B. Mohammadi

Changes of resting state brain networks in amyotrophic lateral sclerosis.

The defining feature of amyotrophic lateral sclerosis is degeneration of upper and lower motor neurons but extramotor involvement, evidenced for example by executive dysfunction, has also been demonstrated. Here we employed a novel functional imaging approach, the analysis of resting state activity, followed by the definition of functionally connected brain networks by independent component analysis (ICA) to assess differences between ALS patients (n=20) and healthy controls (n=20). ICA analysis revealed 5 typical brain networks among which the so-called default mode network and the sensori-motor network showed distinct differences between patients and controls. The default mode network showed less activation in patients in several regions including the ventral anterior cingulate cortex, posterior cingulate cortex and the left and right inferior parietal cortex, regions that have been linked previously to executive functions. The sensori-motor network showed group differences in the premotor cortex. We propose that resting state analysis affords a new and simple means to assess disease-related neurofunctional alterations in widespread brain networks. A decisive advantage is that no task is demanded from the subjects and, thus, the problem of differential task difficulty and effort between groups is circumvented.

Emotional and cognitive aspects of empathy and their relation to social cognition—an fMRI-study

The present functional magnetic resonance imaging (fMRI) study sought to characterize neural processes related to aspects of empathy and social cognition. It has been hypothesized previously that merely observing emotions in others automatically activates associated representations of the emotional state in the observer. We tested this prediction by presenting drawings depicting either one or two persons in an emotionally charged or neutral situation. Importantly and in contrast to previous imaging studies on empathy or social cognition, we did not instruct participants to assess the depicted persons feelings or thoughts, but told them to simply watch the pictures to be able to perform a memory task unrelated to the main experimental question. This novel design allowed us to assess automatically elicited empathy-related effects (contrasting emotional and neutral situations) and to compare them with automatic social cognitive processes (contrasting stimuli with two persons vs. one person). We observed empathy-related increased hemodynamic responses in areas previously shown to be related to emotion processing (ventromedial and ventrolateral prefrontal cortex, PFC) and to social cognitive processes (superior temporal sulcus, STS, and medial PFC). The medial PFC activation was negatively correlated with participants predisposition to feel distressed in emotional social situations, suggesting that interindividual differences in these higher-order functions might also impact empathic responses in social interactions.

Functional neuroimaging at different disease stages reveals distinct phases of neuroplastic changes in amyotrophic lateral sclerosis.

Some previous functional magnetic resonance imaging (fMRI) studies have revealed increased activation in amyotrophic lateral sclerosis (ALS) patients but longitudinal data on such activation changes are lacking. To assess the time course of changes in fMRI patterns and their potential contribution to the understanding of ALS pathophysiology, we, therefore, investigated a total of 22 patients with ALS and matched control participants while they performed a blocked motor task. Patients were assigned to three groups according to whether they had no (MRC grade 5), mild (MRC 4), or marked (MRC 3) weakness of the examined right hand. Significant activations were seen in primary motor and premotor cortex, somatosensory cortex, supplementary motor area and subcortical areas in all groups. The size of the activated area in the contralateral sensorimotor cortex was increased to a similar degree in all three ALS groups compared to control participants irrespective of weakness on clinical examination. Whereas movement related signal change and beta weights extracted from the activated cluster were unchanged relative to controls in ALS patients with no weakness, a marked decrease of these parameters was seen in patients with weakness. Two distinct stages of neuroplastic changes could be identified in ALS (first: increase of the activated area in contralateral sensorimotor cortex; second: reduction of signal change and beta weights with increasing weakness). We interpret the increase of the activated area as a result of decreased intracortical inhibition and the reduction of movement related signal change and beta weights as a consequence of loss of upper motor neurons. Hum Brain Mapp, 2011.

Music-Supported Therapy induces plasticity in the sensorimotor cortex in chronic stroke: A single-case study using multimodal imaging (fMRI-TMS)

Primary objective: Music-Supported Therapy (MST) has been developed recently in order to improve the use of the affected upper extremity after stroke. This study investigated the neuroplastic mechanisms underlying effectiveness in a patient with chronic stroke. Methods: MST uses musical instruments, a midi piano and an electronic drum set emitting piano sounds, to retrain fine and gross movements of the paretic upper extremity. Data are presented from a patient with a chronic stroke (20 months post-stroke) with residual right-sided hemiparesis who took part in 20 MST sessions over the course of 4 weeks. Results: Post-therapy, a marked improvement of movement quality, assessed by 3D movement analysis, was observed. Moreover, functional magnetic resonance imaging (fMRI) of a sequential hand movement revealed distinct therapy-related changes in the form of a reduction of excess contralateral and ipsilateral activations. This was accompanied by changes in cortical excitability evidenced by transcranial magnetic stimulation (TMS). Functional MRI in a music listening task suggests that one of the effects of MST is the task-dependent coupling of auditory and motor cortical areas. Conclusions: The MST appears to be a useful neurorehabilitation tool in patients with chronic stroke and leads to neural reorganization in the sensorimotor cortex.

Brain activations reflect individual discount rates in intertemporal choice

Humans discount the value of future rewards following a hyperbolic function and thus may prefer a smaller immediate reward over a larger delayed reward. Marked interindividual differences in the steepness of this discounting function can be observed which can be quantified by the parameter k of the discount function. Here, we asked how differences in delay discounting behaviour are reflected by brain activation patterns. Sixteen healthy participants were studied in a slow event-related functional magnetic resonance imaging experiment at 3T. In each trial, participants had to decide between a smaller but immediately available monetary reward (ranging between 14 and 84 Euro) and a larger delayed reward (26 to 89 Euro; delay 5 to 169days) by button press. Participants had the chance to receive the reward corresponding to one of their decisions at the end of the experiment. As expected, participants differed widely with respect to the steepness of their discount function. By contrasting decisions at or near the individual participants indifference point (as determined by parameter k) with trials either well below or well above this point two different brain networks with opposing activation patterns were revealed: Trials below or above the indifference point were associated with activation in the ventral striatum and ventromedial prefrontal cortex, whereas decisions at the indifference point gave rise to activation in medial prefrontal cortex. The opposite effects in the two systems at individual indifference point were interpreted as a reflection of response conflict.

Decreased brain activation to tongue movements in amyotrophic lateral sclerosis with bulbar involvement but not Kennedy syndrome

Neuroimaging studies in amyotrophic lateral sclerosis (ALS) investigating movements of the hands have in general found increased activation compared to healthy controls, which has been interpreted in terms of cortical adaptation as a result of corticospinal tract damage. Here, we investigated brain activations to vertical tongue movements using functional MRI at 3xa0tesla. Whereas healthy controls, patients with Kennedy syndrome, and ALS patients without bulbar involvement showed robust and indistinguishable activations in pre- and postcentral areas and the thalamus, ALS patients with bulbar involvement showed a significant decrease of cortical activity and missing thalamic activity. This decrease stands in marked contrast to the increase of activity observed in ALS patients when performing limb movements. We discuss these divergent findings with regard to the different physiological properties of tongue and limb movements. These findings may also help to explain the faster time-course of the disease in patients with bulbar involvement.

Experience with long-term treatment with albumin-supplemented botulinum toxin type A

In earlier studies, we have demonstrated the efficacy of albumin-supplemented botulinum toxin type A (ASBTA) in principle. Here, we present long-term data from 106 patients who received ASTBA over 5–10xa0years for the treatment of cervical dystonia, blepharospasm and hemifacial spasm. Vials of Dysport® were diluted in 0.1% albumin solution to a concentration of 25xa0units/ml. Overall patients and indications, the mean latency to response was 7.1xa0±xa02.2xa0days, the mean duration of response was 12.3xa0±xa03.1xa0weeks and the mean global clinical improvement (scale 0–3) was 2.6xa0±xa00.2. Only one patient had neutralizing antibodies against BoNT-A. Side effects were less frequent than known for conventional BoNT-A and generally mild. These findings were confirmed by analysis of data of 71 patients who have been reconverted from ASBTA to conventional dilutions of Dysport® or Botox®. We conclude that long-term treatment with ASBTA is effective, safe and help to reduce costs.

P538: Amyotrophic lateral sclerosis affects cortical and subcortical activity underlying movement execution and inhibition

s of Poster Presentations / Clinical Neurophysiology 125, Supplement 1 (2014) S1–S339 S195 Statistical analysis: Qualitative variables are analyzed using test based on the chi-square distribution homogeneity expected to do so when possible and by Fisher exact test values otherwise. To compare quantitative variables ANOVA is performed, for repeated measures with 2 studied factors: intrasubject factor(starting time and ending time) and intersubject factor-type of treatment: placebo vs intrathecal infusion and intraspinal implant. Results: 26 patients have reached one-year follow-up (11 A, 8 B, 7 C). Parameters like CMAP amplitude and motor nerve conduction velocity of the nerves studied of each arm decrease with the time. There is a trend close statistical significance of similar behavior between the arms that receive aBMNCs. There is no difference between these two arms. Emphasizes the increased incidence of fasciculations in the biceps muscle. Conclusions: – Intraspinal implant and intrathecal infusion of aBMNCs in patients diagnosed with ALS are safe and feasible. – No major complications or significant morbidity is observed. – Stem cells could modify the characteristics of the F response and the incidence of fasciculations. – None of the other parameters were influence by cell implant. – We do not have conclusive statistical evidence that cell therapy alter the natural course of the disease. – Is necessary another analysis once the study has progressed, to confirm or reject the trends we have found nowadays. Acknowledgement: This work has been supported by EC10-023 and EC11288 grants from the Department of Pharmacy and Health Products of the Ministry of Health, Social Services and Equality and RD12/0019/0001 grant from Carlos iii Institute of Health. Spain. P537 Spreading of amyotrophic lateral sclerosis lesions – multifocal hits and local propagation? T. Sekiguchi1, T. Kanouchi2, K. Shibuya3, Y.-I. Noto4, Y. Yagi5, A. Inaba6, K. Abe7, S. Misawa3, S. Orimo6, T. Kobayashi7, T. Kamata5, M. Nakagawa4, S. Kuwabara3, H. Mizusawa1, T. Yokota1 1Tokyo Medical and Dental University, Department of Neurology and Neurological Science, Tokyo, Japan; 2Tokyo Medical and Dental University Hospital of Medicine, Clinical Laboratory, Tokyo, Japan; 3Chiba University, Department of Neurology, Chiba, Japan; 4Kyoto Prefectural University of Medicine, Department of Neurology, Kyoto, Japan; 5Musashino Red Cross Hospital, Department of Neurology, Musashino, Japan; 6Kanto Central Hospital, Department of Neurology, Tokyo, Japan; 7Nakano General Hospital, Deparment of Neurology, Tokyo, Japan Objective: To investigate whether or not the lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation in the rostrocaudal direction along the spinal cord, as has been hypothesised (the “single seed and simple propagation” hypothesis). Methods: Subjects included 36 patients with sporadic ALS and initial symptoms in the bulbar, respiratory or upper limb regions. Patients with complicating lumbar spinal disease and any other neuropathies were excluded by MRI and nerve conduction studies. Abnormal spontaneous activities in needle electromyography (nEMG) – that is, fibrillation potentials, positive sharp waves (Fib/PSWs) or fasciculation potentials (FPs) – were compared among the unilateral muscles innervated by different spinal segments, especially between the T10 and L5 paraspinal muscles, and between the vastus medialis and biceps femoris. Axon length and the proportion of muscle fibre types, which are both related to motoneuronal vulnerability in ALS, are similar in the paired muscles. Results: Fourteen of 36 patients showed a non-contiguous distribution of nEMG abnormalities from the onset site, with skipping of intermediate segments. In eight of them, the non-contiguous pattern was evident between paired muscles with the same motoneuronal vulnerability. FPs, known to precede Fib/PSWs, were shown more frequently than Fib/PSWs in all the lumbosacral segments but L5. Conclusions: In sporadic ALS, the distribution of lower motoneuron involvement cannot be explained by the “single seed and simple propagation” hypothesis alone. We propose a “multifocal hits and local propagation” hypothesis instead. The 2nd hit seems to occur at L5 and then spread to neighbouring lumbosacral segments. P538 Amyotrophic lateral sclerosis affects cortical and subcortical activity underlying movement execution and inhibition B. Mohammadi1,2, K. Kollewe3, D.M. Cole4, M. Heldmann2, A. Samii1, R. Dengler3, S. Petri3, T.F. Muente2, U.M. Kraemer2 1International Neuroscience Institute, CNS-LAB, Hannover, Germany; 2University of Luebeck, Department of Neurology, Luebeck, Germany; 3Medical School of Hannover, Neurology, Hannover, Germany; 4University of Zurich, Institute for Biomedical Engineering, Zurich, Switzerland Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons. Evidence suggests that ALS additionally affects other brain areas including premotor cortex and supplementary motor area. We studied movement execution and inhibition in ALS patients using a stop-signal paradigm and functional magnetic resonance imaging (fMRI). Methods: Seventeen ALS patients and 17 age-matched healthy controls were included. Participants performed in a stop-signal task that required responding with button press to a rightor left-pointing black arrow (gostimuli). In stop-trials, a red arrow (stop-stimulus) was presented shortly after the black arrow indicating to withhold the prepared movement. A total of 512 trials were presented (25% stop-trials). Magnetic-resonance images were acquired on a 3-T Siemens Magnetom Scanner. Results: Patients had marginally higher reaction times in go-trials, but did not differ significantly in their inhibition performance. ALS patients showed however stronger inhibition-related activity in inferior, superior and middle frontal gyrus as well as in putamen and pallidum. Error-related activity on the other hand was found to be stronger in healthy controls, particularly in the insula bilaterally. In go task we found execution related increase of the activated area in contralateral sensorimotor cortex in ALS patients. Conclusions: ALS patients and controls showed specific differences in neural networks underlying motor execution, motor inhibition and error monitoring. The results provide further evidence for altered prefrontal functions in ALS. P539 An original method to investigate the origin of the fasciculation potentials M. de Carvalho1, M. Swash1,2 1Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Physiology Institute, Lisbon, Portugal; 2United Kingdom Question: The origin of fasciculation potentials (FPs) in amyotrophic lateral sclerosis (ALS) and in benign fasciculation syndrome (BFS) remains controversial. We used a novel technique to investigate the origin of the FPs in benign fasciculation syndrome and in patients with ALS. Methods: We studied 52 patients (29 men and 23 women) aged 36-75 years (mean 59.6, SD 10.1y) clinically suspected as suffering from ALS, referred for diagnostic testing. All patients progressed to ALS. We also included 11 patients with BFS, aged 38-70 years (mean 58.5, SD 11.7y), these patients had normal strength and their EMG showed normal MUP analysis, there was no progression to other disorders in the following two years. All ALS patients included had normal muscle strength of at least one tibialis anterior muscle; they were classified according MUP analysis of the investigated tibialis anterior. We recorded FPs in tibialis anterior using two separate concentric needle electrodes, ensuring by slight voluntary contraction and by electrical nerve stimulation that each electrode recorded motor unit potentials innervated by different axons. The relative number of time-locked versus independent FPs was recorded. Results: Thirty-two of the 52 ALS patients showed neurogenic change in the TA muscle. In these patients 5-146/patient (mean 34.3+32.5) FPs were recorded total 1096. In the 20 TA muscles without neurogenic change 5-97/patient (mean 28.1+25.4) FPs were recorded total 544. In patients with BFS, 5-43 FPs/patient (mean 21.3+13.0) were recorded total of 234. Time-locked FPs recorded by both electrodes were most frequent in benign fasciculation syndrome (44%) and ALS without reinnervation (27%), but reinnervation (abnormal MUP analysis) in ALS was associated with fewer time-locked FPs (14%). Conclusions: These observations suggest that in chronic partial denervation FPs are more likely to arise distally and that FPs in benign fasciculation syndrome more frequently arise proximally. The origin of FPs, so characteristic

S35-3 Detection of upper motor neuron involvement in amyotrophic lateral sclerosis (ALS)

Upper motor neuron (UMN) signs are frequently difficult to detect in patients with ALS. Transcranial magnetic stimulation (TMS) and MRI techniques offer options to solve this task. The diagnostic yield of conventional single pulse TMS in ALS patients without clinical UMN signs is low. Short interval paired pulse TMS looking for reduction of intracortical inhibition has proven more successful although it has not been widely used. Ipsilateral MEPs having a similar pathomechanism as mirror movements seem to be a sensitive tool and should be further explored. The triple stimulation technique (Magistris et al, 1996) seems to have the greatest potential to detect UMN involvement in the absence of clinical signs and deserves a wider distribution. These technique has also been shown to be able to detect UMN involvement in a significant number of patients with Multiple System Atrophy. Another hope is MRI. Conventional cranial MRI occasionally reveals signal changes in the area of the corticospinal tract although these changes are seen rarely and may also be present in healthy persons. Diffusion tensor imaging can detect structural changes in fibre tracts such as the corticospinal tract. It shows significant changes in groups of ALS patients and also in some individuals. It is unproven, however, that it can detect changes in individual patients without clinical upper motor neuron signs. This holds also true for other MRI techniques such as spectroscopy. Voxel based morphometry shows cortical atrophy beyond the motor areas in comparisons between ALS patients and healthy controls. It can, however, not be used on an individual level. High field techniques (7 Tesla) and fMRI may be promising. Detection of UMN signs in ALS can still be a demanding task. Since it is of greatest diagnostic importance further research in this field is required.

68. Cortical and subcortical motor activity in patients with sporadic ALS studied with fMRI

we studied cortico-cortical connectivity between left dorsal premotor cortex (PMd) and left primary motor hand area (M1-HAND) during movement selection. Methods: In 18 healthy subjects, we probed the connectivity between left PMd and M1-HAND with two highly focal minicoils (Mag& More, Munich, Germany). The first coil was placed over the motor hot spot of the right first dorsal interosseous (FDI) muscle (i.e. M1 site). The second coil was placed 2 cm anterior and 1 cm medially to the motor hot spot of the FDI muscle to stimulate the premotor cortex. We first applied a suprathreshold biphasic pulse (S1) to left M1-HAND that induced a MEP amplitude of app. 0.5– 1 mV in the right FDI when given alone. The second biphasic stimulus (S2) was applied to the left PMd at different interstimulus intervals (ISIs) after S1, ranging from 2.0 to 5.6 ms. The stimulus intensity (SI) of the S2 was set at 70 or 90 % of the S1 intensity. Results: The optimal ISI and S2 intensity that induced the strongest MEP facilitation varied across subjects. The premotor S2 induced short-lasting MEP facilitation which peaked at an early (2.4– 2.8 ms) and late ISIs (3.6–4.4 ms). This short-latency facilitation pattern resembles conventional I-wave interaction found with doublepulse TMS given through a single coil placed over the M1-HAND. Paired S1–S2 stimulation of left M1-HAND (S1) and PMd (S2) resulted in a facilitation of MEP amplitudes relative to single-pulse TMS of the M1-HAND alone. Conclusions: Here, we introduce a new TMS paradigm which tests the effective connectivity in an ipsilateral premotor-to-motor pathway. This proof-of-principle study shows that highly focal TMS provides an effective means of probing the time course and context dependency of cortico-cortical connectivity between two adjacent cortical areas in the intact human brain.