The relationship between motor cortex excitability and severity of Alzheimer's disease: a transcranial magnetic stimulation study

Introduction

In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have been limited to test motor cortical excitability. The aim of this study was to investigate the inhibitory circuits of the motor cortex and to relate these to measures of cognitive function in AD patients. Results were compared with those of a control group of healthy subjects matched for age, sex and education.

Patients and methods

Forty-five AD patients and 37 healthy volunteers were included in the study. Each participant received a neurological evaluation, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR). Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), motor evoked potential (MEP), cortical silent period (CSP), and transcallosal inhibition (TI).

Results

AD patients showed significantly reduced rMT, aMT and shorter MEP onset latency; in addition there was a prolongation of both CSP and TI. There was a significant positive correlation between the MMSE and CDR, on the one hand, and aMT and rMT, on the other hand, whereas the correlation was negative with CSP and TI durations.

Conclusion

AD is associated with hyperexcitability of the motor cortex, which supports the hypothesis that changes in GABAb and glutamate function are important factors in cognitive impairment.     

Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease.

OBJECTIVE: To assess the effects of focal motor cortex stimulation on motor performance and cortical excitability in patients with Parkinson's disease (PD). METHODS: Repetitive transcranial magnetic stimulation (rTMS) was performed on the left motor cortical area corresponding to the right hand in 12 'off-drug' patients with PD. The effects of subthreshold rTMS applied at 0.5 Hz (600 pulses) or at 10 Hz (2000 pulses) using a 'real' or a 'sham' coil were compared to those obtained by a single dose of l-dopa. The assessment included a clinical evaluation by the Unified Parkinson's Disease Rating Scale and timed motor tasks, and a neurophysiological evaluation of cortical excitability by single- and paired-pulse TMS techniques. RESULTS: 'Real' rTMS at 10 or 0.5 Hz, but not 'sham' stimulation, improved motor performance. High-frequency rTMS decreased rigidity and bradykinesia in the upper limb contralateral to the stimulation, while low-frequency rTMS reduced upper limb rigidity bilaterally and improved walking. Concomitantly, 10 Hz rTMS increased intracortical facilitation, while 0.5 Hz rTMS restored intracortical inhibition. CONCLUSIONS: Low- and high-frequency rTMS of the primary motor cortex lead to significant but differential changes in patients with PD both on clinical and electrophysiological grounds. The effects on cortical excitability were opposite to previous observations made in healthy subjects, suggesting a reversed balance of cortical excitability in patients with PD compared to normals. However, the underlying mechanisms of these changes remain to determine, as well as the relationship with clinical presentation and response to l-dopa therapy. SIGNIFICANCE: The present study gives some clues to appraise the role of the primary motor cortex in PD. Clinical improvement induced by rTMS was too short-lasting to consider therapeutic application, but these results support the perspective of the primary motor cortex as a possible target for neuromodulation in PD.     

Effect of levetiracetam on cortical excitability: a transcranial magnetic stimulation study

Background and purpose:  We studied the effect of levetiracetam (LEV), an anticonvulsant with a novel mechanism of action, on cortical excitability, measured using transcranial magnetic stimulation (TMS). For this purpose, 38 healthy volunteers were assessed in two TMS sessions, before and after an oral dose of 3000 mg LEV.
Methods:  Resting motor threshold (RMT), intracortical facilitation (ICF) and intracortical inhibition (ICI), cortical silent period (CSP) threshold and duration and motor-evoked potential (MEP) amplitude were calculated.
Results:  After treatment with LEV, RMT was increased (mean ± SD: 63 ± 14% of the maximum stimulator output) compared with baseline (58 ± 11%). CSP threshold was decreased after LEV (54 ± 10%; baseline, 57 ± 11%). CSP duration was increased after LEV (116 ± 37 ms; baseline: 102 ± 33 ms). LEV did not affect ICF or ICI or mean MEP amplitude significantly.
Conclusions:  Our results indicate that LEV modulates some aspects of cortical excitability. Whereas the increase in the RMT most probably reflects the effect of LEV on ion channel activity, effects on the CSP might represent a modulation of GABA receptors at cortical and spinal level.     

Therapeutic applications of repetitive transcranial magnetic stimulation (rTMS) in movement disorders: A review

Repetitive transcranial magnetic stimulation (rTMS) is emerging as a valuable adjunctive therapeutic modality in movement disorders. It is a non-invasive technique of repeated stimulation of the cerebral cortex by a train of magnetic pulses. The therapeutic effect of rTMS was first noted in depression. Later several researchers have investigated the role of rTMS in various movement disorders, notably Parkinson's disease, dystonia, Tourette's syndrome etc. The rTMS protocols used in these studies vary widely, lacks uniformity and often the results are not consistent. The optimal rTMS parameters for each disorder are yet to be established. This review discusses the current knowledge on the therapeutic applications of rTMS in various movement disorders.     

Reduced motor cortical inhibition in migraine: A blinded transcranial magnetic stimulation study

Objective

To investigate motor cortical excitability, inhibition, and facilitation with navigated transcranial magnetic stimulation (TMS) in migraine in a blinded cross-sectional study.

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex is a relatively non-invasive technique with putative therapeutic effects in major depression. However, the exact neurophysiological basis of these effects needs further clarification. Therefore, we studied the impact of ten daily sessions of left, dorsolateral prefrontal rTMS on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 30 patients. As compared to the non-responders, responders (33%) showed changes in parameters pointing towards a reduced cortical excitability. These results suggest that repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex may have inhibitory effects on motor cortical neuronal excitability in patients with major depressive disorder. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of antidepressant stimulation techniques like rTMS.     

Combined dementia-risk biomarkers in Parkinson's disease: A prospective longitudinal study

Neuropsychological (mostly posterior-cortical) deficits, quantitative magnetic resonance imaging (MRI) atrophy patterns, and low cerebrospinal fluid (CSF) levels of amyloid-β have been separately related to worsening cognition in Parkinson's disease (PD). However, these biomarkers have not been longitudinally assessed in combination as PD-dementia predictors. In this prospective longitudinal study, 27 non-demented PD patients underwent CSF, neuropsychological and 3-T brain-MRI studies at baseline and were re-assessed 18 months later in terms of progression to dementia (primary outcome) and longitudinal neuropsychological and cortical thickness changes (secondary outcomes). At follow-up 11 patients (41%) had progressed to dementia. Lower CSF amyloid-β, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions were significant baseline dementia predictors in binary logistic regressions as quantitative and/or dichotomised traits. All participants without baseline biomarker abnormalities remained non-demented whereas all with abnormalities in each biomarker type progressed to dementia, with intermediate risk for those showing abnormalities in a single to two biomarker types (p = 0.006). Both the dementia-outcome and low baseline CSF amyloid-β were prospectively associated with limbic and posterior-cortical neuropsychological decline and frontal, limbic and posterior-cortical thinning from baseline to follow-up. These findings suggest that the combination of CSF amyloid-β, neuropsychological and cortical thickness biomarkers might provide a basis for dementia-risk stratification and progression monitoring in PD.     

A prospective pilot study of repetitive transcranial magnetic stimulation for gait dysfunction in Vascular Parkinsonism

Objective

Vascular Parkinsonism (VP) causes significant gait dysfunction in patients who otherwise have good lower limb strength. Its pathophysiology is not clearly understood, and current treatment with physical therapy remains unsatisfactory. The study explores repetitive transcranial magnetic stimulation (rTMS) as a potential new and safe therapy for VP.

Materials and methods

We prospectively applied 5 Hz rTMS treatment to 5 patients who satisfied all the criteria for VP. Repetitive TMS was performed on 5 consecutive days and patients were assessed on (1) timed 10 m walk (T10MW), (2) Unified Parkinson's Disease Rating Scale (UPDRS) motor subsection, (3) Clinician's Global Impression of Change (CGIC), and (4) Patient's Global Impression of Change (PGIC), for up to 6 weeks post-rTMS.

Results

All the outcome measures were found to have improved ratings post-rTMS when compared with baseline, and were statistically significant. The T10MW showed significant improvement at 4 weeks post-rTMS with a trend towards improvement at 2 weeks post-rTMS. The UPDRS motor subscores was significantly reduced at 2 weeks, 4 weeks and 6 weeks post-rTMS. The PGIC and CGIC scores were significantly better post-rTMS. The treatment was well-tolerated and all patients completed the study.

Conclusion

This study demonstrated for the first time that 5 sessions of rTMS could improve gait in a measurable way for up to 6 weeks without any significant side-effects. Repetitive TMS could be a potentially useful adjunct in rehabilitation of VP patients and further research is warranted.     

Cholinergic dysfunction in subcortical ischaemic vascular dementia: a transcranial magnetic stimulation study

Little is known about the neurochemical pathology of vascular dementia (VD); it was suggested that cholinergic mechanisms play a role in the pathogenesis of VD, as well as been established for Alzheimer's disease (AD). A recently devised test of motor cortex excitability, the short latency afferent inhibition (SAI), has been proven to depend upon the activity of cholinergic circuits in the human brain. To evaluate, in vivo, the functional role of the cholinergic system in the cognitive dysfunction associated with VD, we used this test in 20 patients with subcortical ischemic VD (SIVD) and in 25 control subjects. Mean SAI was significantly reduced in the SIVD patients; however, individual data varied widely, with SAI responses ranging from normal to markedly reduced values. These findings provide physiological evidence for an important role for cholinergic mechanisms in the pathogenesis of VD. The evaluation of SAI, similar to that described in AD patients, could help in identifying those patients who are more likely to respond to treatment with cholinergic drugs.     

Repetitive magnetic stimulation of cortical motor areas in Parkinson's disease: implications for the pathophysiology of cortical function.

We investigated the neurophysiological and clinical effects of repetitive magnetic stimulation (rTMS) delivered to the cortical motor areas in healthy subjects and patients with Parkinson's disease. rTMS was delivered with a high speed magnetic stimulator (Cadwell, Kennewick, WA) through a figure-eight coil centred on the primary motor area at a stimulus intensity of 120% motor threshold. Trains of 10 stimuli were delivered at frequencies of 5 Hz while subjects were at rest and during a voluntary contraction of the contralateral first dorsal interosseous muscle. In normal subjects at rest, the muscle evoked responses (MEPs) to each stimulus in a train of magnetic stimuli progressively increased in size during the train. rTMS left the MEPs unchanged in patients off therapy and had a small facilitatory effect in those on therapy. In normal subjects and patients, 5-Hz rTMS trains delivered during a voluntary contraction of the target muscle left the MEP unchanged in size. MEPs were followed by a silent period that increased in duration during the course of the train. The silent period duration increased to a similar extent in patients and controls. The reduced rTMS-induced facilitation of MEPs in patients with Parkinson's disease reflects a decreased facilitation of the excitatory cells in the cortical motor areas.     

重复经颅磁刺激治疗帕金森病2年随访

目的随访观察重复经颅磁刺激(r TMS)治疗帕金森病(PD)患者的疗效。方法应用统一PD评分量表第Ⅲ部分(UPDRSⅢ)、Hoehn-Yahr(H-Y)分级、PD非运动症状(NMS)筛查问卷(NMSQ)、PD睡眠量表(PDSS)、汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)和简易智能量表(MMSE)对37例应用药物和r TMS治疗的PD患者(r TMS+药物组)及45例单纯药物治疗的PD患者(药物组)在基线和2年随访末的运动症状(MS)和非运动症状(NMS)进行评估,对比分析两组患者病情进展。结果 r TMS+药物组2年随访末H-Y分级较基线显著升高(P 0.05);药物组2年随访末UPDRSⅢ、H-Y分级、HAMD、HAMA评分及左旋多巴等效剂量(LED)较基线均显著升高(P 0.05);对两组2年随访末的症状进行比较,药物组的UPDRSⅢ、H-Y分级、HAMD评分及LED较r TMS+药物组升高显著(P 0.05)。结论规律的r TMS辅助常规抗PD药物治疗可减缓PD进展,优于单纯抗PD药物治疗。     

Diagnostic contribution and therapeutic perspectives of transcranial magnetic stimulation in dementia

Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such as excitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of the pathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention.The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment.To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer’s disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression.In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.     

Helicobacter pylori and the risk of dementia: A population-based study

Introduction

Helicobacter pylori infection might increase risk of dementia, but available evidence is inconsistent, and longitudinal studies are sparse. We investigated the association between H. pylori serology and dementia risk in a population-based cohort.