Magnetic Stimulation Techniques Research Articles

Attentional Control of Gait and Falls: Is Cholinergic Dysfunction a Common Substrate in the Elderly and Parkinson’s Disease?

The aim of this study was to address whether deficits in the central cholinergic activity may contribute to the increased difficulty to allocate attention during gait in the elderly with heightened risk of falls. We recruited 50 participants with a history of two or more falls (33 patients with Parkinson’s Disease and 17 older adults) and 14 non-fallers age-matched adults. Cholinergic activity was estimated by means of short latency afferent inhibition (SAI), a transcranial magnetic stimulation (TMS) technique that assesses an inhibitory circuit in the sensorimotor cortex and is regarded as a global marker of cholinergic function in the brain. Increased difficulty to allocate attention during gait was evaluated by measuring gait performance under single and dual-task conditions. Global cognition was also assessed. Results showed that SAI was reduced in patients with PD than in the older adults (fallers and non-fallers) and in older adults fallers with respect to non-fallers. Reduction in SAI indicates less inhibition i.e., less cholinergic activity. Gait speed was reduced in the dual task gait compared to normal gait only in our faller population and changes in gait speed under dual task significantly correlated with the mean value of SAI. This association remained significant after adjusting for cognitive status. These findings suggest that central cholinergic activity may be a predictor of change in gait characteristics under dual tasking in older adults and PD fallers independently of cognitive status.

Perceptual learning modifies the functional specializations of visual cortical areas

Training can improve performance of perceptual tasks. This phenomenon, known as perceptual learning, is strongest for the trained task and stimulus, leading to a widely accepted assumption that the associated neuronal plasticity is restricted to brain circuits that mediate performance of the trained task. Nevertheless, learning does transfer to other tasks and stimuli, implying the presence of more widespread plasticity. Here, we trained human subjects to discriminate the direction of coherent motion stimuli. The behavioral learning effect substantially transferred to noisy motion stimuli. We used transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms underlying the transfer of learning. The TMS experiment revealed dissociable, causal contributions of V3A (one of the visual areas in the extrastriate visual cortex) and MT+ (middle temporal/medial superior temporal cortex) to coherent and noisy motion processing. Surprisingly, the contribution of MT+ to noisy motion processing was replaced by V3A after perceptual training. The fMRI experiment complemented and corroborated the TMS finding. Multivariate pattern analysis showed that, before training, among visual cortical areas, coherent and noisy motion was decoded most accurately in V3A and MT+, respectively. After training, both kinds of motion were decoded most accurately in V3A. Our findings demonstrate that the effects of perceptual learning extend far beyond the retuning of specific neural populations for the trained stimuli. Learning could dramatically modify the inherent functional specializations of visual cortical areas and dynamically reweight their contributions to perceptual decisions based on their representational qualities. These neural changes might serve as the neural substrate for the transfer of perceptual learning.

The Neuroanatomical Basis for Posterior Superior Parietal Lobule Control Lateralization of Visuospatial Attention.

The right hemispheric dominance in visuospatial attention in human brain has been well established. Converging evidence has documented that ventral posterior parietal cortex (PPC) plays an important role in visuospatial attention. The role of dorsal PPC subregions, especially the superior parietal lobule (SPL) in visuospatial attention is still controversial. In the current study, we used repetitive transcranial magnetic stimulation (rTMS) and diffusion magnetic resonance imaging (MRI) techniques to test the role of posterior SPL in visuospatial attention and to investigate the potential neuroanatomical basis for right hemisphere dominance in visuospatial function. Transcranial magnetic stimulation (TMS) results unraveled that the right SPL predominantly mediated visuospatial attention compared to left SPL. Anatomical connections analyses between the posterior SPL and the intrahemispheric frontal subregions and the contralateral PPC revealed that right posterior SPL has stronger anatomical connections with the ipsilateral middle frontal gyrus (MFG), with the ipsilateral inferior frontal gyrus (IFG), and with contralateral PPC than that of the left posterior SPL. Furthermore, these asymmetric anatomical connections were closely related to behavioral performances. Our findings indicate that SPL plays a crucial role in regulating visuospatial attention, and dominance of visuospatial attention results from unbalanced interactions between the bilateral fronto-parietal networks and the interhemispheric parietal network.

Technology-based assessment in patients with disorders of consciousness.

A number of studies highlight the difficulty in forming a diagnosis for patients with disorders of consciousness when this is established merely on behavioral assessments. Positron emission tomography (PET), functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and electroencephalography combined with transcranial magnetic stimulation (TMS-EEG) techniques are promoting the clinical characterization of this challenging population. With such technology-based "objective" tools, patients are also differentially able to follow simple commands and in some cases even communicate through modified brain activity. Consequently, the vegetative state and minimally conscious state have been revised and new nosologies have been proposed, namely the unresponsive wakefulness syndrome, the minimally conscious state plus and minus, and the functional locked-in syndrome. To our mind, an integration of different technical modalities is important to gain a holistic vision of the underlying pathophysiology of disorders of consciousness in general and to promote single-patient medical management in particular.

Cortical contributions to the flail leg syndrome: Pathophysiological insights

Cortical hyperexcitability has been identified as an intrinsic feature of amyotrophic lateral sclerosis (ALS). Consequently, the aim of the present study was to determine whether cortical hyperexcitability formed the pathophysiological basis for the flail leg syndrome (FL), an atypical ALS variant. Cortical excitability studies were undertaken on 18 FL patients, using the threshold tracking transcranial magnetic stimulation (TMS) technique, and results were compared to healthy controls, upper and lower limb-onset ALS as well as bulbar-onset and the flail arm variant ALS. Results showed that cortical hyperexcitability was a feature of FL and was heralded by a significant reduction of short-interval intracortical inhibition (FL 7.2 ± 1.8%; controls 13.2 ± 0.8%, p <0.01) and cortical silent period (CSP) duration (FL 181.7 ± 10.8ms; controls 209.8 ± 3.4ms; p <0.05) along with an increase in motor evoked potential amplitude (FL 29.2 ± 5.1%; controls 18.9 ± 1.2%, p <0.05). The degree of cortical hyperexcitability was comparable between FL and other ALS phenotypes, defined by site of disease onset. In addition, the CSP duration correlated with biomarkers of peripheral neurodegeneration in FL. In conclusion, cortical hyperexcitability is a feature of the flail leg syndrome, being comparable to other ALS phenotypes. Importantly, cortical hyperexcitability correlates with neurodegeneration, and as such may contribute to the underlying pathophysiology in FL.

11. Revisiting early diagnosis in ALS

Objectives The currently utilized diagnostic Awaji criteria in Amyotrophic Lateral Sclerosis (ALS) can result in a diagnostic delay of up to ten months. Subsequently we utilized a three pronged approach, initially an individual patient data (IPD) meta-analysis was undertaken to evaluate the diagnostic utility of the Awaji criteria. We then performed the first prospective multicenter study looking at the current diagnostic criteria. Finally we looked at the addition of a novel Transcranial magnetic stimulation (TMS) technique as an objective biomarker of upper motor neuron dysfunction, to further improve the current criteria. Methods An IPD meta-analysis was performed after communicating with key researchers and authors who published diagnostic studies looking at the Awaji criteria. In total IPD was available for 1086 individuals across 8 published studies. Statistical modelling was undertaken using SAS (9.3). The first prospective multicenter study looking at the Awaji criteria was undertaken in Sydney, Australia, according to the STARD criteria in 369 patients. Finally, a prospective multicenter study was undertaken looking at the diagnostic utility of Threshold tracking TMS in 333 patients. Results An IPD meta analysis of 1086 individuals revealed that the current Awaji criteria were more sensitive than the revised El Escorial criteria (rEEC) in all, except one study (7/8 studies). The Awaji criteria were more robust than the rEEC criteria (Sensitivity Awaji 70%, rEEC 45%, P 0.0001). The Awaji criteria performed better than the rEEC in both bulbar and limb onset disease (P 0.0001). In the multicenter prospective study, the Awaji criteria were compared in a cohort of 369 patients. Specificity was 100% across both criteria. Sensitivity was 57% with the Awaji and 39% with the rEEC criteria. Finally in the TMS prospective study, by objectively measuring evidence of UMN dysfunction, an extra 34% of patients could be diagnosed at the first visit. If TMS changes of cortical dysfunction were added to the current Awaji criteria, the sensitivity of the Awaji criteria could be increased to 86%. Furthermore 88% of Awaji ‘Possible’ patients could be reclassified as ‘Probable/Definite’. Conclusion Whilst an individual patient data meta-analysis revealed a better sensitivity for the Awaji criteria when compared to the older rEEC criteria, there were still a number of patients that could not be classified early. Furthermore all the studies that have looked at the Awaji criteria have been single centre in design, and generally retrospective in nature. The first prospective multicenter study looking at the Awaji criteria, revealed that the sensitivity of the Awaji criteria was lower than expected, most likely related to the inclusion of patients with early onset disease. Finally by utilizing an objective neurophysiological marker of UMN dysfunction, the diagnosis of ALS could be made earlier, when will then hopefully translate into earlier recruitment into clinical trials, ideally within the critical time frame for therapeutic response.

3. Cortical dysfunction in Machado–Jospeh disease

Background and aims Machado Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3) is an inherited neurodegenerative disorder characterized by cerebellar ataxia and variable expression of clinical features beyond the cerebellum, including amyotrophy and motor neurone disease. To gain further insights into motor cortex pathophysiology in MJD, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical dysfunction and whether this contributed to the development of clinical manifestations. Methods Clinical assessments were combined with threshold-tracking transcranial magnetic stimulation and peripheral nerve excitability techniques in 11 genetically characterized MJD patients and results compared to 40 age-matched healthy controls. The International Cooperative Ataxia Rating Scale (ICARS) was used to quantify the severity of ataxia in MJD patients. Results Clinical severity varied, ranging from presymptomatic in 2 patients to severe as reflected by the broad spectrum in ICARS score (range 0–59, median 27). Short-interval intracortical inhibition (SICI) was significantly reduced in presymptomatic (5.3 ± 0.5%) and symptomatic MJD patients (-1.3 ± 1.4%) compared to healthy controls (10.3 ± 0.7%, P 0.0001), evident prior to clinical onset of ataxia and related to worsening severity (R = −0.67, P 0.05). SICI reduction was accompanied by decreases in resting motor threshold and cortical silent period in pre-symptomatic patients and inversely related to severity of clinical ataxia. CMCT was also significantly prolonged in all MJD patients (symptomatic MJD 7.5 ± 0.4 ms; pre-symptomatic MJD 6.2 ± 0.5 ms controls 5.3 ± 0.2 ms, P 0.0005) and a feature of neurodegeneration related to clinical severity (R = 0.72, P = 0.01). Markers of peripheral motor neurodegeneration and excitability were not associated with cortical hyperexcitability or ataxia. Conclusion Simultaneous investigation of clinical status, central and peripheral nerve excitability has established that cortical dysfunction is evident in patients with MJD and precedes the development of cerebellar symptoms, ataxia and peripheral neurodegeneration. Taken together this indicates that cortical dysfunction may be an early feature that may herald widespread neurodegeneration in MJD.

Central and peripheral motor drive to the palatal muscles

To characterize the motor command of the soft palate muscles using a magnetic stimulation technique. Motor evoked potentials (MEPs) were recorded in 10right-handed and 5left-handed subjects at the midline of the palate or on the right or left hemipalate to peripheral and cortical magnetic stimulation. Mean palatal MEP amplitude ranged from 0.06 to 0.26mV to peripheral stimulation and from 0.36 to 1.09mV to cortical stimulation. In hemipalate recordings, MEPs to peripheral stimulation had greater amplitude when recorded ipsilaterally to the stimulation side, whereas MEPs to cortical stimulation were symmetrical. In midline recordings, right-handed subjects showed greater palatal MEP amplitude to right (rather than left) peripheral stimulation and to left (rather than right) cortical stimulation. Mean palatal MEP latency ranged from 4.0 to 4.1ms to peripheral stimulation and from 9.0 to 10.2ms to cortical stimulation; mean central conduction time ranged from 4.9 to 6.2ms. Palatal MEPs were easily and reliably obtained, including selective responses in each hemipalate. A bilateral cortical command of the palate is supported by our results, with a possible predominant motor drive from the left hemisphere in right-handed subjects.

Combining Multiple Data Acquisition Systems to Study Corticospinal Output and Multi-segment Biomechanics

Transcranial magnetic stimulation techniques allow for an in-depth investigation into the neural mechanisms that underpin human behavior. To date, the use of TMS to study human movement, has been limited by the challenges related to precisely timing the delivery of TMS to features of the unfolding movement and, also, by accurately characterizing kinematics and kinetics. To overcome these technical challenges, TMS delivery and acquisition systems should be integrated with an online motion tracking system. The present manuscript details technical innovations that integrate multiple acquisition systems to facilitate and advance the use of TMS to study human movement. Using commercially available software and hardware systems, a step-by-step approach to both the hardware assembly and the software scripts necessary to perform TMS studies triggered by specific features of a movement is provided. The approach is focused on the study of upper limb, planar, multi-joint reaching movements. However, the same integrative system is amenable to a multitude of sophisticated studies of human motor control.

Combining Multiple Data Acquisition Systems to Study Corticospinal Output and Multi-segment Biomechanics.

Transcranial magnetic stimulation techniques allow for an in-depth investigation into the neural mechanisms that underpin human behavior. To date, the use of TMS to study human movement, has been limited by the challenges related to precisely timing the delivery of TMS to features of the unfolding movement and, also, by accurately characterizing kinematics and kinetics. To overcome these technical challenges, TMS delivery and acquisition systems should be integrated with an online motion tracking system. The present manuscript details technical innovations that integrate multiple acquisition systems to facilitate and advance the use of TMS to study human movement. Using commercially available software and hardware systems, a step-by-step approach to both the hardware assembly and the software scripts necessary to perform TMS studies triggered by specific features of a movement is provided. The approach is focused on the study of upper limb, planar, multi-joint reaching movements. However, the same integrative system is amenable to a multitude of sophisticated studies of human motor control.

Cortical Function in Asymptomatic Carriers and Patients With C9orf72 Amyotrophic Lateral Sclerosis.

The identification of the chromosome 9 open reading frame 72 (c9orf72) gene hexanucleotide repeat expansion represents a major advance in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis. The pathophysiological mechanism by which the c9orf72 gene expansion leads to neurodegeneration is not yet elucidated. Cortical hyperexcitability is potentially an important pathophysiological process in sporadic ALS and familial ALS (FALS). To investigate whether cortical hyperexcitability forms the pathophysiological basis of c9orf72 FALS using the threshold-tracking transcranial magnetic stimulation technique. Prospective case-control single-center study that took place at hospitals and outpatient clinics from January 1, 2013, to January 1, 2015. Clinical and functional assessments along with transcranial magnetic stimulation studies were taken on 15 patients with c9orf72 FALS and 11 asymptomatic expansion carriers of c9orf72 who were longitudinally followed up for 3 years. Results were compared with 73 patients with sporadic ALS and 74 healthy control participants. Cortical excitability variables, including short-interval intracortical inhibition, were measured in patients with c9orf72 FALS and results were compared with asymptomatic c9orf72 carriers, patients with sporadic ALS, and healthy control participants. Mean (SD) short-interval intracortical inhibition was significantly reduced in patients with c9orf72 FALS (1.2% [1.8%]) and sporadic ALS (1.6% [1.2%]) compared with asymptomatic c9orf72 expansion carriers (10.2% [1.8%]; F = 16.1; P < .001) and healthy control participants (11.8% [1.0%]; F = 16.1; P < .001). The reduction of short-interval intracortical inhibition was accompanied by an increase in intracortical facilitation (P < .01) and motor-evoked potential amplitude (P < .05) as well as a reduction in the resting motor threshold (P < .05) and cortical silent period duration (P < .001). This study establishes cortical hyperexcitability as an intrinsic feature of symptomatic c9orf72 expansion-related ALS but not asymptomatic expansion carriers.

Neurophysiologic peculiarities of pediatric primary headaches

In spite of the high prevalence of primary headaches in pediatric age, most neurophysiologic studies in these diseases have concerned only adulthood. The neurophysiologic investigation of the pathophysiological mechanisms subtending migraine and tension-type headache in children and adolescents could be particularly interesting, since during the developmental age the migrainous phenotype is scarcely influenced by many environmental factors that can typically act on adult headache patients. Reduced habituation of evoked potential amplitude, that represents the neurophysiologic abnormality most frequently found in adult migraineurs, was confirmed also in migraine children, although it was shown to involve also children with tension-type headache. Some studies have shown abnormalities in the maturation of brain functions in migraine children and adolescents. While the visual system maturation is slowed in young migraineurs, the psychophysiological mechanisms subtending somatosensory spatial attention in migraine children are more similar to those of healthy adults than to those of age-matched controls. There are still some unexplored fields that will have to be subjects of future studies. In particular, the technique of transcranial magnetic stimulation, which has given an important contribution to our knowledge of primary headache pathophysiology in adults, has not yet been used in young migraineurs. It will possibly provide further elements about brain excitability in migraine children.

Overactive visuomotor connections underlie the photoparoxysmal response. A TMS study.

The photoparoxysmal response (PPR) involves rapid spread of epileptic activity from visual to parietal and frontal areas. We used a transcranial magnetic stimulation (TMS) technique to assess the physiologic connections between primary visual (V1) and motor (M1) areas in patients with idiopathic generalized epilepsy (IGE). We hypothesized that in PPR-positive patients, M1 would respond excessively to inputs from V1. Eleven photosensitive patients with IGE who had a PPR at the time of the study were compared with 10 similar patients without a PPR, and with 11 healthy subjects of similar age and sex. The connection between V1 and M1 was assessed in resting participants by delivering a conditioning stimulus (CS) over the phosphene hotspot of the visual cortex (intensity 90% phosphene threshold, PT) followed at random interstimulus intervals (ISIs; 15, 18, 21, 24, 27, 30, 35 and 40 msec) by a test stimulus (TS) over the left motor cortex to elicit a motor evoked potential (MEP) of ~1 mV from the right first dorsal interosseous muscle. In healthy subjects, a CS over V1 suppressed M1 at ISIs between 18 and 40 msec. Similar effects occurred in IGE patients without a PPR. This was not true in PPR-positive IGE patients, in whom this type of physiologic inhibition was significantly (p < 0.05) reduced. IGE patients with a PPR have an overactive functional response of M1 to inputs traveling from V1. This may represent one core factor for the anterior spread of the PPR itself and for the origin of the abnormal epileptic motor phenomenon, such as myoclonus.

Therapeutic advances in tremor.

Although tremor is a highly prevalent movement disorder, progress in this field is limited because of the poor understanding of many of the underlying conditions. This review summarizes recent treatment attempts since 2013. For essential tremor, recent innovations are phase I or II studies of Octanol, several clinically relevant refinements for deep brain stimulation, and the development of the new magnetic resonance imaging guided focused ultrasound technique. Further new invasive and noninvasive electrical and magnetic stimulation techniques have been tested for essential tremor and parkinsonian tremor. For multiple sclerosis tremor, some open-label observations have shown positive results (natalizumab, dalfampridine, levetiracetam), whereas controlled trials using cannabinoids have been negative. Functional tremor has shown a positive response to retrainment. Neuroprosthetic devices have been tested in a variety of tremor conditions. Several promising medical and surgical treatment trials are underway and will be completed shortly.

Probing the interaction of the ipsilateral posterior parietal cortex with the premotor cortex using a novel transcranial magnetic stimulation technique

ObjectiveFunctional imaging studies have shown that control of planned movement involves a distributed network that involves the premotor (PMv) and posterior parietal cortices (PPC). Similarly, anatomical studies show that these regions are densely interconnected via white matter tracts. We therefore hypothesized that the PPC influence over the motor cortex is partly via a connection with the PMv. MethodsUsing a novel three-pulse ipsilateral transcranial magnetic stimulation technique, we preconditioned the PPC (80% RMT) at ISIs from 4–15ms prior to stimulating the PMv and M1 at ISIs of 4 and 6ms. ResultsAs previously shown, PMv–M1 paired-pulse stimulation resulted in inhibition of the MEP (90% RMT, 4–6ms) and PPC–M1 paired-pulse stimulation resulted in facilitation of the MEP (90% RMT, 4–8ms). PPC–M1 paired-pulse stimulation at 80% RMT preconditioning had no effect on M1. PPC–PMv–M1 stimulation resulted in reversal of inhibition observed with PMv–M1 stimulation at ISIs ranging from 6 to 15ms. ConclusionsThe reversal of inhibition observed with PPC–PMv–M1 stimulation suggests that the parietal connection to the PMv plays a role in the modulation of M1. SignificanceThis is the first study to stimulate three intrahemispheric regions in order to test a disynaptic connection with M1. The described network may be important in a variety of movement disorders.

Exploring the Evolution of Cortical Excitability Following Acute Stroke

Background. Evolution of changes in intracortical excitability following stroke, particularly in the contralesional hemisphere, is being increasingly recognized in relation to maximizing the potential for functional recovery. Objective. The present study utilized a prospective longitudinal design over a 12-month period from stroke onset, to investigate the evolution of intracortical excitability involving both motor cortices and their relationship to recovery, and whether such changes were influenced by baseline stroke characteristics. Methods. Thirty-one patients with acute unilateral ischemic stroke were recruited from a tertiary hospital stroke unit. Comprehensive clinical assessments and cortical excitability were undertaken at stroke onset using a novel threshold-tracking paired-pulse transcranial magnetic stimulation technique, and repeated at 3-, 6-, and 12-month follow-up in 17 patients who completed the longitudinal assessment. Results. Shortly following stroke, short-interval intracortical inhibition (SICI) was significantly reduced in both lesioned and contralesional hemispheres that correlated with degree of recovery over the subsequent 3 months. Over the follow-up period, ipsilesional SICI remained reduced in all patient groups, while SICI over the contralesional hemisphere remained reduced only in the groups with cortical stroke or more baseline functional impairment. Conclusions. The current study has demonstrated that evolution of intracortical excitability, particularly over the contralesional hemisphere, may vary between patients with differing baseline stroke and clinical characteristics, suggesting that ongoing contralesional network recruitment may be necessary for those patients who have significant disruptions to the integrity of ipsilesional motor pathways. Results from the present series have implications for the development of neuromodulatory brain stimulation protocols to harness and thereby facilitate stroke recovery.

The Photoparoxysmal Response Reflects Abnormal Early Visuomotor Integration in the Human Motor Cortex.

Visual-paired associative stimulation (V-PAS) is a transcranial magnetic stimulation (TMS) technique able to investigate long-term potentiation (LTP) and depression (LTD)-like plasticity in the primary motor cortex (M1) arising through early visuomotor integration. Abnormal early visuomotor integration might contribute to the pathophysiology of intermittent photic stimulation (IPS)-induced photoparoxysmal response (PPR). We applied V-PAS in 25 healthy subjects (HS), 25 PPR-positive patients, with and without idiopathic generalized epilepsy (IGE), and 8 PPR-negative patients with IGE. V-PAS consisted of primary visual area activation achieved by visual evoked potentials coupled with TMS-induced M1 activation at 100ms interstimulus interval (ISI) (V-PAS100). Before and after V-PAS, we measured changes in motor evoked potentials (MEPs). We compared MEPs after 1Hz repetitive TMS (rTMS) and 0.25Hz-V-PAS100. To examine possible V-PAS-induced after-effects at other ISIs, we delivered V-PAS at 40 (V-PAS40) and 140ms ISIs (V-PAS140). To clarify whether V-PAS100 increases parieto-/premotor-to-M1 connectivity, before and after V-PAS100, we examined MEPs evoked by paired-pulse techniques. V-PAS100 increased MEPs more in PPR-positive patients than in HS. PPR-negative patients had normal response to V-PAS100. 1Hz-rTMS, 0.25Hz-V-PAS100 and V-PAS40 elicited similar responses in HS and PPR-positive patients, whereas V-PAS140 induced stronger after-effects in PPR-positive patients than HS. After V-PAS, MEPs elicited by facilitatory paired-pulse protocols decreased similarly in HS and PPR-positive patients. Conversely, MEPs elicited by inhibitory protocols decreased in HS, whereas in PPR-positive patients, they turned from inhibition to facilitation. We suggest that abnormal early visuomotor integration contributes to the pathophysiology of PPR.

Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study

Diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with substantial diagnostic delays. We assessed the sensitivity and specificity of a threshold tracking transcranial magnetic stimulation (TMS) technique, which might allow early detection of upper motor neuron dysfunction, for the diagnosis of the disorder. We did a prospective study of patients referred to three neuromuscular centres in Sydney, Australia, in accordance with the Standards for Reporting of Diagnostic Accuracy. Participants had definite, probable, or possible ALS, as defined by the Awaji criteria; or pure motor disorder with clinical features of upper and lower motor neuron dysfunction in at least one body region, progressing over a 6 month follow-up period; or muscle wasting and weakness for at least 6 months. All patients underwent threshold tracking TMS at recruitment (index test), with application of the reference standard, the Awaji criteria, to differentiate patients with ALS from those with non-ALS disorders. The investigators who did the index test were masked to the results of the reference test and all other investigations. The primary outcome measures were the sensitivity and specificity of TMS in differentiating ALS from non-ALS disorders; these measures were derived from receiver operator curve analysis. Between Jan 1, 2010, and March 1, 2014, we screened 333 patients; 281 met our inclusion criteria. We eventually diagnosed 209 patients with ALS and 68 with non-ALS disorders; the diagnosis of four patients was inconclusive. The threshold tracking TMS technique differentiated ALS from non-ALS disorders with a sensitivity of 73·21% (95% CI 66·66-79·08) and specificity of 80·88% (69·53-89·40) at an early stage in the disease. All patients tolerated the study well, and we did not record any adverse events from performance of the index test. The threshold tracking TMS technique reliably distinguishes ALS from non-ALS disorders and, if these findings are replicated in larger studies, could represent a useful diagnostic investigation when combined with the Awaji criteria to prove upper motor neuron dysfunction at early stages of ALS. Motor Neuron Disease Research Institute of Australia, National Health and Medical Research Council of Australia, and Pfizer.

Separate Pathways for Automatic and Intentional Visuo-Manual Reach Transformations: New Perspectives for Hemiparesia Rehabilitation Using Moving Objects

Reaching implies effector and target locations to be computed and updated continuously all along the visuo-motor transformation process, before and during movement execution, aiming in making these instantaneous locations coincide spatially. So instead of a neuro-anatomical dissociation between areas devoted to motor planning versus control, there might be 1) an automatic pathway of visual-to-motor transformation which relies on a comparison at the level of oculo-centric coordinates between visual target and hand locations from multimodal sources of information and 2) intentional pathways relying on the allocentric comparison between visual locations of the hand and of the target. Converging evidence from patients with optic ataxia, neuroimaging and transcranial magnetic stimulation techniques, and investigations in primates, has led to ascribe the automatic pathway to the direct connection between the medio-dorsal occipito-parietal cortex (the caudal part of the superior parietal lobule) and the dorsal premotor cortex (and further the primary motor cortex). Studies involving patients with visual agnosia (infero-temporal cortex), Parkinson disease (basal ganglia) or neglect (inferior parietal lobule) have put forward a more diffuse putative neural substrate for the intentional visual-to-motor pathway. If most strokes affect the intentional motor function while preserving the automatic pathway of visual-to-motor transformation, we propose a new rehabilitation method for hemiparesia relying on the stimulation of the automatic pathway using moving rather than stationary objects. Preliminary data are included.

Sport neuroscience revisited (?): a commentary.

Sport neuroscience revisited (?): a commentary.