Subthalamic stimulation in a patient with multiple system atrophy: a clinicopathological report

INTRODUCTION: Efficacy of high frequency subthalamic nucleus (STN) stimulation has been demonstrated in idiopathic Parkinson's disease (IPD). However, since it may be difficult to differentiate IPD from multiple system atrophy with parkinsonian presentation (MSA-P), a few cases of MSA-P has been treated by deep brain stimulation (DBS) and showed no sustained improvement of clinical signs. We report a patient with a clinical misdiagnosed MSA-P, later confirmed by neuropathological study, who was improved by DBS for one year. CASE REPORT: A 63-year-old parkinsonian patient had been treated by levodopa for 6 years with a persistent good response. Over one year he progressively developed disabling fluctuations with severe axial syndrome and vegetative non motor symptoms in off periods. After checking usual contraindications, he was included in surgical procedure protocol (bilateral STN stimulation). During the first year after surgery, the clinical status improved with disappearance of non motor fluctuations, a 45 percent decrease of the OFF UPDRS III score, and a 39 percent reduction of the treatment. However after one year, axial symptoms reappeared with recurrent falls, as well as increasing dysarthry and swallowing difficulties which were only slightly improved by levodopa. He developed severe urinary disorders increased by a prostatic adenoma which led to surgical treatment. During the post operative period, 2 years after DBS, he died suddenly from an unexplained cause. A cerebral autopsy was performed and showed a good position of the two electrodes in the STN. Microscopic studies revealed severe neuronal depletion in the substantia nigra but no Lewy bodies. Immunohistochemical methods demonstrated numerous argyrophilic glial cytoplasmic inclusions positive for alpha-synuclein and ubiquitin in the STN, putamen, globus pallidus, pontine nuclei and cerebellar white matter, significant of MSA. CONCLUSION: This case shows that DBS can improve parkinsonian signs in MSA-P with persistent dopa sensitivity. However, probably because of striatal degeneration progression, this improvement is time limited and STN DBS cannot be recommended in MSA.     

Multi-infarct disorder presenting as corticobasal degeneration (DCB): vascular pseudo-corticobasal degeneration?

We report on five patients with a clinical presentation of corticobasal degeneration (CBD), including gradually progressive, asymmetric, L-DOPA-resistant parkinsonism associated variously with apraxia, focal action myoclonus, focal dystonia, cortical sensory loss and alien limb phenomenon. Some patients also presented an atypical CBD clinical history or signs - notably sudden onset. The disease was however not suggestive of another diagnosis. Magnetic resonance imaging of the brain revealed extensive vascular lesions. Only five similar cases have been published to our knowledge. Although we cannot exclude underlying CBD pathology, our cases illustrate the fact that multi-infarct pathology can masquerade as CBD or alter the clinical phenotype of the disease.     

Transcranial magnetic stimulation (TMS) in basic and clinical neuroscience research

Introduction

Non-invasive brain stimulation methods such as transcranial magnetic stimulation (TMS) are starting to be widely used to make causality-based inferences about brain-behavior interactions. Moreover, TMS-based clinical applications are under development to treat specific neurological or psychiatric conditions, such as depression, dystonia, pain, tinnitus and the sequels of stroke, among others.

Background

TMS works by inducing non-invasively electric currents in localized cortical regions thus modulating their activity levels according to settings, such as frequency, number of pulses, train and regime duration and intertrain intervals. For instance, it is known for the motor cortex that low frequency or continuous patterns of TMS pulses tend to depress local activity whereas high frequency and discontinuous TMS patterns tend to enhance it. Additionally, local cortical effects of TMS can result in dramatic patterns in distant brain regions. These distant effects are mediated via anatomical connectivity in a magnitude that depends on the efficiency and sign of such connections.

Perspectives

An efficient use of TMS in both fields requires however, a deep understanding of its operational principles, its risks, its potential and limitations. In this article, we will briefly present the principles through which non-invasive brain stimulation methods, and in particular TMS, operate.

Conclusion

Readers will be provided with fundamental information needed to critically discuss TMS studies and design hypothesis-driven TMS applications for cognitive and clinical neuroscience research.     

Transcranial magnetic stimulation: applications in neuropsychiatry

In the 1990s, it is difficult to open a newspaper or watch television and not find someone claiming that magnets promote healing. Rarely do these claims stem from double-blind, peer-reviewed studies, making it difficult to separate the wheat from the chaff. The current fads resemble those at the end of the last century, when many were falsely touting the benefits of direct electrical and weak magnetic stimulation. Yet in the midst of this popular interest in magnetic therapy, a new neuroscience field has developed that uses powerful magnetic fields to alter brain activity--transcranial magnetic stimulation. This review examines the basic principles underlying transcranial magnetic stimulation, and describes how it differs from electrical stimulation or other uses of magnets. Initial studies in this field are critically summarized, particularly as they pertain to the pathophysiology and treatment of neuropsychiatric disorders. Transcranial magnetic stimulation is a promising new research and, perhaps, therapeutic tool, but more work remains before it can be fully integrated in psychiatry's diagnostic and therapeutic armamentarium.     

Cortical excitability and transcallosal inhibition in chronic tinnitus: Transcranial magnetic study

INTRODUCTION: It has been proposed that tinnitus may be caused by maladaptive plasticity of processing in the central auditory pathways, and that this may be due in part to a generalised deficit in NMDA-dependent glutamatergic synapses. STUDY AIM: To test this hypothesis, we used transcranial magnetic stimulation to assess the excitability of a number of well-defined synaptic connections in the motor cortex of patients with tinnitus. PATIENTS AND METHODS: Thirty-seven patients with chronic tinnitus and 12 normal age- and sex-matched volunteers were used as a control group. We measured resting and active motor thresholds (rMT/aMT) and the duration of the contralateral and ipsilateral cortical silent periods (CSP and ISP). Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were evaluated using a paired pulse stimulation paradigm in the left (dominant) hemisphere. RESULTS: There was no difference between patients and healthy subjects in rMT or aMT or the onset latency of the ISP. The CSP was shorter in patients (P=0.046) whereas the ISP was longer than in healthy subjects (P=0.048) but there was no difference between the hemispheres nor any relation to tinnitus side in patients with predominantly unilateral symptoms. There was no difference in the time course of SICI/ICF between patients and control groups and no significant correlation between tinnitus handicap inventory (THI) score and any of the measures of cortical excitability. CONCLUSIONS: There are small changes incortical excitability in patients with chronic tinnitus. However, given the number of factors we examined in each individual, such minor changes seem unlikely to be an important factor in development of clinical symptoms.     

Transcranial and direct cortical stimulation for motor evoked potential monitoring in intracerebral aneurysm surgery

STUDY AIM: To analyse the parallel use of transcranial electrical stimulation (TES) and direct cortical stimulation (DCS) for eliciting muscle motor evoked potentials (MMEPs) in intracranial aneurysm surgery; to correlate permanent or transient TES- and/or DCS-MMEP changes with surgical maneuvers and clinical motor outcome. PATIENTS AND METHODS: TES and DCS were intraoperatively performed in 108 patients (51.5+/-14.7 years); MMEPs were obtained in muscles belonging to the vascular territory of interest. Monopolar, anodal stimulation was achieved with a train of five stimuli consisting of an individual pulse width of 0.5ms, an interstimulus interval of 4ms, a train repetition rate of 0.5-2Hz, and maximum stimulation intensities up to 200mA (TES) versus 25mA (DCS). RESULTS: In 95/108 (88%) patients, no changes in MMEPs occurred and none of these patients suffered a permanent severe motor deficit. In 14/108 (12%) patients, we observed nine (64%) temporary changes, four (29%) permanent deteriorations and one (7%) permanent MMEP loss. Out of 14 MMEP changes, nine (64%) occurred with TES, compared to 13 (93%) with DCS (Fishers'p=0.165). Parallel changes in TES- and DCS-MMEPs occurred in 8/14 patients (57%), in which case a permanent loss was always followed by a permanent severe motor deficit. Sixty-seven percent of all permanent changes occurred with DCS-MMEPs, compared to 33% with TES-MMEPs (p=0.567, NS). DISCUSSION AND CONCLUSIONS: In aneurysm surgery, provided that close-to-motor-threshold stimulation and the most focal stimulating electrode montage are used, TES- and DCS-MMEPs do not differ in their capacity to detect an impending lesion of the motor cortex or its efferent pathways. TES stimulation can cause significant muscular contraction during surgery, potentially disrupting the operating surgeon. DCS maintains the singular advantage of stimulating a very focal and superficial motor cortex stimulation that does not result in patient movement.     

Transcranial magnetic stimulation for geriatric depression: Promises and pitfalls

As the global population gets older, depression in the elderly is emerging as an important health issue. A major challenge in treating geriatric depression is the lack of robust efficacy for many treatments that are of significant benefit to depressed working age adults. Repetitive transcranial magnetic stimulation (rTMS) is a novel physical treatment approach used mostly in working age adults with depression. Many TMS trials and clinics continue to exclude the elderly from treatment citing lack of evidence in this age group. In this review, we appraise the evidence regarding the safety and efficacy of rTMS in the elderly. A consistent observation supporting a high degree of tolerability and safety among the elderly patients emerged across the Randomised Controlled Trials and the uncontrolled trials. Further, there is no reliable evidence negating the utility of rTMS in the elderly with depression. We also identified several factors other than age that moderate the observed variations in the efficacy of rTMS in the elderly. These factors include but not limited to: (1) brain atrophy; (2) intensity and number of pulses (dose-response relationship); and (3) clinical profile of patients. On the basis of the current evidence, the practice of excluding elderly patients from TMS clinics and trials cannot be supported.     

Treatment with intravenous rt-PA in a general hospital context: A review of the Saint-Jean Hospital experience from Perpignan, France

INTRODUCTION: Intravenous recombinant tissue plasminogen activator (rt-PA) has approval for use despite of its authorization for treatment of ischemic stroke within the 3-hour time window in 2003, is rarely used in community hospital (CH). It therefore remains questionable if the positive results of the key studies conducted in specialized centers may be extended to community hospitals less specialized in the management of stroke. METHODS: We report the results of an observational cohort study including 39 patients treated with intravenous rt-Pa (according to the NINDS rt-PA stroke trail treatment protocol) at St Jean Hospital (Perpignan, France) between March 1, 2002 and August 31, 2005. Results are compared to those of the treated arm of the NINDS study. RESULTS: 1.2p.cent of ischemic stroke were treated with intravenous rt-Pa. Results are similar to those of the NINDS study: The outcome was favorable (modified Rankin score (mRS) with 0 or 1) for 44p.cent of the patients (as compared to 39p.cent in the NINDS study (X2 = 0.34; p = 0.5)) and there was no significant difference in term of death or outcome as assessed by mRS at 3 months (X2 = 0.09; p = 0.75 and X2 = 0.77; p = 0.75, respectively). No symptomatic hemmorrhagic transformation related to the use of rt-Pa was observed. CONCLUSION: Our results indicate that rt-PA therapy for ischemic stroke may be as safe and effective in the setting of a community hospital as it is in specialized centers.     

Epileptogenic and non-epileptogenic zones: blood flow studies of temporo-limbic seizures

To assess the contribution of ictal SPECT to the definition of the epileptogenic zone (EZ) prior to surgery in focal drug-resistant epilepsies, we investigated the effect of the timing of injection and seizure semiology on patterns of perfusion and cerebral blood flow changes (CBF) beyond the EZ. In the rat model of amygdala-kindled seizures, we measured CBF changes with the quantitative [(14)C]-iodoantipyrine autoradiographic method during secondary generalized (SGS, n=26 fully-kindled rats) and focal seizures (FS, n=19 partially kindled rats), according to sequential timing of injection with respect to seizure onset. During SGS, the correct lateralization and rough localization of the focus within limbic structures was only possible at the early ictal and post-ictal times, in between we observed widespread rCBF increases. The switch from hyper to hypoperfusion occurred at the time of late ictal injection. The accurate localization of the EZ was obtained in the study of the more subtle FS (stage 0). At stage 1 of the kindling, there was already a remote widespread spreading of hyperperfusion. In patients surgically cured from a mesio-temporal lobe epilepsy (mean post-operative follow-up: 66 months), we retrospectively studied 26 pairs of ictal and interictal pre-operative SPECTs, classified in 3 groups according to the progression of ictal semiology. Using visual analysis of subtracted SPECTs (SISCOM) and group comparisons with a control group (using SPM), we observed more widespread combined hyper and hypoperfusion with the increasing complexity of seizures. In simple partial seizures, the SISCOM analysis allowed a correct localization of the focus in 4/8 patients, whereas the SPM analysis failed to detect significant changes, due to individual variation, spatial normalization and small magnitude of CBF changes. In complex partial seizures with automatisms, SISCOM and SPM analysis showed antero-mesial temporal hyperperfusion (overlapping the EZ), extending to the insula, basal ganglia, and thalamus in the group of patients having dystonic posturing (DP group) in addition to automatisms. Ictal hypoperfusion involved pre-frontal and parietal regions, the anterior and posterior cingulate gyri, to a greater extent in the DP group. In both human and animals studies, we observed a correlation between the extent of composite patterns of hyper/hypoperfusion and the severity of seizures, and the recruitment of remote sub-cortical structures. Hypoperfused areas belong to neural networks involved in perceptual decision making and motor planning, whose transient disruption could support purposeless actions, i.e. motor automatisms.     

Transcranial magnetic stimulation applications and potential use in chronic pain: studies in waiting

Transcranial magnetic stimulation (TMS) is a new technology which uses electromagnetic principles to produce small electrical currents in the cortex. Evidence indicates that TMS can produce plastic changes in the CNS which are observable at both the cellular and physiological levels. It is proposed that studies are justified to determine whether TMS can provide short-term or long-term relief in chronic pain.     

Transcranial magnetic stimulation as a tool for understanding neurophysiology in Huntington's disease: A review

Structural and functional magnetic resonance imaging modalities have been critical in advancing our understanding of the neuroanatomical and pathophysiological changes that emerge during the premanifest and symptomatic stages of Huntington's disease (HD). However, the relationship between underlying neuropathology and the motor, cognitive and behavioural changes associated with the disorder still remain poorly understood. Less conventional technologies, such as transcranial magnetic stimulation (TMS) and electroencephalography (EEG), provide a unique opportunity to further investigate the causal relationships between targeted neural circuits and objective neurophysiological responses together with overt behaviours. In this review, we discuss previous successful applications of TMS in other neurological disorders and its prospective use in HD. We also address the added value of multimodal TMS techniques, such as TMS–EEG, in investigating the integrity of neural networks in non-motor regions in HD. We conclude that neurophysiological outcome measures are likely to contribute towards characterising further the trajectory of decline across functional domains in HD, enhance understanding of underlying neural mechanisms, and offer new avenues for elucidating sensitive endophenotypic biomarkers of disease progression.     

Myoclonus and transcranial magnetic stimulation

The neural dysfunction at the origin of myoclonus may locate at various anatomical levels within the central nervous system, including the motor cortices. Transcranial magnetic stimulation (TMS) can be used to assess the balance between inhibitory and excitatory processes involved in the regulation of motor cortex activity and thereby, may be of value to determine the pathophysiological mechanisms of myoclonus. Using paired-pulse paradigms with various interstimulus intervals, TMS studies showed that intracortical inhibition (ICI) was reduced in progressive myoclonic epilepsy (PME). In contrast, ICI was decreased only for short interstimulus intervals in patients with juvenile myoclonic epilepsy (JME). Transcallosal inhibition and sensorimotor integration were also both altered in PME but not in JME. Actually, the loss of inhibitory regulation within the central nervous system might represent an intrinsic mechanism of myoclonus, whether of epileptic origin or not. Finally, the other TMS parameters of excitability (motor threshold, silent period, intracortical facilitation) were found normal in most cases of myoclonus. According to these observations, it was quite conceivable that the application of repetitive trains of TMS (rTMS) at inhibitory low-frequency (around 1 Hz) might be able to relieve myoclonus by restoring ICI. A few reported cases illustrate the efficacy of low-frequency rTMS to alleviate myoclonic symptoms. Therapeutic-like perspectives are opened for rTMS in these forms of myoclonus that are related to motor cortical hyperexcitability secondary to the loss of ICI.     

Transcranial magnetic stimulation in partial epilepsy: drug-induced changes of motor excitability

Single-pulse transcranial magnetic stimulation (s-TMS) with recording of motor evoked potentials (MEPs) from thenar muscles of both hands was performed on 84 patients with cryptogenic partial epilepsy and 50 healthy controls. We analyzed the cortical latency (CL), central conduction time (CCT), and threshold intensity (TI) required to elicit liminal MEPs at rest. In the patients, CL and CCT were normal, but TI was significantly higher than in the controls. Of the 84 patients, 65 were taking one or more antiepileptic drugs and 19 were untreated. The untreated patients had a significantly lower TI than the treated patients. In the treated patients, the TI increase paralleled the number of drugs taken. Additionally, in 2 subgroups of patients undergoing major modifications of antiepileptic treatment, TI dropped after partial withdrawl of medication and increased following the commencement of therapy. The results suggest that anticonvulsants depress the excitability of human motor pathways in epileptic subjects.     

Transcranial magnetic stimulation of the trigeminal nerve: Intraoperative study on stimulation characteristics in man

We studied responses from the masseter and nasalis muscles following magnetic stimulation (magStim) and compared these responses with those obtained by direct electrical stimulation of the trigeminal (NV) and facial (NVII) nerve near the root exit zone during microvascular decompression operations of NVII. We found that (1) magStim threshold to excite the nerve is high for NV and low for NVII; (2) excitation of all motor fibers is impossible for NV, and easy for NVII; (3) optimal coil placement is critical for NV, but not critical for NVII; and (4) between and within subjects, the excitation site is variable on NV, but stable on NVII. We estimated that the anatomical location of magStim to be either within or outside the cerebrospinal fluid for NV, and to be in the labyrinthine segment of the facial canal for NVII. Physical models explain and clinical lesion models support these differences found between NV and NVII. © 1995 John Wiley & Sons, Inc.     

Transcranial magnetic stimulation: a new tool in the fight against depression

Since its introduction to the clinical realm in 1985, transcranial magnetic stimulation (TMS) has rapidly developed into a tool for exploring central nervous system function in both health and disease. The antidepressant effects of TMS were initially observed in 1993. Since then, a solid body of evidence has accumulated suggesting antidepressant effects for both slow TMS (sTMS) and repetitive TMS (rTMS). This review is divided into four parts. First, it addresses the basic concepts governing TMS, and then, second, it discusses the technical parameters involved in administering TMS. Knowledge of these parameters is necessary for understanding how TMS is administered, and how manipulation of the technique impacts on the results obtained. Third, we review the most relevant studies on the antidepressant effects of sTMS and rTMS published to date. Finally, we discuss cortical excitability and how the understanding of this basic neurophysiological function of cortical neurons can be used for monitoring the effects of TMS. In our discussion, we conclude that the time has arrived for TMS to be offered to depressed patients as a treatment.     

Transcranial magnetic stimulation (TMS)/repetitive TMS in mild cognitive impairment and Alzheimer's disease

Several Transcranial Magnetic Stimulation (TMS) techniques can be applied to noninvasively measure cortical excitability and brain plasticity in humans. TMS has been used to assess neuroplastic changes in Alzheimer's disease (AD), corroborating findings that cortical physiology is altered in AD due to the underlying neurodegenerative process. In fact, many TMS studies have provided physiological evidence of abnormalities in cortical excitability, connectivity, and plasticity in patients with AD. Moreover, the combination of TMS with other neurophysiological techniques, such as high‐density electroencephalography (EEG), makes it possible to study local and network cortical plasticity directly. Interestingly, several TMS studies revealed abnormalities in patients with early AD and even with mild cognitive impairment (MCI), thus enabling early identification of subjects in whom the cholinergic degeneration has occurred. Furthermore, TMS can influence brain function if delivered repetitively; repetitive TMS (rTMS) is capable of modulating cortical excitability and inducing long‐lasting neuroplastic changes. Preliminary findings have suggested that rTMS can enhance performances on several cognitive functions impaired in AD and MCI. However, further well‐controlled studies with appropriate methodology in larger patient cohorts are needed to replicate and extend the initial findings. The purpose of this paper was to provide an updated and comprehensive systematic review of the studies that have employed TMS/rTMS in patients with MCI and AD.     

Transcranial direct current stimulation in Parkinson's disease: Neurophysiological mechanisms and behavioral effects

Recent research has highlighted the potential of transcranial direct current stimulation (tDCS) to complement rehabilitation effects in the elderly and in patients with neurological diseases, including Parkinson's disease (PD). TDCS can modulate cortical excitability and enhance neurophysiological mechanisms that compensate for impaired learning in PD. The objective of this systematic review is to provide an overview of the effects of tDCS on neurophysiological and behavioral outcome measures in PD patients, both as a stand-alone and as an adjunctive therapy. We systematically reviewed the literature published throughout the last 10 years. Ten studies were included, most of which were sham controlled. Results confirmed that tDCS applied to the motor cortex had significant results on motor function and to a lesser extent on cognitive tests. However, the physiological mechanism underlying the long-term effects of tDCS on cortical excitability in the PD brain are still unclear and need to be clarified in order to apply this technique optimally to a wider population in the different disease stages and with different medication profiles.     

Transcranial magnetic stimulation in hereditary ataxias: Diagnostic utility,pathophysiological insight and treatment

Transcranial magnetic stimulation (TMS) is a valuable technique to assess and modulate human brain function in normal and pathological conditions. This critical review surveys the contributions of TMS to the diagnosis, insight into pathophysiology and treatment of genetically confirmed hereditary ataxias, a heterogeneous group of neurodegenerative disorders that can affect motor cortex and the corticospinal tract. Most studies were conducted on small sample sizes and focused on diagnostic approaches. The available data demonstrate early involvement of the corticospinal tract and motor cortex circuitry, and support the possible efficacy of cerebellar repetitive TMS (rTMS) as therapeutic approach. Further TMS-based studies are warranted, to establish biomarkers for early diagnosis and disease monitoring, explore the involvement of the cerebello-dentato-thalamo-cortical projection, study the effects of rTMS-induced plasticity, and utilize rTMS for treatment.