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Silent period (SP) is widely used in transcranial magnetic stimulation studies. Methodologically, SP is usually elicited at stimulus intensities corresponding to a certain percentage of corticomotor threshold. Because this approach might lead to factitious SP changes, the present study was designed to develop, in a stepwise manner, a method for investigating SP independently of corticomotor threshold. First, stimulus-response (S-R) curves of SP against stimulus intensity (SI) were constructed and quantitatively described in healthy volunteers. Second, various methodological issues such as the optimum model for describing the relationship between SP duration and SI and the importance of the type of stimulating coil were addressed. Finally, the proposed method and a commonly used method (eliciting SPs at 130% MT SI) were directly compared for a group of epileptic patients for whom administration of oxcarbazepine resulted in significant corticomotor threshold elevation. Twenty-one subjects (eleven females, median age, 38 years) were studied. SPs were obtained with a figure-of-eight coil using a standardized procedure (recording, FDI). Pilot experiments indicated that at least four trials were required, at each intensity level, to estimate the mean SP duration within 10% of the true mean. Therefore, SPs were determined from the average of four trials with 5% increments from 5 to 100% maximum SI. In a second set of experiments, SPs were obtained for fifteen subjects using a circular coil. In a third set of experiments, eight epileptic patients were studied before and after administration of oxcarbazepine (mean dose 1553 mg, range 900-1800 mg). The S-R curves were fitted to a Boltzman function and to first-order to fourth-order polynomial and sigmoid functions. The Boltzman function described the data accurately (R2=0.947-0.990). In addition, direct comparison of the six models with an F-test proved the superiority of the first. The best-fit parameters of the reference curve, i.e. the maximum and minimum values, the slope, and V50 (the SI at which SP duration is halfway between Min and Max) were 230.8+/-3.31 ms (x+/-SEM), -11.51+/-3.31 ms, 11.56+/-0.65%, and 49.82+/-0.65%, respectively. When the curves obtained with the circular coil were compared with those obtained with the figure-of-eight coil, there were differences between V50 (51.69+/-0.72 vs 47.95+/-0.82, P<0.001) and SP threshold (31.15 vs 24.77, P<0.01) whereas the other best-fit values did not differ significantly. Oxcarbazepine increased corticomotor threshold from 45.3+/-5.8% at baseline to 59.4+/-10.4% (P<0.001). According to the commonly used method, the drug significantly prolonged SP (from 117.6+/-42.4 ms to 143.5+/-46.5 ms, P<0.001) and, consequently, enhanced brain inhibition. In contrast, study of the SP curves led to the conclusion that oxcarbazepine does not affect the Max value and slope but significantly increases V50 and SP threshold (from 54.5+/-4.9% to 59.9+/-7.2% and from 29.1+/-6.4% to 34.6+/-6.8%, respectively, P<0.01). These findings imply...

TMS studies on the CNS effects of benzodiazepines have provided contradictory results. The objective of this study is to describe the effects of lorazepam on silent period (SP) and corticomotor excitability. Twelve healthy male subjects (median age 35 years) were studied at baseline, following i.v. lorazepam administration and after reversal of the benzodiazepine effects with i.v. flumazenil. Lorazepam was given at a low-dose in one subject (0.0225 mg/kg bolus + 2 microg/kg/h infusion) and at a high-dose (0.045 mg/kg bolus + 2.6 microg/kg/h infusion) in the rest. Threshold (Thr) was measured at 1% steps. SPs were investigated with two complementary methods. First, SPs were elicited using a wide range of stimulus intensities (SIs) (from 5 to 100% maximum SI at 5% increments). At each SI, four SPs were obtained and the average value of SP duration was used to construct a stimulus/response (S/R) curve of SI versus SP .The resulting S/R curves were then fitted to a Boltzman function, the best-fit values of which were statistically compared for each experimental condition (i.e., baseline vs. lorazepam vs. flumazenil). Second, a large number of SPs (n=100) was elicited during each of the three experimental conditions using blocks of four stimuli with an intensity alternating between MT and 200% MT. This method was employed so as to reveal the dynamic, time-varying effects of lorazepam and flumazenil on SP duration at two stimulus intensity (SI) levels. MEP recruitment curves were constructed at rest and during activation and fitted to a Boltzman function the best-fit values of which were statistically compared for each experimental condition. Lorazepam at a low dose did not affect Thr, SP, or the active MEP recruitment curves. The high dose also had no effect on Thr and the active MEPs whereas the resting MEP recruitment curves were depressed post-lorazepam at the higher range of stimulus intensities. With regard to SP, the Max value of the S/R curve decreased from 251+/-4.6 ms at baseline to 215.2+/-3.1 ms post-lorazepam (P<0.01). V50 also decreased significantly (from 47.92+/-0.9% to 43.73+/-0.81%, P<0.01) whereas there was no significant change regarding slope and SP Thr. The statistical analysis of the SP S/R curves as well as the study of SPs at two SI levels revealed that lorazepam reduced SP duration when high intensity stimuli were used (>60%). In contrast, at low SIs a small increase in SP duration was noted post-drug. Enhancement of GABAergic inhibition by lorazepam results in a reduction of SP duration when high SIs is used. At the lower range of SIs, a small but statistically significant increase in SP duration is observed. The kinetic behavior of this phenomenon as well as the possible underlying mechanisms are discussed.

Background: As the population of older adults is growing, the interest in a simple way to detect characterize amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer’s disease (AD), is becoming increasingly important. Serious game (SG) -based cognitive and motor performance profiles while performing everyday activities and dual-task walking (DTW) “motor signatures” are two very promising markers that can be detected in predementia states. We aim to compare the consistency, or conformity, of measurements made by a custom SG with DTW (NAV), a SG without DTW (DOT), neuropsychological measures and genotyping as markers for early detection of aMCI.Methods: The study population included three groups: early AD (n = 86), aMCI (n = 65), and healthy control subjects (n = 76), who completed the custom SG tasks in three separate sessions over a 3-month period. Outcome measures were neuropsychological data across-domain and within-domain intra-individual variability (IIV) and DOT and NAV latency-based and accuracy-based IIV. IIV reflects a transient, within-person change in behavioral performance, either during different cognitive domains (across-domain) or within the same domain (within-domain). Test–retest reliability of the DOT and NAV markers were assessed using an intraclass correlation (ICC) analysis.Results: Results indicated that performance data, such as the NAV latency-based and accuracy-based IIV, during the task displayed greater reliability across sessions compared to DOT. During the NAV task-engagement, the executive function, planning, and motor performance profiles exhibited moderate to good reliability (ICC = 0.6–0.8), while during DOT, executive function and spatial memory accuracy profiles exhibited fair to moderate reliability (ICC = 0.3–0.6). Additionally, reliability across tasks was more stable when three sessions were used in the ICC calculation relative to two sessions.Discussion: Our findings suggest that “motor signature” data during the NAV tasks were a more reliable marker for early diagnosis of aMCI than DOT. This result accentuates the importance of utilizing motor performance data as a metric for aMCI populations where memory decline is often the behavioral outcome of interest. In conclusion, custom SG with DTW performance data provide an ecological and reliable approach for cognitive assessment across multiple sessions and thus can be used as a useful tool for tracking longitudinal change in observational and interventional studies on aMCI.

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Malignant multiple sclerosis (MS) is a rare but clinically important subtype of MS characterized by the rapid development of significant disability in the early stages of the disease process. These patients are refractory to conventional immunomodulatory agents and the mainstay of their treatment is plasmapheresis or immunosuppression with mitoxantrone, cyclophosphamide, cladribine or, lately, bone marrow transplantation. We report on the case of a 17-year old patient with malignant MS who was treated with high-dose chemotherapy plus anti-thymocyte globulin followed by autologous stem cell transplantation. This intervention resulted in an impressive and long-lasting clinical and radiological response. It is concluded that intensive immunosuppression followed by autologous stem cell transplantation is a viable therapeutic option in patients with malignant MS unresponsive to conventional forms of treatment.

Background: TMS is being increasingly used as a noninvasive brain stimulation technique for the therapeutic management of partial epilepsies. However, the acute effects of TMS on epileptiform discharges (EDs, i.e. interictal epileptiform activity and subclinical electrographic seizure patterns) remain unexplored. Objective: To investigate whether TMS can modulate EDs in partial epilepsy. Methods: In Experiment Set 1, the safety of the TMS protocol was investigated in 10 well-controlled by anti-epileptic drugs (AEDs) epileptic patients. In Experiment Set 2, the effects of TMS on EDs were studied in three subjects with intractable frontal lobe epilepsies, characterized by particularly frequent EDs. TMS was applied over the electrographic focus with a circular and a figure of eight coil while recording EEG with a 60-channel TMS-compatible EEG system. The effectiveness of TMS in aborting EDs was investigated using survival analysis and brain connectivity analysis. Results: The TMS protocol was well-tolerated. TMS was an effective method to abort EDs even when adjusting for its latency with respect to ED onset (CMH test, p < 0.0001). While the effective brain connectivity around the epileptic focus increased significantly during EDs (p < 0.01), with TMS administration the increase was not statistically significant. Conclusion: TMS can modulate EDs in patients with epileptogenic foci in the cortical convexity and is associated with reversal of ED-induced changes in brain connectivity.

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