Nicole E. Neef

Right-shift for non-speech motor processing in adults who stutter

INTRODUCTION In adults who do not stutter (AWNS), the control of hand movement timing is assumed to be lateralized to the left dorsolateral premotor cortex (PMd). In adults who stutter (AWS), the network of speech motor control is abnormally shifted to the right hemisphere. Motor impairments in AWS are not restricted to speech, but extend to non-speech orofacial and finger movements. We here investigated the lateralization of finger movement timing control in AWS. METHODS We explored PMd function in 14 right-handed AWS and 15 age matched AWNS. In separate sessions, they received subthreshold repetitive transcranial magnetic stimulation (rTMS) for 20 min at 1Hz over the left or right PMd, respectively. Pre- and post-stimulation participants were instructed to synchronize their index finger taps of either hand with an isochronous sequence of clicks presented binaurally via earphones. Synchronization accuracy was measured to quantify the effect of the PMd stimulation. RESULTS In AWNS inhibition of left PMd affected synchronization accuracy of the left hand. Conversely, in AWS TMS over the right PMd increased the asynchrony of the left hand. CONCLUSIONS The present data indicate an altered functional connectivity in AWS in which the right PMd seems to be important for the control of timed non-speech movements. Moreover, the laterality-shift suggests a compensatory role of the right PMd to successfully perform paced finger tapping.

Reduced intracortical inhibition and facilitation in the primary motor tongue representation of adults who stutter

OBJECTIVE We aimed at detecting neurophysiological changes, in the primary motor tongue representation in adults with persistent stuttering. METHODS Using transcranial magnetic stimulation in 12 patients and 14 controls, we examined motor threshold, motor-evoked potential (MEP) input-output curve, short-term intracortical inhibition (SICI) and intracortical facilitation (ICF), based on eight trials per conditioning-test interval. RESULTS In controls inhibition of the MEP-amplitude at short inter-stimulus intervals (ISI) and facilitation of the MEP-amplitude at long ISIs was evident. Patients showed an inhibition at ISI 3 ms and weaker non-significant inhibition at ISI 2 ms; this delay of inhibitory activity was especially prominent in the right hemisphere. Facilitation was reduced at ISI 10 and 15 ms in patients. Furthermore, MEP input-output curve was steeper in patients. Motor thresholds did not differ between groups. CONCLUSIONS In persistent stuttering intracortical excitability of the primary motor tongue representation is altered with a deviant time course for inhibitory activity in the right hemisphere and reduced paired-pulse facilitation. SIGNIFICANCE These results specify changes in intracortical networks possibly mediated by altered GABAergic regulations in persistent stuttering. Thus, a better understanding of pathomechanisms and a potential role in understanding pharmacological treatment responses emerge by using transcranial magnetic stimulation.

Normal interhemispheric inhibition in persistent developmental stuttering.

Imaging studies suggest a right hemispheric (pre)motor overactivity in patients with persistent developmental stuttering (PDS). The interhemispheric inhibition (IHI) studied with transcranial magnetic stimulation is an established measure of the interplay between right and left motor areas. We assessed IHI in 15 young male adults with PDS and 15 age‐matched fluent‐speaking subjects. We additionally studied the ipsilateral silent period (iSP) duration. We found no significant between‐group difference for IHI or for iSP duration. We conclude that the interplay between the primary motor cortices is normal in patients with PDS. The abnormal right motor and premotor activity observed in functional imaging studies on PDS are not likely to reflect altered primary motor cortex excitability, but are likely to have a different origin.

Left posterior-dorsal area 44 couples with parietal areas to promote speech fluency, while right area 44 activity promotes the stopping of motor responses

Area 44 is a cytoarchitectonically distinct portion of Brocas region. Parallel and overlapping large-scale networks couple with this region thereby orchestrating heterogeneous language, cognitive, and motor functions. In the context of stuttering, area 44 frequently comes into focus because structural and physiological irregularities affect developmental trajectories, stuttering severity, persistency, and etiology. A remarkable phenomenon accompanying stuttering is the preserved ability to sing. Speaking and singing are connatural behaviours recruiting largely overlapping brain networks including left and right area 44. Analysing which potential subregions of area 44 are malfunctioning in adults who stutter, and what effectively suppresses stuttering during singing, may provide a better understanding of the coordination and reorganization of large-scale brain networks dedicated to speaking and singing in general. We used fMRI to investigate functionally distinct subregions of area 44 during imagery of speaking and imaginary of humming a melody in 15 dextral males who stutter and 17 matched control participants. Our results are fourfold. First, stuttering was specifically linked to a reduced activation of left posterior-dorsal area 44, a subregion that is involved in speech production, including phonological word processing, pitch processing, working memory processes, sequencing, motor planning, pseudoword learning, and action inhibition. Second, functional coupling between left posterior area 44 and left inferior parietal lobule was deficient in stuttering. Third, despite the preserved ability to sing, males who stutter showed bilaterally a reduced activation of area 44 when imagine humming a melody, suggesting that this fluency-enhancing condition seems to bypass posterior-dorsal area 44 to achieve fluency. Fourth, time courses of the posterior subregions in area 44 showed delayed peak activations in the right hemisphere in both groups, possibly signaling the offset response. Because these offset response-related activations in the right hemisphere were comparably large in males who stutter, our data suggest a hyperactive mechanism to stop speech motor responses and thus possibly reflect a pathomechanism, which, until now, has been neglected. Overall, the current results confirmed a recently described co-activation based parcellation supporting the idea of functionally distinct subregions of left area 44.

Structural connectivity of right frontal hyperactive areas scales with stuttering severity

Persistent stuttering reflects atypical brain activity and connectivity, most notably within the left hemisphere speech production networks. Neef et al. link right frontal overactivations common to stuttering to structural networks that support right hemisphere specialisations. In particular, severe stuttering reflects increased activity in a global motor response inhibition network.

P653: Intermittent theta burst stimulation inhibits human motor cortex when applied with mostly monophasic (anterior-posterior) pulses

P652 – Figure 2 P653 Intermittent theta burst stimulation inhibits human motor cortex when applied with mostly monophasic (anterior-posterior) pulses M. Sommer1,2, M. Ciocca2,3, R. Hannah2, P. Hammond2, N. Neef4, W. Paulus1, J.C. Rothwell2 1University of Goettingen, Clinical Neurophysiology, Goettingen, Germany; 2UCL Institute of Neurology, Queen Square, Sobell Department of Motor Neuroscience and Movement Disorders, London, United Kingdom; 3Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Centro Clinico per la Neurostimolazione, le Neurotecnologie ed i Disordini del Movimento, Milan, Italy; 4Bernstein Focus Neurotechnology, Goettingen, Germany Question: Does the current direction influence the effect of intermittent theta burst stimulation (iTBS) on human motor cortex excitability? Methods: We stimulated the dominant hand representation of the motor cortex in 15 healthy subjects, using “unidirectional biphasic” pulses with an M-ratio (i.e, degree of monophasicity) of 0.2, generated by a prototype controllable TMS machine (cTMS-3, Rogue Resolutions Ltd., Cardiff, UK), connected to a standard figure-of-eight coil with physical attributes similar to a Magstim D70 coil. iTBS was applied conventionally, using 20 sequences of 2 seconds iTBS (10 bursts at 5 Hz burst repetition frequency, each burst consisting of 3 pulses of 80% AMT intensity repeated at 50 Hz frequency). In two separate sessions pulses differing in current direction and shape were applied: a) posterio-anterior (PA) current direction in the brain, 75 microseconds (iTBS_PA75). b) AP current direction, 45 microseconds (iTBS_AP45). Before and for 30 minutes after iTBS, we monitored the modulation of motor evoked potential (MEP) amplitude from the dominant first dorsal interosseus using conventional, monophasic, suprathreshold pulses generated by a Magstim 2002 stimulator, inducing PA currents in the brain, at 0.2 Hz frequency. Results: The posterior effective current direction (iTBS_AP45) yielded a pronounced and slightly delayed inhibition of MEP amplitude in all but one subjects. iTBS_PA75 had a variable and inconsistent effect. The relatively consistent effect of iTBS_AP45 was unrelated to the MEP latency differences. The divergent iTBS_PA75 effects was in part related to the latency differenceAP–LM in that long latency differences were correlated with the induction of inhibition rather than facilitation. Conclusions: Current direction influences the outcome of iTBS, with a preference for currents running from anterior to posterior in the motor cortex. P654 Effect of transcranial static magnetic field stimulation over the sensorimotor cortex on somatosensory evoked potentials in human H. Kirimoto, H. Tamaki, T. Matsumoto, K. Sugawara, H. Onishi Niigata University of Health and Welfare, Institute for Human Movement and Medical Sciences, Niigata, Japan Introduction: The motor cortex in the human brain can be modulated by the application of transcranial static magnetic field stimulation (tSMS) through the scalp. Oliviero et al. (2011) reported that 10 minutes of tSMS can reduce the amplitude of motor evoked potentials (MEP) for up to 6 min after the magnet has been removed. The mechanisms that underlie this reduction in excitability remain unclear; however, it is possible that this reduction in excitability is promoted by the distortion of ion channels. The aim of the present study was to investigate the possibility of a noninvasive modulation of the primary somatosensory cortex excitability by the application of tSMS in healthy humans. Methods: tSMS and sham stimulation over the sensorimotor cortex was applied to 10 subjects for periods of 10 and 15 min. For tSMS, a cylindrical neodymium magnet (NdFeB; diameter, 50 mm; height, 30 mm) with a maximum energy density of 41 MGOe and a nominal strength of 735 N (75 kg) was used. Based on the accepted method for attaching scalp electrodes for experiments or EEG tests, the NdFeB magnet was centered over position C3 of the international 10-20 system, and thus stimulated both primary motor and somatosensory cortices (Fig. 1). Somatosensory evoked potentials (SEPs) following right median nerve stimulation were recorded before and immediately, 5 min, and 10 min after tSMS from the F3 (frontal component) and C3’ (parietal component; 2.5 cm posterior to C3). In another session, SEPs were recorded from 6 of the 10 subjects every 3 min during 15 min of tSMS. Results: Figure 2 shows grand averaged wave forms of SEPs recorded before and immediately, 5 min, and 10 min after tSMS from the F3. Amplitudes of N18 (frontal component) and N20 (parietal component) significantly decreased immediately after 10 and 15 min of tSMS, and returned to baseline by 5 min after intervention. tSMS while recording SEPs every 3 min (peripheral nerve simulated) and sham stimulation showed no effect.

Altered morphology of the nucleus accumbens in persistent developmental stuttering

PURPOSE Neuroimaging studies in persistent developmental stuttering repeatedly report altered basal ganglia functions. Together with thalamus and cerebellum, these structures mediate sensorimotor functions and thus represent a plausible link between stuttering and neuroanatomy. However, stuttering is a complex, multifactorial disorder. Besides sensorimotor functions, emotional and social-motivational factors constitute major aspects of the disorder. Here, we investigated cortical and subcortical gray matter regions to study whether persistent developmental stuttering is also linked to alterations of limbic structures. METHODS The study included 33 right-handed participants who stutter and 34 right-handed control participants matched for sex, age, and education. Structural images were acquired using magnetic resonance imaging to estimate volumetric characteristics of the nucleus accumbens, hippocampus, amygdala, pallidum, putamen, caudate nucleus, and thalamus. RESULTS Volumetric comparisons and vertex-based shape comparisons revealed structural differences. The right nucleus accumbens was larger in participants who stutter compared to controls. CONCLUSION Recent theories of basal ganglia functions suggest that the nucleus accumbens is a motivation-to-movement interface. A speaker intends to reach communicative goals, but stuttering can derail these efforts. It is therefore highly plausible to find alterations in the motivation-to-movement interface in stuttering. While behavioral studies of stuttering sought to find links between the limbic and sensorimotor system, we provide the first neuroimaging evidence of alterations in the limbic system. Thus, our findings might initialize a unified neurobiological framework of persistent developmental stuttering that integrates sensorimotor and social-motivational neuroanatomical circuitries.

P561: Central integration of dual somatosensory input to the orofacial representation in adults who stutter

fixed-effects analysis of 8 patients showed widespread activation, primarily in the bilateral primary motor cortex, supplementary motor area, superior temporal cortex, bilateral thalamus and right cerebellum (Fig. 1, T=4.7, p<0.05 (FWE), k=100). The final group analysis will be presented at the conference. Conclusions: Postural tremor in ET is associated with activation in the motor circuit, including bilateral cerebellar activations. In contrast, arm and hand extension correlates with ipsilateral cerebellar activations. These preliminary findings reconfirm earlier findings that the bilateral cerebellum is involved in ET (Bucher et al., 1997). References: Bucher, S.F., Seelos, K.C., Dodel, R.C., Reiser, M. & Oertel, W.H. (1997). Activation mapping in essential tremor with functional magnetic resonance imaging. Annals of Neurology, vol. 41, no. 1, pp. 32-40. van Rootselaar AF, Renken R, de Jong BM, Hoogduin JM, Tijssen MA, Maurits NM. fMRI analysis for motor paradigms using EMG-based designs: a validation study. Hum Brain Mapp. 2007 Nov;28(11):1117-27.

P 156. Deficient speech motor preparation in stuttering

Introduction Persistent developmental stuttering (PDS) is a speech fluency disorder that affects 1% of the population, predominantly males. Its etiology is unclear and likely multifactoral, with contributions from intrinsic factors pertaining to brain anatomy and neurophysiology, particularly abnormal right-hemispheric lateralization of blood flow in motor and premotor areas. Clinically, a major feature of stuttering is the paroxysmal inability to smoothly sequence articulatory gestures, resulting in frustraneous partial repetitions of the initial gestures. Objectives Attempting to further clarify the pathophysiology of the intermittent losses of motor control, we investigated changes in motor cortex excitability in the transition phase between articulatory gestures. We therefore studied speech-related modulation of excitability in the motor representation of the tongue. Materials and methods Thirteen fluent speakers and 13 adults who stutter were asked to build compound verbs with the verbal prefix “auf”. Single-pulse transcranial magnetic stimulation was applied over the primary motor cortex during the transition phase between a fixed labiodental articulatory configuration towards various articulatory configurations at five different latencies after transition onset. Bilateral electromyography was recorded from self-adhesive electrodes placed on the upper top of the tongue. Off-line, we extracted the motor evoked potential amplitudes and normalized these amplitudes to the individual baseline excitability during pronouncing of the prefix. Results Fluent-speaking control subjects showed a gradual increase of motor evoked potential amplitudes before the target articulatory gesture in the left motor cortex, and to a much lesser extent after stimulation of the right motor cortex. By contrast, stuttering adults lacked any premovement facilitation in the left motor cortex, but showed some premovement facilitation in the right motor cortex. Conclusion For decades theories of speech production postulate that the selection and the execution of speech units arise from facilitation of target units & inhibition of others. We present the first measurement of motor unit facilitation during speaking in real time. Excitability tuning of layer V pyramidal cell populations is quantified by MEP recordings from the tongue. Such data can guide the much needed integration of psycholinguistic and motor control approaches to speech production at a neurobiological level. Excitability tuning was absent in adults afflicted with PDS, indicating that the internal, speech-related signals triggering motor cortex facilitation were insufficient in strength or timing. This corroborates a disconnection hypothesis of speech-related brain areas in individuals suffering from PDS.