Penelope Talelli

A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS

The brain‐derived neurotrophic factor gene (BDNF) is one of many genes thought to influence synaptic plasticity in the adult brain and shows a common single nucleotide polymorphism (BDNF Val66Met) in the normal population that is associated with differences in hippocampal volume and episodic memory. It is also thought to influence possible synaptic changes in motor cortex following a simple motor learning task. Here we extend these studies by using new non‐invasive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS) techniques that directly test the excitability and plasticity of neuronal circuits in human motor cortex in subjects at rest. We investigated whether the susceptibility to TMS probes of plasticity is significantly influenced by the BDNF polymorphism. Val66Met carriers were matched with Val66Val individuals and tested on the following protocols: continuous and intermittent theta burst TMS; median nerve paired associative stimulation; and homeostatic plasticity in the TDCS/1 Hz rTMS model. The response of Met allele carriers differed significantly in all protocols compared with the response of Val66Val individuals. We suggest that this is due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. The circuits tested here are implicated in the pathophysiology of movement disorders such as dystonia and are being assessed as potential new targets in the treatment of stroke. Thus the polymorphism may be one factor that influences the natural response of the brain to injury and disease.

Exploring theta burst stimulation as an intervention to improve motor recovery in chronic stroke

OBJECTIVE To explore the effects of a single session of repetitive Transcranial Magnetic Stimulation, given as Theta Burst Stimulation, on behavioural and physiological measures of hand function in chronic stroke patients. METHODS Six chronic stroke patients with incomplete recovery of the hand were tested under three conditions: excitatory TBS over the stroke hemisphere (iTBS(SH)), inhibitory TBS (cTBS(IH)) over the intact hemisphere and sham stimulation. Behavioural outcomes included simple and choice reaction time paradigms. Physiological effects were assessed using single pulse TMS on both sides. Changes were sought for up to 40min after TBS. RESULTS Immediately after iTBS(SH) simple reaction times in the paretic hands were decreased and, compared to sham stimulation, remained significantly shorter throughout the testing period. The amplitude of the MEPs at rest and during background contraction and the area under the Input-Output curves were also increased on the stroke side after iTBS(SH). cTBS(IH) suppressed the MEPs evoked in the healthy hands but did not change motor behaviour or the electrophysiology of the paretic hands. No side effects were encountered. CONCLUSIONS TBS seems safe in chronic stroke patients. iTBS over the stroke hemisphere transiently improved motor behaviour and corticospinal output in the paretic hands. SIGNIFICANCE Excitatory TBS may represent a useful rTMS protocol to apply to the stroke hemisphere in future longer term therapy trials.

Arm function after stroke: Neurophysiological correlates and recovery mechanisms assessed by transcranial magnetic stimulation

Transcranial Magnetic Stimulation has been used for over 20 years to investigate recovery of motor function in stroke patients. In particular, it has been used to quantify the extent of damage to the corticospinal output, reorganisation of the cortical representation of the affected body parts and excitability of intracortical and cortico-cortical circuitries in both hemispheres. In this review, we provide a detailed account of most of the published data with particular reference to methodological issues that affect their interpretation.

Distinguishing SWEDDs Patients with Asymmetric Resting Tremor from Parkinson's Disease: A Clinical and Electrophysiological Study

Approximately 10% of patients diagnosed clinically with early Parkinsons disease (PD) have normal dopaminergic functional imaging (Scans Without Evidence of Dopaminergic Deficit [SWEDDs]). An important subgroup of SWEDDs are those with asymmetric rest tremor resembling parkinsonian tremor. Clinical and pathophysiological features which could help to distinguish SWEDDs from PD have not been explored. We therefore studied clinical details including non‐motor symptoms in 25 tremulous SWEDDs patients in comparison to 25 tremor‐dominant PD patients. Blinded video rating was used to compare examination findings. Electrophysiological tremor parameters and also response to a cortical plasticity protocol using paired associative stimulation (PAS) was studied in 9 patients with SWEDDs, 9 with tremor‐dominant PD (with abnormal dopamine transporter single photon emission computed tomography findings), 8 with segmental dystonia, and 8 with essential tremor (ET). Despite clinical overlap, lack of true bradykinesia, presence of dystonia, and head tremor favored a diagnosis of SWEDDs, whereas re‐emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs, and presence of non‐motor symptoms favored PD. A single tremor parameter could not differentiate between groups, but the combination of re‐emergent tremor and highest tremor amplitude at rest was characteristic of PD tremor. SWEDDs and segmental dystonia patients exhibited an abnormal exaggerated response to the PAS protocol, in contrast to a subnormal response in PD and a normal response in ET. We conclude that despite clinical overlap, there are features that can help to distinguish between PD and SWEDDs which may be useful in clinical practice. The underlying pathophysiology of SWEDDs differs from PD but has similarities with primary dystonia.

Neural correlates of age-related changes in cortical neurophysiology

Functional imaging studies of cortical motor systems in humans have demonstrated age-related reorganisation often attributed to anatomical and physiological changes. In this study we investigated whether aspects of brain activity during a motor task were influenced not only by age, but also by neurophysiological parameters of the motor cortex contralateral to the moving hand. Twenty seven right-handed volunteers underwent functional magnetic resonance imaging whilst performing repetitive isometric right hand grips in which the target force was parametrically varied between 15 and 55% of each subjects own maximum grip force. For each subject we characterised two orthogonal parameters, B(G) (average task-related activity for all hand grips) and B(F) (the degree to which task-related activity co-varied with peak grip force). We used transcranial magnetic stimulation (TMS) to assess task-related changes in interhemispheric inhibition from left to right motor cortex (IHIc) and to perform measures relating to left motor cortex excitability during activation of the right hand. Firstly, we found that B(G) in right (ipsilateral) motor cortex was greater with increasing values of age(2) and IHIc. Secondly, B(F) in left ventral premotor cortex was greater in older subjects and in those in whom contralateral M1 was less responsive to TMS stimulation. In both cases, neurophysiological parameters accounted for variability in brain responses over and above that explained by ageing. These results indicate that neurophysiological markers may be better indicators of biological ageing than chronological age and point towards the mechanisms by which reconfiguration of distributed brain networks occurs in the face of degenerative changes.

Theta Burst Stimulation in the Rehabilitation of the Upper Limb: A Semirandomized, Placebo-Controlled Trial in Chronic Stroke Patients

Background. Noninvasive cortical stimulation could represent an add-on treatment to enhance motor recovery after stroke. However, its clinical value, including anticipated size and duration of the treatment effects, remains largely unknown. Objective. The authors designed a small semi-randomized clinical trial to explore whether long-lasting clinically important gains can be achieved by adding theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (TMS), to a rehabilitation program for the hand. Methods. A total of 41 chronic stroke patients received excitatory TBS to the ipsilesional hemisphere or inhibitory TBS to the contralesional hemisphere in 2 centers; each active group was compared with a group receiving sham TBS. TBS was followed by physical therapy for 10 working days. Patients and therapists were blinded to the type of TBS. Primary outcome measures (9-hole Peg Test [9HPT], Jebsen Taylor Test [JTT], and grip and pinch-grip dynamometry) were assessed 4, 30, and 90 days post treatment. The clinically important difference was defined as 10% of the maximum score. Results. There were no differences between the active treatment and sham groups in any of the outcome measures. All patients achieved small sustainable improvements—9HPT, 5% of maximum (confidence interval [CI] = 3%-7%); JTT, 5.7% (CI = 3%-8%); and grip strength, 6% (CI = 2%-10%)—all below the defined clinically important level. Conclusions. Cortical stimulation did not augment the gains from a late rehabilitation program. The effect size anticipated by the authors was overestimated. These results can improve the design of future work on therapeutic uses of TMS.

Clinical applications of transcranial magnetic stimulation in patients with movement disorders

Transcranial magnetic stimulation (TMS) is a method of non-invasive brain stimulation that affects the cerebral cortex but not deep structures. In patients with movement disorders the most common application of TMS has been to test the excitability of connections within and among motor areas of the cortex, which has provided useful information on pathophysiology; however, inter-individual variability in the responses has resulted in difficulties in translating this method into a clinically applicable diagnostic use. Repeated stimulation (eg, 1 Hz for 20 min) can result in long-term plastic changes in the motor system, which has led to increased interest in possible therapeutic applications. In this Review, we describe the theoretical background to TMS techniques and discuss the uses of TMS as a potential diagnostic tool in movement disorders. The difficulties in bringing the technique into regular clinical diagnostic practice will be discussed and the evidence for the potential of repetitive TMS as a therapeutic tool in patients with movement disorders will be reviewed.

Does brain stimulation after stroke have a future

Purpose of reviewTranscranial methods of cortical stimulation can induce long-term changes in excitability of the cerebral cortex in humans and may be useful as therapeutic interventions in stroke rehabilitation. Recent findingsTwo approaches have been tested: (1) increasing excitability of the cortex in the stroke hemisphere and (2) suppression of the non-stroke hemisphere to reduce potential interference with function of the stroke hemisphere. The interventions have been transcranial direct current stimulation, transcranial magnetic stimulation and implanted epidural stimulation. All have been reported to give 10–20% functional improvement in small numbers of patients in single-session studies as well as in a small number of longer-term therapeutic trials. Preliminary experiments in aphasic patients using transcranial magnetic stimulation in an interference design show, however, that stimulation of the nonstroke hemisphere can in some patients reduce verbal fluency, questioning the general applicability of the second approach. SummaryCortical stimulation appears to be a safe and promising intervention for stroke patients. More studies are needed to assess its long-term benefits on substantial numbers of patients. We need to know what type of intervention is best, which patients are likely to benefit, the optimum time to intervene and the duration of any benefits.

Abnormal motor cortex plasticity in premanifest and very early manifest Huntington disease

Background Cognition is affected early in Huntington disease (HD), and in HD animal models there is evidence that this reflects abnormal synaptic plasticity. The authors investigated whether there is any evidence for abnormal synaptic plasticity using the human motor cortex-rTMS model and, if so, if there is any difference between premanifest HD gene carriers and very early manifest HD patients or any relationship with ratings of the severity of motor signs. Methods Fifteen HD gene carriers (seven premanifest, eight very early manifest) and 14 control participants were given a continuous train of 100 bursts of theta burst stimulation (cTBS: three pulses at 50 Hz and 80% AMT repeated every 200 ms). The size of the motor-evoked potential was measured at regular intervals until 21 min after cTBS. Results HD gene carriers and controls responded differently to theta burst stimulation (F4.9,131.9=1.37, p=0.048) with controls having more inhibition than HD gene carriers (F1,27=13.3, p=0.001). Across all time points, mean inhibition differed between the groups (F2,26=6.32, p=0.006); controls had more inhibition than either HD gene carrier subgroup (p=0.006 for premanifest and p=0.009 for early symptomatic), whereas there was no difference between premanifest and early symptomatic HD gene carriers. The measure of cortical plasticity was not associated with any clinical ratings (Unified Huntington Disease Rating Scale motor score, estimate of age at onset). Conclusions Motor cortex plasticity is abnormal in HD gene carriers but is not closely linked to the development of motor signs of HD.

Pattern-specific role of the current orientation used to deliver Theta Burst Stimulation.

OBJECTIVE To evaluate the role of current direction on the after-effects of Theta Burst Stimulation (TBS) delivered with a biphasic Magstim 200(2) stimulator. METHODS Inhibitory (cTBS) and excitatory TBS (iTBS) were delivered over the motor cortex of healthy individuals using reversed and standard current orientations (initial current in the antero-posterior direction) at 80% and 100% of their respective active motor thresholds (AMT). The after-effects on the MEP amplitude were measured for 25 min. The effects of the most effective reversed cTBS paradigm on intracortical inhibition (SICI) and facilitation (ICF) were also tested. RESULTS Reversing the current direction reduced AMT by 26%+/-2%. Compared to standard cTBS, reversed cTBS induced stronger and longer-lasting inhibition of corticospinal excitability when delivered at 100% AMTrev. SICI was reduced after cTBS100%revAMT while ICF was unchanged. The after-effects of reversed iTBS were quite variable regardless of the intensity. CONCLUSIONS cTBS applied with antero-posterior current is more effective in suppressing subsequent MEPs than conventionally orientated cTBS when the absolute stimulation intensity is similar. On the contrary, posterior current orientation reduces the efficacy of iTBS. SIGNIFICANCE The current direction may affect the power of inhibitory and excitatory TBS in opposite ways; this should be considered in order to optimise the after-effects of biphasic RTMS.