathology alone, suggested that neuropathological heterogeneity was essentially continuously distributed. The FTLD-MND cases exhibited consistently high loadings on PC2 and overlapped with subtypes 2 and 3 of FTLD-TDP. The data suggest: (1) FTLD-MND cases have a consistent pathology, variations in the density of NCI in the DG being the major TDP-43-immunoreactive difference between cases, (2) there are considerable similarities in the neuropathology of FTLD-TDP with and without MND, but with greater neuronal loss in FTLD-MND, and (3) FTLD-MND cases are part of the FTLD-TDP 'continuum' overlapping with FTLD-TDP disease subtypes 2 and 3. © 2012 Nova Science Publishers, Inc. All rights reserved.

Neuropathological heterogeneity in frontotemporal lobar degeneration with TDP-43 proteinopathy: a quantitative study of 94 cases using principal components analysis

Studies suggest that frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) is heterogeneous with division into four or five subtypes. To determine the degree of heterogeneity and the validity of the subtypes, we studied neuropathological variation within the frontal and temporal lobes of 94 cases of FTLD-TDP using quantitative estimates of density and principal components analysis (PCA). A PCA based on the density of TDP-43 immunoreactive neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal intranuclear inclusions (NII), and dystrophic neurites (DN), surviving neurons, enlarged neurons (EN), and vacuolation suggested that cases were not segregated into distinct subtypes. Variation in the density of the vacuoles was the greatest source of variation between cases. A PCA based on TDP-43 pathology alone suggested that cases of FTLD-TDP with progranulin (GRN) mutation segregated to some degree. The pathological phenotype of all four subtypes overlapped but subtypes 1 and 4 were the most distinctive. Cases with coexisting motor neuron disease (MND) or hippocampal sclerosis (HS) also appeared to segregate to some extent. We suggest: 1) pathological variation in FTLD-TDP is best described as a ‘continuum’ without clearly distinct subtypes, 2) vacuolation was the single greatest source of variation and reflects the ‘stage’ of the disease, and 3) within the FTLD-TDP ‘continuum’ cases with GRN mutation and with coexisting MND or HS may have a more distinctive pathology.

Survival in the pre-senile dementia frontotemporal lobar degeneration with TDP-43 proteinopathy:effects of genetic, demographic and neuropathological variables

Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight. Survival was significantly reduced in cases with associated motor neuron disease (FTLD-MND) but increased with Alzheimer's disease (AD) or hippocampal sclerosis (HS) co-morbidity. Cox regression analysis suggested that reduced survival was associated with increased densities of neuronal cytoplasmic inclusions (NCI) while increased survival was associated with greater densities of enlarged neurons (EN) in the frontal and temporal lobes. The data suggest that: (1) survival in FTLD-TDP is more prolonged than typical in pre-senile dementia but shorter than some clinical subtypes such as the semantic variant of primary progressive aphasia (svPPA), (2) MND co-morbidity predicts poor survival, and (3) NCI may develop early and EN later in the disease. The data have implications for both neuropathological characterization and subtyping of FTLD-TDP.

Strategic development and physicochemical analysis of oral preparations for unstable drugs

Oral liquid formulations are ideal dosage forms for paediatric, geriatric and patient with dysphagia. Dysphagia is prominent among patients suffering from stroke, motor neurone disease, advanced Alzheimer’s and Parkinson’s disease. However oral liquid preparations are particularly difficult to formulate for hydrophobic and unstable drugs. Therefore current methods employed in solving this issue include the use of ‘specials’ or extemporaneous preparations. In order to challenge this, the government has encouraged research into the field of oral liquid formulations, with the EMEA and MHRA publishing list of drugs of interest. The current work investigates strategic formulation development and characterisation of select API’s (captopril, gliclazide, melatonin, L-arginine and lansoprazole), each with unique obstacles to overcome during solubilisation, stabilisation and when developing a palatable dosage from. By preparing a validated calibration protocol for each of the drug candidates, the oral liquid formulations were assessed for stability, according to the ICH guidelines along with thorough physiochemical characterisation. The results showed that pH and polarity of the solvent had the greatest influence on the extent of drug solubilisation, with inclusion of antioxidants and molecular steric hindrance influencing the extent of drug stability. Captopril, a hydrophilic ACE inhibitor (160 mg.mL-1), undergoes dimerisation with another captopril molecule. It was found that with the addition of EDTA and HP-β-CD, the drug molecule was stabilised and prevented from initiating a thiol induced first order free radical oxidation. The cyclodextrin provided further steric hindrance (1:1 molar ratio) resulting in complete reduction of the intensity of sulphur like smell associated with captopril. Palatability is a crucial factor in patient compliance, particularly when developing a dosage form targeted towards paediatrics. L-arginine is extremely bitter in solution (148.7 g.L-1). The addition of tartaric acid into the 100 mg.mL-1 formulation was sufficient to mask the bitterness associated with its guanidium ions. The hydrophobicity of gliclazide (55 mg.L-1) was strategically challenged using a binary system of a co-solvent and surfactant to reduce the polarity of the medium and ultimately increase the solubility of the drug. A second simpler method was developed using pH modification with L-arginine. Melatonin has two major obstacles in formulation: solubility (100 μg.mL-1) and photosensitivity, which were both overcome by lowering the dielectric constant of the medium and by reversibly binding the drug within the cyclodextrin cup (1:1 ratio). The cyclodextrin acts by preventing UV rays from reaching the drug molecule and initiated the degradation pathway. Lansoprazole is an acid labile drug that could only be delivered orally via a delivery vehicle. In oral liquid preparations this involved nanoparticulate vesicles. The extent of drug loading was found to be influenced by the type of polymer, concentration of polymer, and the molecular weight. All of the formulations achieved relatively long shelf-lives with good preservative efficacy.

Modulation of neuronal network activity in the primary motor cortex

In the present study I investigated the mechanisms of modulation of neuronal network activity in rat primary motor cortex using pharmacological manipulations employing the in vitro brain slice technique. Preparation of the brain slice in sucrose-based aCSF produced slices with low viability. Introducing the neuroprotectants N-acetyl-cysteine, taurine and aminoguanidine to the preparatory method saw viability of slices increase significantly. Co-application of low dose kainic acid and carbachol consistently generated beta oscillatory activity in M1. Analyses indicated that network activity in M1 relied on the involvement of GABAA receptors. Dose-response experiments performed in M1 showed that beta activity can be modulated by benzodiazepine site ligands. Low doses of positive allosteric modulators consistently desynchronised beta oscillatory activity, a mechanism that may be driven by a1-subunit containing GABAA receptors. Higher doses increased the power of beta oscillatory activity. Whole-cell recordings in M1 uncovered three interneuronal subtypes regularly encountered in M1; Fast-spiking, regular-spiking non-Pyramidal and low threshold spiking. With the paradoxical effects of positive allosteric modulators in mind, subsequent voltage-clamp recordings in FS cells revealed a constitutively active tonic inhibitory current that could be modulated by zolpidem in two different ways. Low dose zolpidem increased the tonic inhibitory current in FS cells, consistent with the desynchronisation of network oscillatory activity seen at this concentration. High dose zolpidem decreased the inhibitory tonic current seen in FS cells, coinciding with an increase in oscillatory power. These studies indicate a fundamental role for a tonic inhibitory current in the modulation of network activity. Furthermore, desynchronisation of beta activity in M1 decreased as viability of the in vitro brain slice increased, suggesting that the extent of desynchronisation is dependent upon the pathophysiological state of the network. This indicates that low dose zolpidem could be used as a therapeutic agent specifically for the desynchronisation of pathological oscillations in oscillopathies such as Parkinson’s disease.

Visual signs and symptoms of Parkinson's disease

Parkinson's disease (PD) is a common disorder of middle-aged and elderly people, in which there is degeneration of the extra-pyramidal motor system. In some patients, the disease is associated with a range of visual signs and symptoms, including defects in visual acuity, colour vision, the blink reflex, pupil reactivity, saccadic and smooth pursuit movements and visual evoked potentials. In addition, there may be psychophysical changes, disturbances of complex visual functions such as visuospatial orientation and facial recognition, and chronic visual hallucinations. Some of the treatments associated with PD may have adverse ocular reactions. If visual problems are present, they can have an important effect on overall motor function, and quality of life of patients can be improved by accurate diagnosis and correction of such defects. Moreover, visual testing is useful in separating PD from other movement disorders with visual symptoms, such as dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Although not central to PD, visual signs and symptoms can be an important though obscure aspect of the disease and should not be overlooked.

Neuropathological changes in ten cases of neuronal intermediate filament inclusion disease (NIFID):A study using α-internexin immunohistochemistry and principal components analysis (PCA)

Ten cases of neuronal intermediate filament inclusion disease (NIFID) were studied quantitatively. The α-internexin positive neurofilament inclusions (NI) were most abundant in the motor cortex and CA sectors of the hippocampus. The densities of the NI and the swollen achromatic neurons (SN) were similar in laminae II/III and V/VI but glial cell density was greater in V/VI. The density of the NI was positively correlated with the SN and the glial cells. Principal components analysis (PCA) suggested that PC1 was associated with variation in neuronal loss in the frontal/temporal lobes and PC2 with neuronal loss in the frontal lobe and NI density in the parahippocampal gyrus. The data suggest: 1) frontal and temporal lobe degeneration in NIFID is associated with the widespread formation of NI and SN, 2) NI and SN affect cortical laminae II/III and V/VI, 3) the NI and SN affect closely related neuronal populations, and 4) variations in neuronal loss and in the density of NI were the most important sources of pathological heterogeneity. © Springer-Verlag 2005.

Pharmacologically induced and stimulus evoked rhythmic neuronal oscillatory activity in the primary motor cortex in vitro

Parkinson's disease (PD) is associated with enhanced synchronization of neuronal network activity in the beta (15-30 Hz) frequency band across several nuclei of the basal ganglia (BG). Deep brain stimulation of the subthalamic nucleus (STN) appears to reduce this pathological oscillation, thereby alleviating PD symptoms. However, direct stimulation of primary motor cortex (M1) has recently been shown to be effective in reducing symptoms in PD, suggesting a role for cortex in patterning pathological rhythms. Here, we examine the properties of M1 network oscillations in coronal slices taken from rat brain. Oscillations in the high beta frequency range (layer 5, 27.8 +/- 1.1 Hz, n=6) were elicited by co-application of the glutamate receptor agonist kainic acid (400 nM) and muscarinic receptor agonist carbachol (50 mu M). Dual extracellular recordings, local application of tetrodotoxin and recordings in M1 micro-sections indicate that the activity originates within deep layers V/VI. Beta oscillations were unaffected by specific AMPA receptor blockade, abolished by the GABA type A receptor (GABAAR) antagonist picrotoxin and the gap-junction blocker carbenoxolone, and modulated by pentobarbital and zolpidem indicating dependence on networks of GABAergic interneurons and electrical coupling. High frequency stimulation (HFS) at 125 Hz in superficial layers, designed to mimic transdural/transcranial stimulation, generated gamma oscillations in layers 11 and V (incidence 95%, 69.2 +/- 7.3 Hz, n=17) with very fast oscillatory components (VFO; 100-250 Hz). Stimulation at 4 Hz, however, preferentially promoted theta activity (incidence 62.5%, 5.1 +/- 0.6 Hz, n=15) that effected strong amplitude modulation of ongoing beta activity. Stimulation at 20 Hz evoked mixed theta and gamma responses. These data suggest that within M1, evoked theta, gamma and fast oscillations may coexist with and in some cases modulate pharmacologically induced beta oscillations.

Visual symptoms in Parkinson's disease

Parkinson’s disease (PD) is a common disorder of middle-aged and elderly people in which degeneration of the extrapyramidal motor system causes significant movement problems. In some patients, however, there are additional disturbances in sensory systems including loss of the sense of smell and auditory and/or visual problems. This article is a general overview of the visual problems likely to be encountered in PD. Changes in vision in PD may result from alterations in visual acuity, contrast sensitivity, colour discrimination, pupil reactivity, eye movements, motion perception, visual field sensitivity and visual processing speeds. Slower visual processing speeds can also lead to a decline in visual perception especially for rapidly changing visual stimuli. In addition, there may be disturbances of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations. Some of the treatments used in PD may also have adverse ocular reactions. The pattern electroretinogram (PERG) is useful in evaluating retinal dopamine mechanisms and in monitoring dopamine therapies in PD. If visual problems are present, they can have an important effect on the quality of life of the patient, which can be improved by accurate diagnosis and where possible, correction of such defects.

Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease

Background - Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement. Objectives - To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and cognitive impairment in Parkinson’s disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease). Search methods - The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly. Reference lists of relevant studies were searched for additional trials. Selection criteria - Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson’s disease (CIND-PD). Data collection and analysis - Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0. Main results - Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000). For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001). For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial. For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01). For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03). For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03). Authors' conclusions - The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Oculo-visual dysfunction in Parkinson's disease

This review describes the oculo-visual problems likely to be encountered in Parkinson's disease (PD) with special reference to three questions: (1) are there visual symptoms characteristic of the prodromal phase of PD, (2) is PD dementia associated with specific visual changes, and (3) can visual symptoms help in the differential diagnosis of the parkinsonian syndromes, viz. PD, progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD)? Oculo-visual dysfunction in PD can involve visual acuity, dynamic contrast sensitivity, colour discrimination, pupil reactivity, eye movement, motion perception, and visual processing speeds. In addition, disturbance of visuo-spatial orientation, facial recognition problems, and chronic visual hallucinations may be present. Prodromal features of PD may include autonomic system dysfunction potentially affecting pupil reactivity, abnormal colour vision, abnormal stereopsis associated with postural instability, defects in smooth pursuit eye movements, and deficits in visuo-motor adaptation, especially when accompanied by idiopathic rapid eye movement (REM) sleep behaviour disorder. PD dementia is associated with the exacerbation of many oculo-visual problems but those involving eye movements, visuo-spatial function, and visual hallucinations are most characteristic. Useful diagnostic features in differentiating the parkinsonian symptoms are the presence of visual hallucinations, visuo-spatial problems, and variation in saccadic eye movement dysfunction.

Spatial relationships between diffuse prion protein deposits and neuronal perikarya in variant Creutzfeldt-Jakob disease

Two morphological types of prion protein (PrPsc) deposit occur in the cerebral cortex of cases of variant Creutzfeldt-Jakob disease (vCJD), viz., diffuse and florid deposits. The objective of this study was to determine whether diffuse-type PrPsc deposits in areas of the cerebral cortex in six cases of the variant form of CJD (vCJD) were spatially correlated with neurons and whether diffuse deposit size was related to the number of adjacent neurons contributing PrPsc. In cortical gyri, density of surviving neurons was 5.38-12.15 per 50 × 200 µm sample field, neurons being distributed randomly, regularly or were clustered relative to the pia mater. Density of neurons embedded within diffuse deposits, however, was three to eight times their overall density in the section. In addition, diffuse deposit area was positively correlated with the number of embedded neurons. The frequency distribution of diffuse deposits with 0, 1, 2, 3, …, n, embedded neurons did not deviate from a Poisson distribution. These results suggest: (1) diffuse deposits in vCJD develop in situ as a result of the formation of PrPsc in relation to clusters of neurons, (2) size of a diffuse deposit is determined by the number of adjacent neurons which develop PrPsc, and (3) the probability that PrPsc is formed in relation to one neuron is independent of that of its neighbour.

Reflecting on mirror mechanisms:motor resonance effects during action observation only present with low-intensity transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) studies indicate that the observation of other people's actions influences the excitability of the observer's motor system. Motor evoked potential (MEP) amplitudes typically increase in muscles which would be active during the execution of the observed action. This 'motor resonance' effect is thought to result from activity in mirror neuron regions, which enhance the excitability of the primary motor cortex (M1) via cortico-cortical pathways. The importance of TMS intensity has not yet been recognised in this area of research. Low-intensity TMS predominately activates corticospinal neurons indirectly, whereas high-intensity TMS can directly activate corticospinal axons. This indicates that motor resonance effects should be more prominent when using low-intensity TMS. A related issue is that TMS is typically applied over a single optimal scalp position (OSP) to simultaneously elicit MEPs from several muscles. Whether this confounds results, due to differences in the manner that TMS activates spatially separate cortical representations, has not yet been explored. In the current study, MEP amplitudes, resulting from single-pulse TMS applied over M1, were recorded from the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles during the observation of simple finger abductions. We tested if the TMS intensity (110% vs. 130% resting motor threshold) or stimulating position (FDI-OSP vs. ADM-OSP) influenced the magnitude of the motor resonance effects. Results showed that the MEP facilitation recorded in the FDI muscle during the observation of index-finger abductions was only detected using low-intensity TMS. In contrast, changes in the OSP had a negligible effect on the presence of motor resonance effects in either the FDI or ADM muscles. These findings support the hypothesis that MN activity enhances M1 excitability via cortico-cortical pathways and highlight a methodological framework by which the neural underpinnings of action observation can be further explored. © 2013 Loporto et al.

Oscillatory beta activity mediates neuroplastic effects of motor cortex stimulation in humans

Continuous theta burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation protocol that can inhibithumanmotor cortex (M1) excitability and impair movement for ≤1 h. While offering valuable insights into brain function and potential therapeutic benefits, these neuroplastic effects are highly variable between individuals. The source of this variability, and the electrophysiological mechanisms underlying the inhibitory after-effects, are largely unknown. In this regard, oscillatory activity at beta frequency (15-35 Hz) is of particular interest as it is elevated in motor disorders such as Parkinson's disease and modulated during the generation of movements. Here, we used a source-level magnetoencephalography approach to investigate the hypothesis that the presence of neuroplastic effects following cTBS is associated with concurrent changes in oscillatory M1 beta activity. M1 cortices were localized with a synthetic aperture magnetometry beamforming analysis of visually cued index finger movements. Virtual electrode analysis was used to reconstruct the spontaneous and movement-related oscillatory activity in bilateral M1 cortices, before and from 10 to 45 min after cTBS. We demonstrate that 40 s of cTBS applied over left M1 reduced corticospinal excitability in the right index finger of 8/16 participants. In these responder participants only, cTBS increased the power of the spontaneous beta oscillations in stimulated M1 and delayed reaction times in the contralateral index finger. No further changes were observed in the latency or power of movement-related beta oscillations. These data provide insights into the electrophysiological mechanisms underlying cTBS-mediated impairment of motor function and demonstrate the association between spontaneous oscillatory beta activity in M1 and the inhibition of motor function. © 2013 the authors.