James T. Teo

The Role of Contralesional Dorsal Premotor Cortex after Stroke as Studied with Concurrent TMS-fMRI

Contralesional dorsal premotor cortex (cPMd) may support residual motor function following stroke. We performed two complementary experiments to explore how cPMd might perform this role in a group of chronic human stroke patients. First, we used paired-coil transcranial magnetic stimulation (TMS) to establish the physiological influence of cPMd on ipsilesional primary motor cortex (iM1) at rest. We found that this influence became less inhibitory/more facilitatory in patients with greater clinical impairment. Second, we applied TMS over cPMd during functional magnetic resonance imaging (fMRI) in these patients to examine the causal influence of cPMd TMS on the whole network of surviving cortical motor areas in either hemisphere and whether these influences changed during affected hand movement. We confirmed that hand grip-related activation in cPMd was greater in more impaired patients. Furthermore, the peak ipsilesional sensorimotor cortex activity shifted posteriorly in more impaired patients. Critical new findings were that concurrent TMS-fMRI results correlated with the level of both clinical impairment and neurophysiological impairment (i.e., less inhibitory/more facilitatory cPMd-iM1 measure at rest as assessed with paired-coil TMS). Specifically, greater clinical and neurophysiological impairment was associated with a stronger facilitatory influence of cPMd TMS on blood oxygenation level-dependent signal in posterior parts of ipsilesional sensorimotor cortex during hand grip, corresponding to the posteriorly shifted sensorimotor activity seen in more impaired patients. cPMd TMS was not found to influence activity in other brain regions in either hemisphere. This state-dependent influence on ipsilesional sensorimotor regions may provide a mechanism by which cPMd supports recovered function after stroke.

The Future of Restorative Neurosciences in Stroke: Driving the Translational Research Pipeline From Basic Science to Rehabilitation of People After Stroke

Background. Major advances during the past 50 years highlight the immense potential for restoration of function after neural injury, even in the damaged adult human brain. Yet, the translation of these advances into clinically useful treatments is painstakingly slow. Objective. Here, we consider why the traditional model of a “translational research pipeline” that transforms basic science into novel clinical practice has failed to improve rehabilitation practice for people after stroke. Results. We find that (1) most treatments trialed in vitro and in animal models have not yet resulted in obviously useful functional gains in patients; (2) most clinical trials of restorative treatments after stroke have been limited to small-scale studies; (3) patient recruitment for larger clinical trials is difficult; (4) the determinants of patient outcomes and what patients want remain complex and ill-defined, so that basic scientists have no clear view of the clinical importance of the problems that they are addressing; (5) research in academic neuroscience centers is poorly integrated with practice in front-line hospitals and the community, where the majority of patients are treated; and (6) partnership with both industry stakeholders and patient pressure groups is poorly developed, at least in the United Kingdom where research in the translational restorative neurosciences in stroke depends on public sector research funds and private charities. Conclusions. We argue that interaction between patients, front-line clinicians, and clinical and basic scientists is essential so that they can explore their different priorities, skills, and concerns. These interactions can be facilitated by funding research consortia that include basic and clinical scientists, clinicians and patient/carer representatives with funds targeted at those impairments that are major determinants of patient and carer outcomes. Consortia would be instrumental in developing a lexicon of common methods, standardized outcome measures, data sharing and long-term goals. Interactions of this sort would create a research-friendly, rather than only target-led, culture in front-line stroke rehabilitation services.

Neurophysiological evidence for cerebellar dysfunction in primary focal dystonia

Recent studies have suggested that there may be functional and structural changes in the cerebellum of patients with adult onset primary focal dystonia. The aim of this study was to establish whether there is any neurophysiological indicator of abnormal cerebellar function, using the classic eyeblink conditioning paradigm. This paradigm at short intervals is dependent on the olivo-cerebellar circuit and does not require cerebral and basal ganglia structures. Eyeblink conditioning was performed by pairing an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms in 12 patients with primary focal dystonia (seven cervical dystonias, five focal hand dystonias) and eight healthy controls. Healthy controls produced more conditioned eyeblink responses than patients with focal dystonia, indicating an abnormality of associative learning in this patient population. This study provides neurophysiological evidence for functional changes in the olivo-cerebellar pathway of patients with primary focal dystonia. Further work needs to be done to determine if these changes are primary, secondary or epiphenomenal to the disease.

Intracortical circuits modulate transcallosal inhibition in humans

Previous results using paired‐pulse transcranial magnetic stimulation (TMS) have suggested that the excitability of transcallosal (TC) connections between the hand areas of the two motor cortices is modulated by intracortical inhibitory circuits in the same way as corticospinal tract (CTS) projections to spinal motoneurons. Here we describe two further similarities in TC and CTS control using (1) an I‐wave facilitation protocol and (2) preconditioning with rTMS. In experiment 1, excitability of TC pathways was measured using interhemispheric inhibition (IHI) and the ipsilateral silent period (iSP), whilst excitability of CTS pathways was measured by recording the EMG response evoked in the first dorsal interosseous muscle contralateral to the conditioning stimulus (cMEP). The intensity of the conditioning stimulus was first adjusted to threshold for evoking IHI and iSP, then pairs of conditioning stimuli were applied randomly at interstimulus intervals (ISIs) from 1.3 to 4.3 ms. IHI and iSP were facilitated at ISI = 1.5 ms and 3.0 ms, respectively, as was the MEP evoked by the conditioning stimuli in the contralateral hand. We suggest that TC projections receive I‐wave‐like facilitation similar to that seen in CTS projections. In experiment 2, short interval inhibition of the iSP (SICIiSP), and short interval intracortical inhibition of the cMEP (SICIcMEP) were examined before and after 600 pulses of 5 Hz rTMS at 90% resting motor threshold. Both SICIiSP and SICIcMEP were reduced, as was the iSP; the cMEP was unchanged. This shows that the population of inhibitory interneurons that control TC neurons respond in the same way to 5 Hz rTMS as those that control CTS neurons. Taken together, the data from the two experiments suggest that the layer III and layer V pyramidal neurons that give rise to TC and CTS pathways, respectively, are controlled by neuronal circuitry with similar properties.

Tardive dyskinesia is caused by maladaptive synaptic plasticity: a hypothesis.

It has been 50 years since the first patients with tardive dyskinesia (TD) were described, but the pathophysiology is only partially understood and effective treatments have remained elusive. Newer atypical antipsychotics with less nonspecific activity at dopamine receptors have not heralded the end of tardive dyskinesia and merely highlight the incomplete understanding of the disorder.

Human Theta Burst Stimulation Enhances Subsequent Motor Learning and Increases Performance Variability

Intermittent theta burst stimulation (iTBS) transiently increases motor cortex excitability in healthy humans by a process thought to involve synaptic long-term potentiation (LTP), and this is enhanced by nicotine. Acquisition of a ballistic motor task is likewise accompanied by increased excitability and presumed intracortical LTP. Here, we test how iTBS and nicotine influences subsequent motor learning. Ten healthy subjects participated in a double-blinded placebo-controlled trial testing the effects of iTBS and nicotine. iTBS alone increased the rate of learning but this increase was blocked by nicotine. We then investigated factors other than synaptic strengthening that may play a role. Behavioral analysis and modeling suggested that iTBS increased performance variability, which correlated with learning outcome. A control experiment confirmed the increase in motor output variability by showing that iTBS increased the dispersion of involuntary transcranial magnetic stimulation-evoked thumb movements. We suggest that in addition to the effect on synaptic plasticity, iTBS may have facilitated performance by increasing motor output variability; nicotine negated this effect on variability perhaps via increasing the signal-to-noise ratio in cerebral cortex.

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.

Secondary and primary dystonia: pathophysiological differences

Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.

The blink reflex recovery cycle differs between essential and presumed psychogenic blepharospasm

Background: Psychogenic blepharospasm is difficult to distinguish clinically from benign essential blepharospasm (BEB). The blink reflex recovery cycle measures the excitability of human brainstem interneurons and is abnormal in BEB. We wished to study the blink reflex recovery cycle in patients with atypical (presumed psychogenic) blepharospasm (AB). Methods: This was a prospective data collection study investigating the R2 blink reflex recovery cycle at interstimulus intervals (ISI) of 200, 300, 500, 1,000, and 3,000 msec in 10 patients with BEB, 9 patients with AB, and 9 healthy controls. All patients had spasm of the orbicularis oculi muscles. To compare individual patients, an R2 recovery index was calculated as average of the recovery values at ISIs of 200, 300, and 500 msec, with the upper limit of normal defined as mean (control group) + 2 SD. Results: The R2 recovery cycle was significantly disinhibited in patients with BEB, whereas patients with AB did not differ from controls on a group level. The upper limit of normal for the R2 recovery index was 61%. The R2 index was abnormal in 9 out of 10 patients with BEB and in none of the patients with AB. Conclusions: A normal blink reflex recovery cycle indicates normal brainstem interneuron excitability. Assessment of the R2 recovery cycle may provide a useful diagnostic tool to distinguish patients with psychogenic blepharospasm from BEB and is worthy of further study.

Differing effects of intracortical circuits on plasticity

Practice of a motor task leads to an increase in amplitude of motor-evoked potentials (MEP) in the exercised muscle. This is termed practice-dependent plasticity, and is abolished by the NMDA antagonist dextromethorphan and the GABAA agonist lorazepam. Here, we sought to determine whether specific subtypes of GABAA circuits are responsible for this effect by comparing the action of the non-selective agonist, lorazepam with that of the selective GABAA-alpha1 receptor agonist, zolpidem. In seven healthy subjects, transcranial magnetic stimulation (TMS) was used to quantify changes in amplitude of MEP after practice of a ballistic motor task. In addition we measured how the same drugs affected MEP amplitudes and the excitability of a number of cortical inhibitory circuits [short-interval intracortical inhibition (SICI), short-interval afferent inhibition (SAI) and long-interval intracortical inhibition]. This allowed us to explore correlations between drugs effects in measures of cortical excitability and practice-dependent plasticity of MEP amplitudes. As previously reported, lorazepam increased SICI and decreased SAI, while zolpidem only decreased SAI. The new findings were that practice-dependent plasticity of MEPs was impaired by lorazepam but not zolpidem, and that this was negatively correlated with lorazepam-induced changes in SICI but not SAI. This suggests that the intracortical circuits involved in SICI (and not neurons expressing GABAA-alpha1 receptor subunits that are implicated in SAI) may be involved in controlling the amount of practice-dependent MEP plasticity.