Wen-Li Chuang

The theoretical model of theta burst form of repetitive transcranial magnetic stimulation

OBJECTIVE Theta burst stimulation, a form of repetitive transcranial magnetic stimulation, can induce lasting changes in corticospinal excitability that are thought to involve long-term potentiation/depression (LTD/LTD)-like effects on cortical synapses. The pattern of delivery of TBS is crucial in determining the direction of change in synaptic efficiency. Previously we explained this by postulating (1) that a single burst of stimulation induces a mixture of excitatory and inhibitory effects and (2) those effects may cascade to produce long-lasting effects. Here we formalise those ideas into a simple mathematical model. METHODS The model is based on a simplified description of the glutamatergic synapse in which post-synaptic Ca(2+) entry initiates processes leading to different amount of potentiation and depression of synaptic transmission. The final effect on the synapse results from summation of the two effects. RESULTS The model using these assumptions can fit reported data. Metaplastic effects of voluntary contraction on the response to TBS can be incorporated by changing time constants in the model. CONCLUSIONS The pattern-dependent after-effects and interactions with voluntary contraction can be successfully modelled by using reasonable assumptions about known cellular mechanisms of plasticity. SIGNIFICANCE The model could provide insight into development of new plasticity induction protocols using TMS.

Abnormal bidirectional plasticity-like effects in Parkinson’s disease

Levodopa-induced dyskinesia is a major complication of long-term dopamine replacement therapy for Parkinsons disease that becomes increasingly problematic in advanced Parkinsons disease. Although the cause of levodopa-induced dyskinesias is still unclear, recent work in animal models of the corticostriatal system has suggested that levodopa-induced dyskinesias might result from abnormal control of synaptic plasticity. In the present study, we aimed to explore control of plasticity in patients with Parkinsons disease with and without levodopa-induced dyskinesias by taking advantage of a newly developed protocol that tests depotentiation of pre-existing long-term potentiation-like synaptic facilitation. Long-term potentiation-like plasticity and its reversibility were studied in the motor cortex of 10 healthy subjects, 10 patients with Parkinsons disease and levodopa-induced dyskinesias, who took half of the regular dose of levodopa and 10 patients with Parkinsons disease without levodopa-induced dyskinesias, who took either half or the full dose of levodopa. Patients with Parkinsons disease without levodopa-induced dyskinesias had normal long-term potentiation- and depotentiation-like effects when they took their full dose of levodopa, but there was no long-term potentiation-like effect when they were on half dose of levodopa. In contrast, patients with levodopa-induced dyskinesias could be successfully potentiated when they were on half their usual dose of levodopa; however, they were unresponsive to the depotentiation protocol. The results suggest that depotentiation is abnormal in the motor cortex of patients with Parkinsons disease with levodopa-induced dyskinesias and that their long-term potentiation-like plasticity is more readily affected by administration of levodopa than their clinical symptoms.

The effect of continuous theta burst stimulation over premotor cortex on circuits in primary motor cortex and spinal cord

OBJECTIVE To understand the effect of continuous theta burst stimulation (cTBS) given to the premotor area, we studied the circuits within the primary motor cortex and spinal cord after cTBS over the dorsal premotor area (PMd). METHODS Three sets of parameters, including corticospinal excitability, short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) and forearm reciprocal inhibition (RI) were tested. RESULTS Paralleling the effects of cTBS applied directly to the primary motor cortex, cTBS over the left PMd suppressed corticospinal excitability as measured by the change in the size of MEPs evoked by single pulse TMS over primary motor cortex. Premotor cTBS appeared to have a longer lasting, but no more powerful effect on corticospinal excitability than motor cTBS, however, unlike motor cTBS it had no effect on SICI or ICF. Finally, although premotor cTBS had no effect on spinal H-reflexes, it did reduce the third phase of RI between forearm extensor and flexor muscles. CONCLUSIONS Premotor cTBS is a quick and useful way of modulating excitability in cortical and possibly subcortical motor circuits. SIGNIFICANCE Premotor cTBS can be used as an alternative to regular rTMS to evaluate cortical function, motor behaviours and the response to disease therapy.

Reversal of plasticity-like effects in the human motor cortex

A number of experiments in animals have shown that successful induction of plasticity can be abolished if an individually ineffective intervention is given shortly afterwards. Such effects are termed depotentiation/de‐depression. These effects contrast with metaplasticity/homeostatic plasticity in which pretreatment of the system with one protocol modulates the response to a second plasticity‐inducing protocol. Homeostatic plasticity maintains the balance of plasticity in the nervous system at a stable level whereas depotentiation/de‐depression abolishes synaptic plasticity that has just occurred in order to prevent ongoing learning. In the present study, we developed novel protocols to explore the reversal of LTP‐ and LTD‐like effects in healthy conscious humans based on the recently developed theta burst form of repetitive transcranial magnetic stimulation (TBS). The potentiation effect induced by intermittent TBS (iTBS) was completely erased by a short form of continuous TBS (cTBS150) given 1 min after iTBS, whereas the depressive effect of continuous TBS (cTBS) was successfully abolished by a short form of iTBS (iTBS150). The reversal was specific to the nature of the second protocol and was time dependent since it was less effective when the intervention was given 10 min after induction of plasticity. All these features are compatible with those of depotentiation and de‐depression demonstrated in animal studies. The development of the present protocols would be helpful to study the physiology of the reversal of plasticity and learning and to probe the abnormal depotentiation/de‐depression shown in animal models of neurological diseases (e.g. Parkinsons disease with dyskinesia, dystonia and Huntingons disease).

Correlation among subcortical white matter lesions, intelligence and CTG repeat expansion in classic myotonic dystrophy type 1

Objectives –  To analyze the correlation among intelligence, brain magnetic resonance images (MRI) and genotype in classic myotonic dystrophy type 1 (DM1) patients.

Regional Amyloid Deposition in Amnestic Mild Cognitive Impairment and Alzheimer's Disease Evaluated by [18F]AV-45 Positron Emission Tomography in Chinese Population

Background To compare the neocortical amyloid loads among cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimers disease (AD) subjects with [18F]AV-45 positron emission tomography (PET). Materials and Methods [18F]AV-45 PET was performed in 11 CN, 13 aMCI, and 12 AD subjects to compare the cerebral cortex-to-whole cerebellum standard uptake value ratios (SUVRs) of global and individual volumes of interest (VOIs) cerebral cortex. The correlation between global cortical [18F]AV-45 SUVRs and Mini-Mental State Examination (MMSE) scores was analyzed. Results The global cortical [18F]AV-45 SUVRs were significantly different among the CN (1.08±0.08), aMCI (1.27±0.06), and AD groups (1.34±0.13) (p = 0.0003) with amyloidosis positivity rates of 9%, 62%, and 92% in the three groups respectively. Compared to CN subjects, AD subjects had higher SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, and posterior cingulate areas; while aMCI subjects had higher values in the global cortical, precuneus, frontal, occipital and posterior cingulate areas. There were negative correlations of MMSE scores with SUVRs in the global cortical, precuneus, frontal, parietal, occipital, temporal, posterior cingulate and anterior cingulate areas on a combined subject pool of the three groups after age and education attainment adjustment. Conclusions Amyloid deposition occurs relatively early in precuneus, frontal and posterior cingulate in aMCI subjects. Higher [18F]AV-45 accumulation is present in parietal, occipital and temporal gyri in AD subjects compared to the aMCI group. Significant correlation between MMSE scores and [18F]AV-45 SUVRs can be observed among CN, aMCI and AD subjects.

Modulation of the Disturbed Motor Network in Dystonia by Multisession Suppression of Premotor Cortex

Daily sessions of therapeutic transcranial brain stimulation are thought to prolong or amplify the effect of a single intervention. Here we show in patients with focal hand dystonia that additional, new effects build up progressively over time, making it difficult to predict the effect of long term interventions from shorter treatment sessions. In a sham-controlled study, real or sham continuous theta burst stimulation (cTBS) was given once daily for five consecutive days to dorsolateral premotor cortex (PMd). Five days of real, but not sham, premotor cTBS improved intracortical inhibition in primary motor cortex (M1) to a similar extent on day 1 and day 5. However 5 days of cTBS were required to restore the abnormal PMd-M1 interactions observed on day 1. Similarly, excessive M1 plasticity seen at baseline was also significantly reduced by five days of real premotor cTBS. There was only a marginal benefit on writing. The results show that additional, new effects, at sites distant from the point of stimulation, build up progressively over time, making it difficult to predict the effect of long term interventions from shorter treatment sessions. The results indicate that it may take many days of therapeutic intervention to rebalance activity in a complex network.

Abnormal cortical excitability with preserved brainstem and spinal reflexes in sialidosis type I.

OBJECTIVE To examine neurophysiological evidence of functional involvement of the brainstem and spinal cord and motor cortical excitability in sialidosis type I, a rare inherited neurodegenerative disorder caused by mutations in the NEU1 gene. METHODS We investigated particular pathways in the brainstem, spinal cord and motor cortex in 12 genetically proven cases of sialidosis type I by assessing blink reflex recovery cycle (BR), spinal reciprocal inhibition (RI), input-output curves (I/O), short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and silent period (SP). RESULTS The BR and RI were normal. The slope of I/O was significantly increased, and SICI and the duration of SP were reduced in sialidosis patients. CONCLUSIONS Despite reports of pathology involving brainstem and anterior horn neurones, there were no obvious abnormalities in spinal and brainstem reflexes in the present patients, suggesting that the major clinical effects may be caused by changes at a level above the brainstem. SIGNIFICANCE For the first time, the integrity of certain brainstem and spinal cord reflexes in addition to motor cortical facilitatory and inhibitory circuits has been assessed in genetically proven type I sialidosis. This provides new data to aid in understanding of the pathophysiology of motor system dysfunction in this condition.

Brain fluorodeoxyglucose positron emission tomography (18FDG PET) in patients with acute thallium intoxication

Objective. Thallium toxicity induces cellular injury through impaired Na-K-ATPase activity. The aim of this study was to investigate functional imaging and the long-term clinical-imaging correlations of thallium toxicity. Materials and methods. We measured thallium concentrations in blood, urine, stools, and hair of a 48-year-old woman and a 52-year-old man (patients 1 and 2) in the first 3 months after exposure to thallium containing water, and studied their neuropsychological functions. Using fluorodeoxyglucose positron emission tomography (18FDG PET) scans, we examined the brain involvement and correlated the image findings with the clinical presentations. Results. On the 1st, 30th, and 61st days after exposure, the thallium concentrations in patient 1 were 2056, 311, and 7.5 μg/L in the blood, and 11400, 4570, and 36.4 μg/L in the urine. The concentrations in patient 2 were 956, 235, and 15.6 μg/L in the blood, and 11900, 2670, and 101 μg/L in the urine. On the 40th, 50th and 89th days after exposure, the thallium concentration in the stools were 21.6, 3.6, and 0.35 μg/g in patient 1, and 22.2, 3.2, and 0.37 μg/g in patient 2. Executive function, perceptual motor speed, and learning memory were initially abnormal but recovered particularly within the first year. The first 18FDG PET studies of both patients disclosed a decreased uptake of glucose metabolism in the cingulate gyrus, bilateral frontal, and parietal lobes 2–5 months after exposure. The follow-up 18FDG PET scan of patient 2 revealed a partial recovery. Conclusion. This study indicates that damage to the central nervous system after acute thallium poisoning may be reversible after a long-term follow-up. Brain 18FDG PET demonstrated the brain involvement and was correlated with cognitive impairment.

P36-3 Reversal of plasticity-like effects in the human motor cortex

normal control. All strokes were unilateral supratentorial corticospinal tract lesions. During the acute stage of stroke (5 to 20 days after onset), patients were performed same procedures in both paretic and non-paretic side. TTT was operated with a computerized program (QTRACS with multiple excitability protocol TRONDF; copyright, Prof. Hugh Bostock, Institute of Neurology, London, UK). The protocols calculated strengthduration time constant (SDTC) from duration-charge curve, parameters of threshold electrotonus (TE) and current-threshold relationship (CTR) from sequential sub-threshold current, and recovery cycle (RC) from sequential supra-threshold stimulation. Results: Each NET parameter was compared among normal control, paretic and non-paretic side of patients. In stroke group, compared to control group, there was significant increase of STDC in both paretic and non-paretic sides. Although there was no significant difference, paretic side had more increased STDC. Otherwise, all the other parameters were not different among groups. Conclusions: The putative mechanisms of altered nerve excitability properties in this study remains to be elucidated. However the sole change of STDC without alteration of TE suggests transynaptic regulation of persistent Na+ conductance by the acute supratentorial corticospinal lesion. In addition, this mechanism appears to operate rather nonselective for both injured and intact sides.