Radwa A.B. Badawy

TMS and drugs revisited 2014

The combination of pharmacology and transcranial magnetic stimulation to study the effects of drugs on TMS-evoked EMG responses (pharmaco-TMS-EMG) has considerably improved our understanding of the effects of TMS on the human brain. Ten years have elapsed since an influential review on this topic has been published in this journal (Ziemann, 2004). Since then, several major developments have taken place: TMS has been combined with EEG to measure TMS evoked responses directly from brain activity rather than by motor evoked potentials in a muscle, and pharmacological characterization of the TMS-evoked EEG potentials, although still in its infancy, has started (pharmaco-TMS-EEG). Furthermore, the knowledge from pharmaco-TMS-EMG that has been primarily obtained in healthy subjects is now applied to clinical settings, for instance, to monitor or even predict clinical drug responses in neurological or psychiatric patients. Finally, pharmaco-TMS-EMG has been applied to understand the effects of CNS active drugs on non-invasive brain stimulation induced long-term potentiation-like and long-term depression-like plasticity. This is a new field that may help to develop rationales of pharmacological treatment for enhancement of recovery and re-learning after CNS lesions. This up-dated review will highlight important knowledge and recent advances in the contribution of pharmaco-TMS-EMG and pharmaco-TMS-EEG to our understanding of normal and dysfunctional excitability, connectivity and plasticity of the human brain.

Sleep deprivation increases cortical excitability in epilepsy: Syndrome-specific effects

Objective: To use transcranial magnetic stimulation (TMS) to investigate the hypothesis that sleep deprivation increases cortical excitability in people with epilepsy. Methods: We performed paired pulse TMS stimulation, using a number of interstimulus intervals (ISIs) on each hemisphere of 30 patients with untreated newly diagnosed epilepsy (15 idiopathic generalized epilepsy [IGE] and 15 focal epilepsy) and on the dominant hemisphere of 13 healthy control subjects, before and after sleep deprivation. Results: Both hemispheres in patients with IGE and the hemisphere ipsilateral to the EEG seizure focus in those with focal epilepsy showed an increase in cortical excitability following sleep deprivation at a number of ISIs. This change in excitability was most prominent in the patients with IGE. Although there were minor changes after sleep deprivation in control subjects and the contralateral hemisphere in the focal epilepsy group seen at the 250-millisecond ISI, it was less than in the other groups. Conclusions: Sleep deprivation increases cortical excitability in epilepsy; the pattern of change is syndrome dependent.

Changes in cortical excitability differentiate generalized and focal epilepsy

Different pathophysiological mechanisms related to the balance of cortical excitatory and inhibitory influences may underlie focal and generalized epilepsies. We used transcranial magnetic stimulation to search for interictal excitability differences between patients with idiopathic generalized epilepsy (IGE) and focal epilepsy.

The peri-ictal state: cortical excitability changes within 24 h of a seizure

In this study, transcranial magnetic stimulation was used to investigate motor cortical excitability changes in the peri-ictal period, in drug-naive new-onset epilepsy patients. Eighty-seven studies were performed on 58 patients (23 with idiopathic generalized epilepsy and 35 with focal epilepsy) within 72 h before or after a seizure. Fifty studies in 35 patients were within 24 h of a seizure. In all 58 patients, an interictal baseline study was performed, at least 14 days from a seizure. Motor threshold and paired pulse recovery curve results obtained at short (2-15 ms) and long (50-400 ms) interstimulus intervals in each hemisphere (at <24 h pre- or post-seizure and 24-72 h pre- and post-seizure) were compared against the interictal results and normal control values obtained from 32 subjects. The nature of the seizure (generalized, focal or focal with secondary generalization) was also recorded. Increased motor cortex excitability, measured by decreased motor threshold, increased intracortical facilitation and decreased intracortical inhibition at short and long interstimulus intervals was seen in the 24 h before a seizure. Conversely, decreased excitability occurred in the 24 h after a seizure. These effects were bilateral in tonic-clonic seizures in idiopathic generalized epilepsy and also in secondarily generalized seizures in patients with focal epilepsy. Similar changes were seen in the hemisphere ipsilateral to the seizure focus in focal seizures that did not secondarily generalize, accompanied by complex excitability changes in the contralateral hemisphere. These effects were not apparent in the 24-72 h window. These results show that there are major and prolonged changes in motor cortex excitability in the pre and the postictal 24 h. Increased excitation precedes the seizure by hours and there is a similar period of decreased excitability following a seizure.

INCITE: A randomised trial comparing constraint induced movement therapy and bimanual training in children with congenital hemiplegia

BackgroundCongenital hemiplegia is the most common form of cerebral palsy (CP) accounting for 1 in 1300 live births. These children have limitations in capacity to use the impaired upper limb and bimanual coordination deficits which impact on daily activities and participation in home, school and community life. There are currently two diverse intensive therapy approaches. Traditional therapy has adopted a bimanual approach (BIM training) and recently, constraint induced movement therapy (CIMT) has emerged as a promising unimanual approach. Uncertainty remains about the efficacy of these interventions and characteristics of best responders. This study aims to compare the efficacy of CIMT to BIM training to improve outcomes across the ICF for school children with congenital hemiplegia.Methods/DesignA matched pairs randomised comparison design will be used with children matched by age, gender, side of hemiplegia and level of upper limb function. Based on power calculations a sample size of 52 children (26 matched pairs) will be recruited. Children will be randomised within pairs to receive either CIMT or BIM training. Both interventions will use an intensive activity based day camp model, with groups receiving the same dosage of intervention delivered in the same environment (total 60 hours over 10 days). A novel circus theme will be used to enhance motivation. Groups will be compared at baseline, then at 3, 26 and 52 weeks following intervention. Severity of congenital hemiplegia will be classified according to brain structure (MRI and white matter fibre tracking), cortical excitability using Transcranial Magnetic Stimulation (TMS), functional use of the hand in everyday tasks (Manual Ability Classification System) and Gross Motor Function Classification System (GMFCS). Outcomes will address neurovascular changes (functional MRI, functional connectivity), and brain (re)organisation (TMS), body structure and function (range of motion, spasticity, strength and sensation), activity limitations (upper limb unimanual capacity and bimanual motor coordination), participation restrictions (in home, school and recreation), environmental (barriers and facilitators to participation) and quality of life.DiscussionThis paper outlines the theoretical basis, study hypotheses and outcome measures for a matched pairs randomised trial comparing CIMT and BIM training to improve outcomes across the ICF.Trial RegistrationACTRN12609000912280

Cortical hyperexcitability and epileptogenesis: Understanding the mechanisms of epilepsy – Part 1

Epilepsy encompasses a diverse group of seizure disorders caused by a variety of structural, cellular and molecular alterations of the brain primarily affecting the cerebral cortex, leading to recurrent unprovoked epileptic seizures. In this two-part review we examine the mechanisms underlying normal neuronal function and those predisposing to recurrent epileptic seizures starting at the most basic cellular derangements (Part 1) and working up to the highly complex epileptic networks (Part 2). We attempt to show that multiple factors can modify the epileptic process and that different mechanisms underlie different types of epilepsy, and in most situations there is an interplay between multiple genetic and environmental factors.

Predicting seizure control: Cortical excitability and antiepileptic medication

Approximately 30% of patients with newly diagnosed epilepsy do not respond to antiepileptic drugs (AEDs), but this is not predictable. We used transcranial magnetic stimulation to determine the effect of AEDs on cortical excitability in patients with epilepsy and correlated this with a successful response to treatment.

Why do seizures in generalized epilepsy often occur in the morning

Objective: We used transcranial magnetic stimulation to investigate the effect of diurnal variability on cortical excitability in patients with epilepsy. Methods: Thirty drug-naive patients with epilepsy (20 idiopathic generalized epilepsy [IGE], including 10 juvenile myoclonic epilepsy [JME], and 10 focal epilepsy) and 10 control subjects without epilepsy were studied both early in the morning and late in the afternoon. We measured the mean motor thresholds and constructed recovery curves at short (2–15 msec) and long (50–400 msec) interstimulus intervals. Results: An increase in cortical excitability indicated by decreased short and long intracortical inhibition was observed early in the morning compared to the afternoon in patients with JME. In other IGE syndromes, there was decreased long intracortical inhibition only. No effect was found in subjects with focal epilepsy or controls without epilepsy. Conclusion: Cortical excitability measured by transcranial magnetic stimulation increases early in the morning in patients with idiopathic generalized epilepsy, particularly in juvenile myoclonic epilepsy, but not in subjects with focal epilepsy or controls without epilepsy. This may explain the increased seizure susceptibility in this cohort at this time of day.

Networks underlying paroxysmal fast activity and slow spike and wave in Lennox-Gastaut syndrome

Objective: To use EEG-fMRI to determine which structures are critically involved in the generation of paroxysmal fast activity (PFA) and slow spike and wave (SSW) (1.5–2.5 Hz), the characteristic interictal discharges of Lennox-Gastaut syndrome (LGS). Methods: We studied 13 well-characterized patients with LGS using structural imaging and EEG-fMRI at 3 tesla. Ten patients had cortical structural abnormalities. PFA and SSW were considered as separate events in the fMRI analysis. Results: Simultaneous with fMRI, PFA was recorded in 6 patients and SSW in 9 (in 2, both were recorded). PFA events showed almost uniform increases in blood oxygen level–dependent (BOLD) signal in “association” cortical areas, as well as brainstem, basal ganglia, and thalamus. SSW showed a different pattern of BOLD signal change with many areas of decreased BOLD signal, mostly in primary cortical areas. Two patients with prior callosotomy had lateralized as well as generalized PFA. The lateralized PFA was associated with a hemispheric version of the PFA pattern we report here. Conclusion: PFA is associated with activity in a diffuse network that includes association cortices as well as an unusual pattern of simultaneous activation of subcortical structures (brainstem, thalamus, and basal ganglia). By comparison, the SSW pattern is quite different, with cortical and subcortical activations and deactivations. Regardless of etiology, it appears that 2 key, but distinct, patterns of diffuse brain network involvement contribute to the defining electrophysiologic features of LGS.

CORTICAL EXCITABILITY AND REFRACTORY EPILEPSY: A THREE-YEAR LONGITUDINAL TRANSCRANIAL MAGNETIC STIMULATION STUDY

Transcranial magnetic stimulation was used to study the effect of recurrent seizures on cortical excitability over time in epilepsy. 77 patients with firm diagnoses of idiopathic generalized epilepsy (IGE) or focal epilepsy were repeatedly evaluated over three years. At onset, all groups had increased cortical excitability. At the end of follow-up the refractory group was associated with a broad increase in cortical excitability. Conversely, cortical excitability decreased in all seizure free groups after introduction of an effective medication.