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Although shared genetic factors have been previously reported between dystonia and other neurologic conditions, no sequencing study exploring such links is available. In a large dystonic cohort, we aimed at analyzing the proportions of causative variants in genes associated with disease categories other than dystonia.Gene findings related to whole-exome sequencing-derived diagnoses in 1100 dystonia index cases were compared with expert-curated molecular testing panels for ataxia, parkinsonism, spastic paraplegia, neuropathy, epilepsy, and intellectual disability.Among 220 diagnosed patients, 21% had variants in ataxia-linked genes; 15% in parkinsonism-linked genes; 15% in spastic-paraplegia-linked genes; 12% in neuropathy-linked genes; 32% in epilepsy-linked genes; and 65% in intellectual-disability-linked genes. Most diagnosed presentations (80%) were related to genes listed in ≥1 studied panel; 71% of the involved loci were found in the non-dystonia panels but not in an expert-curated gene list for dystonia.Our study indicates a convergence in the genetics of dystonia and other neurologic phenotypes, informing diagnostic evaluation strategies and pathophysiological considerations.

Question Changes in synaptic and neuronal efficacy such as long-term potentiation (LTP) and long-term depression (LTD) are thought to reflect synaptic processes underlying learning and memory. Homeostatic plasticity is considered to stabilize neural activity within a physiologically reasonable and dynamic range. Quadri-pulse-thetaburst stimulation (qTBS) is a recently introduced patterned transcranial magnetic stimulation (TMS) protocol that induced lasting increase or decrease in neuronal excitability of human primary motor cortex (M1) probably corresponding to the model of LTP- and LTD-like plasticity. Here, we aimed to probe homeostatic and metaplastic interactions of an inhibitory priming qTBS protocol on subsequent facilitating and inhibitory qTBS. Methods We investigated the priming mechanisms of inhibitory qTBS on subsequent facilitating qTBS (experiment 1) in 8 healthy volunteers and on subsequent inhibitory qTBS (experiment 2) in 9 healthy volunteers. Inhibitory qTBS consisted of 360 bursts given continuously to M1 (i.e. 1440 full-sine pulses) with bursts of four biphasic TMS pulses (duration 160 μ s) separated by inter-stimulus intervals (ISI) of 50 ms (20 Hz) and inter-burst intervals of 200 ms (5 Hz) (qTBS50/200). Facilitatory qTBS consisted of the same burst pattern but with ISI of 5 ms (200 Hz) (qTBS5/200). TMS was applied by a custom-made magnet stimulator (MSB, Munich). Resting motor threshold (RMT) and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1 mV were measured before priming qTBS50/200 (pre), directly after priming qTBS50/200 (post1), after 15 min (post2) and after 30 min (post3). Following post 3 measurements, the second stimulation (qTBS5/200 or qTBS50/200) was applied and the RMT and MEP were measured for 60 min (post4–post7). Results In experiment 1 (qTBS50/200–qTBS5/200), priming with qTBS50/200 led to a decrease of MEP amplitudes (post1–3), while MEP amplitudes increased following subsequent qTBS5/200 (post 4–7). Mean changes of post 4–7 increased significantly as compared to mean changes of post 1–3. In experiment 2 (qTBS50/200–qTBS50/200), MEP amplitudes decreased following the priming protocol (post 1–3) and returned to baseline with a slight increase on post 6 after the subsequent qTBS50/200 protocol. Mean changes of post 4–7 increased significantly as compared to mean changes of post 1–3. Conclusion Our preliminary results may point towards homeostatic mechanisms of facilitatory qTBS5/200 following priming with qTBS50/200. In contrast, subsequent qTBS50/200 led to a de-depression like effect of MEP amplitudes suggesting metaplastic effects of two inhibitory qTBS protocols applied over M1. Our findings may support the assumption that changes in cortico-spinal excitability following qTBS represent LTP- and LTD-like changes in synaptic transmission and corroborate metaplastic de-depression effects of high-frequency patterned rTMS protocols in human M1.

Background/Question Long-term potentiation (LTP) and long-term depression (LTD) are forms of cortical plasticity and are considered to be synaptic processes underlying learning and memory. Patterned transcranial magnetic stimulation (TMS) such as theta burst stimulation (TBS) or quadri-pulse stimulation (QPS) can induce LTP-like and LTD-like effects in human primary motor cortex (M1), displayed by an increase or decrease in cortico-spinal excitability. Here, we aimed to test the plasticity-inducing capabilities of a novel protocol that merged TBS and QPS – so called quadri-pulse theta burst stimulation (qTBS) – at interstimulus intervals (ISI) that mimic I-wave periodicity (i.e. 1.5 ms/666 Hz) with an effective anterior-posterior (AP) and posterior-anterior (PA) current flow in the brain. Methods We investigated healthy volunteers (n = 12 per protocol) with 360 bursts of qTBS that was continuously given to M1 (i.e. 1440 full-sine pulses). QTBS consisted of repeated bursts of four biphasic TMS pulses (duration: 160 μ s) separated by ISI of 1.5 ms (666 Hz) and inter-burst intervals of 200 ms. (5 Hz). TMS was applied by a custom-made magnetic stimulator (IMETUM, Munich). Resting motor threshold (rMT), and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1mv (SI1mV) were measured before (Pre) qTBS, directly after (Post1), after 15 min (Post2), after 30 min (Post3) and after 60 min (Post4). Results PA-qTBS at 666 Hz caused a decrease in mean MEP amplitudes, whereas AP-qTBS at 666 Hz induced an increase in mean MEP amplitudes outlasting for approximately 60 min. As expected, baseline data of rMT prior to qTBS differed significantly, with higher thresholds in AP direction. Discussion/Conclusion Continuous qTBS at 666 Hz can induce lasting changes in cortico-spinal excitability. Induced current direction in the brain appears to be relevant when qTBS targets I-wave periodicity, corroborating that high-fidelity spike timing mechanisms are critical for inducing bi-directional plasticity in human M1.

Question Neuronal plasticity in form of long-term potentiation (LTP) and long-term depression (LTD) is considered to be the neurophysiological mechanism of learning and memory. There is growing evidence that the induction of LTD-like effects plays a crucial role in mediating therapeutic effects of transcranial magnetic stimulation (TMS). We previously demonstrated that biphasic transcranial quadro-pulse stimulation (QPS) consisting of two-full sine cycles is slightly more effective than with one full-sine cycle in induction of LTP-like effects in human primary motor cortex. Here, we aimed to study the effectiveness of QPS with one and two full-sine cycles in induction of LTD-like effects of synaptic plasticity. Methods We investigated healthy volunteers (n = 7 per protocol) with quadro-pulse stimulation consisting of one (QPS-1) and two (QPS-2) full-sine cycles (duration: 160 μs, respectively) separated by an inter-stimulus interval of 50 ms and an inter-burst interval of 200 ms with a total amount of 1440 pulses. Resting motor threshold (rMT), and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1 mV (SI1mV) were measured before (Pre) intervention, directly after (Post1), after 15 min (Post2), after 30 min (Post3) and after 60 min (Post4). Results We found a significant decrease of MEP amplitudes after QPS-1 but not after QPS-2 at all time points lasting for 1 h (Post 1–4). No significant changes in rMT were observed. Conclusion QPS with one full-sine-cycle induces LTD-like changes in human primary motor cortex at interstimulus intervals of 50 ms. Using two-full sine cycles – previously demonstrating to be more effective in induction of LTP-like plasticity at interstimulus intervals of 5 ms – did not lead to changes in corticomotor excitability. These divergence in the capability to induce corticomotor plasticity suggests different underlying neurophysiological mechanisms. The results may be of interest when applying QPS or other patterned stimulation protocols therapeutically.

Question In transcranial magnetic stimulation (TMS), two pulse waveforms are mainly used to study cortical function. While monophasic stimuli are optimal to measure cortical excitability, the biphasic pulse waveform is increasingly used to induce cortical plasticity and to treat neurological as well as psychiatric illnesses. Methods We used a novel stimulation device (flexTMS) to study variable pulse configurations in young healthy volunteers. Primary outcome measure was cortical resting motor threshold (RMT). We determined the strength-duration relationship for single-pulse biphasic TMS using pulse durations between 120 and 400 μs. To further characterize the biphasic stimulus, we systematically varied amplitude and current direction of the first and second part of the stimulus waveform. Results The strength-duration relation has a parabolic shape for biphasic stimulation with a minimum at a pulse length of approximately 240 μs. Varying the amplitude of the part inducing a posterior-anterior oriented current considerably raised RMT, while changes of the part which induces an anterior-posterior current had little effect. Conclusion Our results clarify the role of pulse duration in biphasic TMS. The part inducing a posterior-anterior current in the brain contributes most to the effect of biphasic stimulation. These findings have important methodological implications and contribute to the understanding of the physiology of TMS.

Question Long-term potentiation (LTP) and long-term depression (LTD) are forms of cortical plasticity and are considered to be synaptic processes underlying learning and memory. Transcranial magnetic stimulation (TMS) with monophasic quadro-pulses (QPS) demonstrated to be effective to induce LTD-and LTP-like plasticity in human motor cortex (M1). Here, we aimed to study whether biphasic QPS at different inter-stimulus-and inter-burst-intervals induces plastic changes in human M1. Methods We investigated healthy volunteers ( n = 10 per protocol) with quadro-pulse stimulation (QPS) consisting of repeated bursts of four biphasic TMS pulses (duration: 160 μs) separated by inter-stimulus intervals of 1.5 ms and 50 ms and inter-burst intervals of 200 ms, 1 s and 5 s resulting in 6 different protocols (QPS 1.5−200 , QPS 1.5−1 , QPS 1.5−5 , QPS 50−200 , QPS 50−1 , QPS 50−5 ; 1440 total stimulus counts per protocol). TMS was applied by a custom-made magnetic stimulator (IMETUM, Munich). Resting motor threshold (rMT), and motor evoked potential (MEP) amplitudes with stimulus intensities to target amplitudes of 1mv and 0.4 mV (SI 1mV and SI 0.4mV ) were measured before (Pre) QPS directly after (Post1), after 15 min (Post2), after 30 min (Post3) and after 60 min (Post4). Results We found a significant increase of MEPs after QPS 1.5−5 at SI 0.4mV and a significant decrease after QPS 50−200 , QPS 50−5 and QPS 1.5−200 at SI 1 mV . QPS 1.5−1 and QPS 50−1 had no significant effect on MEPs, respectively. Significant changes in rMT, referring to a model of intrinsic plasticity, were observed for QPS 50−200 but not for QPS 50−5 . Conclusion Biphasic QPS demonstrated to induce intensity and frequency dependent LTP-or LTD-like effects displayed by an increase or decrease in MEP amplitudes. This form of stimulation might offer new opportunities in investigations of cortical plasticity in humans.