In vivo functional evaluation of central cholinergic circuits in vascular dementia

OBJECTIVE: Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation of motor cortex. This test, named short latency afferent inhibition (SAI) has been shown in healthy subjects to be sensitive to the blockage of muscarinic acetylcholine receptors and it is impaired in Alzheimer disease (AD) patients, a cholinergic form of dementia, while it is normal in non-cholinergic forms of dementia such as fronto-temporal dementia. The objective of present study was to evaluate central cholinergic circuits in patients with Vascular Dementia (VaD). METHODS: We evaluated SAI in a group of patients with VaD and compared the data with those from a group of AD patients and a control group of age-matched healthy individuals. RESULTS: Mean SAI was normal in VaD patients while it was significantly reduced in AD patients. The analysis of individual data showed abnormal SAI in 75% of AD and in only 25% of VaD. CONCLUSIONS: SAI is normal in most of VaD patients in contrast with AD patients. This test might be used for the functional evaluation of central cholinergic circuits in VaD patients. SIGNIFICANCE: SAI testing may represent a useful additional tool for the evaluation of patients with VaD however, further studies are required in order to evaluate whether this method can be used for the differential diagnosis between pure VaD and different forms of dementia.     

Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation

BACKGROUND: A recently devised test of motor cortex excitability (short latency afferent inhibition) was shown to be sensitive to the blockade of muscarinic acetylcholine receptors in healthy subjects. The authors used this test to assess cholinergic transmission in the motor cortex of patients with AD. METHODS: The authors evaluated short latency afferent inhibition in 15 patients with AD and compared the data with those of 12 age-matched healthy controls. RESULTS: Afferent inhibition was reduced in the patients (mean responses +/- SD reduced to 85.7% +/- 15.8% of the test size) compared with controls (mean responses +/- SD reduced to 45.3% +/- 16.2% of the test size; p < 0.001, unpaired t-test). Administration of a single oral dose of rivastigmine improved afferent inhibition in a subgroup of six patients. CONCLUSIONS: The findings suggest that this method can be used as a noninvasive test of cholinergic pathways in AD. Future studies are required to evaluate whether short latency afferent inhibition measurements have any consistent clinical correlates.     

A review of transcranial magnetic stimulation in vascular dementia

Vascular dementia (VaD) is a clinical syndrome that encompasses a wide spectrum of cognitive disorders caused by cerebrovascular disease. The subcortical ischemic form of VaD is clinically homogeneous and a major cause of cognitive impairment in the elderly. Vascular lesions contribute to cognitive decline in neurodegenerative dementias, and VaD and Alzheimer's disease often coexist and share clinical features and multiple neurotransmission involvement. These similarities have led several investigators to use transcranial magnetic stimulation (TMS) to enucleate a neurophysiological profile of VaD. TMS studies have identified a pattern of cortical hyperexcitability probably related to the disruption of the integrity of white matter lesions due to cerebrovascular disease. The present review provides a perspective of these TMS techniques by further understanding the role of different neurotransmission pathways and plastic remodeling of neuronal networks in the pathogenesis of VaD.     

Effects of repetitive transcranial magnetic stimulation on cognitive function and cholinergic activity in the rat hippocampus after vascular dementia

Repetitive transcranial magnetic stimulation(rTMS) is a non-invasive treatment that can enhance the recovery of neurological function after stroke. Whether it can similarly promote the recovery of cognitive function after vascular dementia remains unknown. In this study, a rat model for vascular dementia was established by the two-vessel occlusion method. Two days after injury, 30 pulses of rTMS were administered to each cerebral hemisphere at a frequency of 0.5 Hz and a magnetic field intensity of 1.33 T. The Morris water maze test was used to evaluate learning and memory function. The Karnovsky-Roots method was performed to determine the density of cholinergic neurons in the hippocampal CA1 region. Immunohistochemical staining was used to determine the number of brain-derived neurotrophic factor(BDNF)-immunoreactive cells in the hippocampal CA1 region. rTMS treatment for 30 days significantly improved learning and memory function, increased acetylcholinesterase and choline acetyltransferase activity, increased the density of cholinergic neurons, and increased the number of BDNF-immunoreactive cells. These results indicate that r TMS can ameliorate learning and memory deficiencies in rats with vascular dementia. The mechanism through which this occurs might be related to the promotion of BDNF expression and subsequent restoration of cholinergic system activity in hippocampal CA1 region.     

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.     

A review of repetitive transcranial magnetic stimulation use in the treatment of schizophrenia

Patients with schizophrenia often fail to respond to standard antipsychotic medications or have a partial treatment response. Few treatment options are available for these patients. Repetitive transcranial magnetic stimulation (rTMS) was developed and investigated over the last 10 years as a potential treatment option for various psychiatric conditions. Increasingly, studies are focusing on potential applications of rTMS in schizophrenia. To date, most of these studies were symptom-specific rather than focused on the treatment of the disorder in general. The most extensive literature focuses on the use of low-frequency stimulation to attempt to disrupt or reduce the intensity of persistent refractory auditory hallucinations. This research tends to suggest that rTMS could have a role in this subset of patients. There is also preliminary but limited evidence that rTMS could have a role in reducing the negative symptoms of schizophrenia and perhaps in augmenting cognitive function. These findings also highlight the pressing need for further research including multisite studies to confirm the value of these options.     

Safety of transcranial magnetic stimulation in Parkinson's disease: A review of the literature

BackgroundTranscranial magnetic stimulation (TMS) has been used in both physiological studies and, more recently, the therapy of Parkinson's Disease (PD). Prior TMS studies in healthy subjects and other patient populations demonstrate a slight risk of seizures and other adverse events. Our goal was to estimate these risks and document other safety concerns specific to PD patients.MethodsWe performed an English-Language literature search through PudMed to review all TMS studies involving PD patients. We documented any seizures or other adverse events associated with these studies. Crude risks were calculated per subject and per session of TMS.ResultsWe identified 84 single pulse (spTMS) and/or paired-pulse (ppTMS) TMS studies involving 1091 patients and 77 repetitive TMS (rTMS) studies involving 1137 patients. Risk of adverse events was low in all protocols. spTMS and ppTMS risk per patient for any adverse event was 0.0018 (95% CI: 0.0002–0.0066) per patient and no seizures were encountered. Risk of an adverse event from rTMS was 0.040 (95% CI: 0.029–0.053) per patient and no seizures were reported. Other adverse events included transient headaches, scalp pain, tinnitus, nausea, increase in pre-existing pain, and muscle jerks. Transient worsening of Parkinsonian symptoms was noted in one study involving rTMS of the supplementary motor area (SMA).ConclusionWe conclude that current TMS and rTMS protocols do not pose significant risks to PD patients. We would recommend that TMS users in this population follow the most recent safety guidelines but do not warrant additional precautions.     

Efficacy of repetitive transcranial magnetic stimulation in depression: A review of the evidence

Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment in psychiatry. We reviewed all published evidence on the efficacy of this treatment option in depressive disorders. An extensive electronic and manual search for eligible research reports identified only 12 studies that met the predetermined criteria for inclusion. rTMS was administered differently in most studies, and patient characteristics varied widely. A formal meta-analysis of the studies was thus not possible. Instead, we conducted a qualitative evaluation of the included studies. The antidepressive efficacy was not consistent, and where efficacy was demonstrated, it was modest in most studies. Some patients had good but transient responses to rTMS. Treatment gains were not maintained beyond the treatment period. Comparisons with electroconvulsive therapy (ECT) indicated the superiority of ECT. More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS. We conclude that there is insufficient evidence for rTMS as a valid treatment for depression at present.     

The contribution of transcranial magnetic stimulation in the diagnosis and in the management of dementia

Transcranial magnetic stimulation (TMS) is emerging as a promising tool to non-invasively assess specific cortical circuits in neurological diseases. A number of studies have reported the abnormalities in TMS assays of cortical function in dementias. A PubMed-based literature review on TMS studies targeting primary and secondary dementia has been conducted using the key words “transcranial magnetic stimulation” or “motor cortex excitability” and “dementia” or “cognitive impairment” or “memory impairment” or “memory decline”. Cortical excitability is increased in Alzheimer’s disease (AD) and in vascular dementia (VaD), generally reduced in secondary dementias. Short-latency afferent inhibition (SAI), a measure of central cholinergic circuitry, is normal in VaD and in frontotemporal dementia (FTD), but suppressed in AD. In mild cognitive impairment, abnormal SAI may predict the progression to AD. No change in cortical excitability has been observed in FTD, in Parkinson’s dementia and in dementia with Lewy bodies. Short-interval intracortical inhibition and controlateral silent period (cSP), two measures of gabaergic cortical inhibition, are abnormal in most dementias associated with parkinsonian symptoms. Ipsilateral silent period (iSP), which is dependent on integrity of the corpus callosum is abnormal in AD. While single TMS measure owns low specificity, a panel of measures can support the clinical diagnosis, predict progression and possibly identify earlier the “brain at risk”. In dementias, TMS can be also exploited to select and evaluate the responders to specific drugs and, it might become a rehabilitative tool, in the attempt to restore impaired brain plasticity.     

The study of central nervous information processing with transcranial magnetic stimulation

In cognitive neuroscience different methods are used to study central nervous information processing. Transcranial magnetic stimulation (TMS) is a non-invasive, well tolerated technique to interfere with cortical neuronal activity with high temporal and fair spatial resolution. In the past 10 years the use of TMS expanded from its application as a diagnostic routine procedure in neurology to the study of various cognitive functions. In this paper the physical and technical aspects of TMS and studies on the effects of single pulse versus repetitive TMS in the motor cortex are reviewed. Then, research on visual perception and attention is presented and studies on higher cognitive functions, such as speech, memory, and emotions are discussed.     

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.     

Experience with transcranial magnetic stimulation in evaluation of spinal cord injury

Abstract

Nine subjects (seven male, two female) underwent transcranial magnetic stimulation (TMS) toward the evaluation of spinal cord injury (SCI). The evaluation of SCI with TMS tended to support clinical findings. Those subjects with clinically complete injuries demonstrated no evoked muscle response below the level or injury. Those subjects with clinically incomplete injuries showed trends toward prolonged evoked muscle latencies on the weaker side. Facilitation tended to enhance distal muscle responses. With incomplete spinal injurYI the facilitation maneuver allowed the recording of weak muscle responses as well as those otherwise not present at rest. Maximum anal sphincter contraction also hf;lped facilitate muscle responses and tended to impart less noise in the recordings. Facilitation failed, however to produce a response in those subjects with clinically complete injuries. No subject experienced adverse effects during the study. TMS promises to be an effective tool for the evaluation of SCI. [Neural Res 1997; 19: 497-500]     

Structural and functional neuroimaging of electroconvulsive therapy and transcranial magnetic stimulation

Neuroimaging has long been utilized to provide a measure of the effects of electroconvulsive therapy (ECT) on brain structure and function as well as to better understand its mechanisms of action. In a similar fashion, functional neuroimaging may provide the means to elucidate both the underlying neurobiological effects and therapeutic potential of transcranial magnetic stimulation (TMS). This article will review findings of neuroimaging studies of both TMS and ECT, concentrating on how such studies may help guide treatment.