Sotirios Papagiannopoulos

Silent period to transcranial magnetic stimulation: construction and properties of stimulus-response curves in healthy volunteers

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 that oxcarbazepine does not enhance brain inhibitory mechanisms. Thus, in situations characterized by significant changes in corticomotor threshold the proposed method provides results clearly different from a commonly used approach. It is concluded that S–R curves obtained with a figure-of-eight coil in 5% increments and fitted to a Boltzman function provide an accurate, comprehensive, and clinically applicable method for exploring SP.

Transcranial magnetic stimulation (TMS) modulates epileptiform discharges in patients with frontal lobe epilepsy: a preliminary EEG-TMS study.

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.

Autologous stem-cell transplantation in malignant multiple sclerosis: a case with a favorable long-term outcome.

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. Multiple Sclerosis 2008; 17 : 278—283. http://msj.sagepub.com

θ-burst stimulation of the right neocerebellar vermis selectively disrupts the practice-induced acceleration of lexical decisions.

The present study reports an experiment of cerebellar transcranial magnetic stimulation in a lexical decision task. In contrast to the study by Argyropoulos (2011), no effect of cerebellar stimulation was observed on priming sizes. However, when subjects confronted the same stimuli in the second session of participation, lexical decision latencies did not become any shorter after stimulation of the right neocerebellar vermis, in contrast to all other conditions. This finding is discussed in the light of current research in cerebellar cognitive and linguistic functions, and provides some first evidence for the recently entertained hypothesis that neocerebellar loci are significant in acquiring, storing, and retrieving associative memory traces of repeatedly co-occurring neural events in the language domain.

Reliability of a novel serious game using dual-task gait profiles to early characterize aMCI

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.

Frequency distribution of dextromethorphan O-demethylation in a Greek population

OBJECTIVE To determine the CYP2D6 phenotype in a Greek population by using dextromethorphan (DM) as a probe drug. METHODS DM (30 mg) was given orally to 102 unrelated Greek subjects and 8-hour urine samples were collected. Concentrations of DM and its metabolite dextrorphan (DX) were determined using a validated HPLC assay. Metabolic molar ratio (MR) of DM to free DX in log form was used as an in vivo index of metabolic status. RESULTS The frequency distribution histogram of MR was bimodal. An antimode of 0.25 for the mean log MR was determined using probit analysis. Seven of 102 subjects (6.9%) were poor metabolizers (PMs). CONCLUSION The PM frequency of CYP2D6 in Greek subjects was similar to other Caucasian populations.

Miller-Fisher Syndrome: Are Anti-GAD Antibodies Implicated in Its Pathophysiology?

Miller-Fisher syndrome (MFS) is considered as a variant of the Guillain-Barre syndrome (GBS) and its characteristic clinical features are ophthalmoplegia, ataxia, and areflexia. Typically, it is associated with anti-GQ1b antibodies; however, a significant percentage (>10%) of these patients are seronegative. Here, we report a 67-year-old female patient who presented with the typical clinical features of MFS. Workup revealed antibodies against glutamic acid decarboxylase (GAD) in relatively high titers while GQ1b antibodies were negative. Neurological improvement was observed after intravenous gamma globulin and follow-up examinations showed a continuous clinical amelioration with simultaneous decline of anti-GAD levels which finally returned to normal values. This case indicates that anti-GAD antibodies may be associated with a broader clinical spectrum and future studies in GQ1b-seronegative patients could determine ultimately their clinical and pathogenetic significance in this syndrome.

P11-14 Transcranial magnetic stimulation terminates epileptiform discharges in patients with partial epilepsy: a combined EEG-TMS study

Chronic stroke patients with moderate-to-severe hemiparesis often suffer from motor deficits associated with flexor hypertonia, as well as motor weakness in their paretic upper-limbs. The enhancement of the extensor function, to counteract the flexor hypertonia, might be useful for those patients. However, the beneficial effects of training in chronic-phase patients are relatively limited. Additional extensor training of the affected hand did not change the clinical outcome (Trombly, 1986). As presented before, we found that combining extensor training with repetitive transcranial magnetic stimulation (rTMS; EEx-TMS) could facilitate use-dependent plasticity (UDP) both in stroke and healthy people, and can achieve functional recovery that cannot be attained by either intervention alone in stroke patients. In previous reports, therapeutic TMS protocols for stroke patients could induce long-lasting effects by repeating the stimulation for 1 month (Khedr et al., 2005; Fregni et al., 2006). Therefore, we examined whether 12 times (once a day, on two days a week for 6 week) of repeating the EEx-TMS session (EEx: voluntary upper-limb extensors contraction of wrist and fingers in paretic side supported by neuromuscular stimulation, TMS: 5 Hz high frequency stimulation) could induce the long-term effects, resulting in sustained functional improvements of paretic upper limbs in nine chronic stroke patients. As a result, we found that repeating the EEx-TMS sessions over 6 weeks (12 times in total) could produce sustained improvements of function (active range of movement of hands, grip power and pinch force) and hypertonia of the paretic upper limb for >2 weeks in chronic stroke patients. The 12 times repeating of the EEx-TMS session could induce the long-term effects, resulting in sustained functional improvements of paretic upper limbs in chronic stroke patients. This method could be a powerful rehabilitative approach for hemiparetic stroke patients.

P37.7 The effects of imipenem, a GABA-A receptor antagonist, on silent period to transcranial magnetic stimulation

period times (CSP) were measured with single stimulus transcranial magnetic stimulation (TMS). After TMS studies, second EEG recordings were performed within an hour. Results: No seizures were recorded in or afterwards the study, there were no statistically significant difference between the first and second EEG recordings. (Kappa measure of agreement %84) MT values of JME patients were higher than asymptomatic brothers/sisters and healthy individuals. (p 0.0, p 0.0) CSP of JME patients were longer than healthy individuals with statistically significant difference. (p 0.37) CSP of asymptomatic brothers/sisters were also longer than healthy individuals without any statistical difference (p 0.71). Discussion: Higher MT values in JME patients were thought to be related to the anti-epileptic drug therapies. Longer CSP times in JME patients can be explained by the increased excitability of the cortical inhibitory neurons. CSP times in brothers/sisters were also found elongated without any statisticaly significant difference. This can also be explained with the same mechanism.

Lorazepam effects on silent period and corticomotor excitability

Materials and methods 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 μg/kg/h infusion) and at a high-dose (0.045 mg/kg bolus + 2.6 μg/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, 4 SPs were obtained and the average value of SP duration was used to construct a stimulus/ response (S/R) curve of SI vs. 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 was elicited during the three experimental conditions using blocks of 4 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. Finally, active MEP recruitment curves were constructed and fitted to a Boltzman function the best-fit values of which were statistically compared for each experimental condition.