Transcranial magnetic stimulation studies in complex regional pain syndrome type I: A review

The sensory and motor cortical representation corresponding to the affected limb is altered in patients with complex regional pain syndrome (CRPS). Transcranial magnetic stimulation (TMS) represents a useful non‐invasive approach for studying cortical physiology. If delivered repetitively, TMS can also modulate cortical excitability and induce long‐lasting neuroplastic changes. In this review, we performed a systematic search of all studies using TMS to explore cortical excitability/plasticity and repetitive TMS (rTMS) for the treatment of CRPS. Literature searches were conducted using PubMed and EMBASE. We identified 8 articles matching the inclusion criteria. One hundred fourteen patients (76 females and 38 males) were included in these studies. Most of them have applied TMS in order to physiologically characterize CRPS type I. Changes in motor cortex excitability and brain mapping have been reported in CRPS‐I patients. Sensory and motor hyperexcitability are in the most studies bilateral and likely involve corresponding regions within the central nervous system rather than the entire hemisphere. Conversely, sensorimotor integration and plasticity were found to be normal in CRPS‐I. TMS examinations also revealed that the nature of motor dysfunction in CRPS‐I patients differs from that observed in patients with functional movement disorders, limb immobilization, or idiopathic dystonia. TMS studies may thus lead to the implementation of correct rehabilitation strategies in CRPS‐I patients. Two studies have begun to therapeutically use rTMS. This non‐invasive brain stimulation technique could have therapeutic utility in CRPS, but further well‐designed studies are needed to corroborate initial findings.     

Pharmacologic influences on TMS effects.

Transcranial magnetic stimulation (TMS) has been used increasingly to probe the physiology of the human cortex. Besides measuring directly the cortical excitability in motor and visual systems, this noninvasive method can be used to study short- and long-term cortical plasticity. One possible method to examine basic mechanisms underlying cortical excitability and plasticity in humans is the combination of TMS and pharmacologic interventions. In this review the author describes TMS paradigms used to study mechanisms of plasticity in the intact human motor system and its excitability using pharmacologic methods.     

Clinical and research methods for evaluating cortical excitability.

The evaluation of motor cortical output after transcranial magnetic stimulation (TMS) is a means of investigating how the motor cortex reacts to external stimuli (i.e., a method to assess the excitability of the motor cortex). The recording of the descending volleys at the surface of the spinal cord provides a direct measure of the motor cortical output. However, this approach is highly invasive and can be used only during particular conditions. On the other hand, electromyographic recordings of the motor phenomena induced by TMS provide a completely painless, noninvasive, indirect measure of the cortical output, with these phenomena obviously reflecting the excitability of the spinal motoneurons as well as that of the muscle itself. The authors review how the electromyographic activity induced by TMS can provide valuable information about motor cortical excitability for use in clinical practice and research.     

The effects of motor cortex rTMS on corticospinal descending activity

Repetitive transcranial magnetic stimulation (rTMS) of the human motor cortex can produce long-lasting changes in the excitability of the motor cortex to single pulse transcranial magnetic stimulation (TMS). rTMS may increase or decrease motor cortical excitability depending critically on the characteristics of the stimulation protocol. However, it is still poorly defined which mechanisms and central motor circuits contribute to these rTMS induced long-lasting excitability changes. We have had the opportunity to perform a series of direct recordings of the corticospinal volley evoked by single pulse TMS from the epidural space of conscious patients with chronically implanted spinal electrodes before and after several protocols of rTMS that increase or decrease brain excitability. These recordings provided insight into the physiological basis of the effects of rTMS and the specific motor cortical circuits involved.     

Cabergoline reverses cortical hyperexcitability in patients with restless legs syndrome

OBJECTIVE: To reverse the profile of abnormal intracortical excitability in patients with restless legs syndrome (RLS) by administering the dopaminergic agonist cabergoline. METHODS: The effects of this drug on motor cortex excitability were examined with a range of transcranial magnetic stimulation (TMS) protocols before and after administration of cabergoline over a period of 4 weeks in 14 patients with RLS and in 15 healthy volunteers. Measures of cortical excitability included central motor conduction time; resting and active motor threshold to TMS; duration of the cortical silent period; short latency intracortical inhibition (SICI) and intracortical facilitation using a paired-pulse TMS technique. RESULTS: Short latency intracortical inhibition was significantly reduced in RLS patients compared with the controls and this abnormal profile was reversed by treatment with cabergoline; the other TMS parameters did not differ significantly from the controls and remained unaffected after treatment with cabergoline. Cabergoline had no effect on cortical excitability of the normal subjects. CONCLUSIONS: As dopaminergic drugs are known to increase SICI, our findings suggest that RLS may be caused by a central nervous system dopaminergic dysfunction. This study demonstrates that the cortical hyperexcitability of RLS is reversed by cabergoline, and provides physiological evidence that this dopamine agonist may be a potentially efficacious option for the treatment of RLS.     

Effects of deep brain stimulation on the primary motor cortex: Insights from transcranial magnetic stimulation studies

Deep brain stimulation (DBS) implanted in different basal ganglia nuclei regulates the dysfunctional neuronal circuits and improves symptoms in movement disorders. However, the understanding of the neurophysiological mechanism of DBS is at an early stage. Transcranial magnetic stimulation (TMS) can be used safely in movement disorder patients with DBS, and can shed light on how DBS works. DBS at a therapeutic setting normalizes the abnormal motor cortical excitability measured with motor evoked potentials (MEP) produced by primary motor cortical TMS. Abnormal intracortical circuits in the motor cortex tested with paired-pulse TMS paradigm also show normalization with DBS. These changes are accompanied with improvements in symptoms after chronic DBS. Single-pulse DBS produces cortical evoked potentials recorded by electroencephalography at specific latencies and modulates motor cortical excitability at certain time intervals measured with MEP. Combination of basal ganglia DBS with motor cortical TMS at stimulus intervals consistent with the latency of cortical evoked potentials delivered in a repetitive mode produces plastic changes in the primary motor cortex. TMS can be used to examine the effects of open and closed loop DBS. Patterned DBS and TMS delivered in a repetitive mode may be developed as a new therapeutic method for movement disorder patients.     

Cortical excitability and age-related volumetric MRI changes.

OBJECTIVE: Normative data on transcranial magnetic stimulation (TMS)-derived measures of cortical excitability in the elderly is sparse. Nevertheless, elderly subjects are included as controls in studies utilizing TMS to investigate disease states. Age-associated increased ventricular cerebrospinal fluid CSF (vCSF) and white matter hyperintensity (WMH) MRI volumes have uncertain significance in non-demented elderly. Information regarding cortical excitability in neurologically intact elderly would augment our understanding of the pathophysiology of aging and assist in the interpretation of TMS studies involving elderly subjects. METHODS: Twenty-four healthy elderly subjects underwent TMS testing to determine outcomes of resting motor threshold (RMT) cortical silent period (cSP) and central motor conduction time for examination in relation to WMH, vCSF, and CNS volumes. RESULTS: Increased vCSF and WMH volumes were associated with decreased right and left hemisphere RMT. Smaller CNS volumes were associated with decreased right hemisphere RMT and shorted cSP. CONCLUSIONS: Commonly observed age-associated MRI changes are associated with findings consistent with increased cortical excitability. SIGNIFICANCE: Age-related MRI findings likely reflect changes at a cellular level, and may influence cognitive and motor integrity in the elderly. Future TMS studies investigating cortical excitability may wish to consider neuroimaging markers of neurodegeneration prior to enrolling elderly subjects as controls.     

Transcranial magnetic stimulation techniques in clinical investigation

Transcranial magnetic stimulation (TMS) is a technique that can activate cortical motor areas and the corticospinal tract without causing the subject discomfort. Since TMS was introduced, numerous applications of the technique have been developed for the evaluation of neurologic diseases. Standard TMS applications (central motor conduction time, threshold and amplitude of motor evoked potentials) allow the evaluation of motor conduction in the CNS. Conduction studies provide specific information in neurologic conditions characterized by clinical and subclinical upper motor neuron involvement. In addition, they have proved useful in monitoring motor abnormalities and the recovery of motor function. TMS also gives information on the pathophysiology of the processes underlying the various clinical conditions. More complex TMS applications (paired-pulse stimulation, silent period, ipsilateral silent period, input-output curve, and evaluation of central fatigue) allow investigation into the mechanisms of diseases causing changes in the excitability of cortical motor areas. These techniques are also useful in monitoring the effects of neurotrophic drugs on cortical activity. TMS applications have an important place among the investigative tools to study patients with motor disorders.     

Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS

BACKGROUND: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABA(A) receptor, and (11)C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms. METHODS: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. (11)C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical (11)C-flumazenil binding that might explain differences in cortical excitability seen using TMS. RESULTS: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical (11)C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS. CONCLUSIONS: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. (11)C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.     

Motor Cortical Excitability Assessed by Transcranial Magnetic Stimulation in Psychiatric Disorders: A Systematic Review

BackgroundTranscranial magnetic stimulation (TMS) is a popular neurostimulation technique suitable for the investigation of inhibitory and facilitatory networks in the human motor system. In the last 20 years, several studies have used TMS to investigate cortical excitability in various psychiatric disorders, leading to a consequent improvement in pathophysiological understanding. However, little is known about the overlap and specificity of these findings across these conditions.ObjectiveTo provide a systematic review of TMS studies (1985–2013) focusing on motor cortical excitability in dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome (TS), substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)).MethodsSystematic literature-based review.ResultsAcross disorders, patients displayed a general pattern of cortical disinhibition, while the most consistent results of reduced short-interval intracortical inhibition could be found in schizophrenia, OCD and Tourette Syndrome. In dementia, the most frequently reported finding was reduced short-latency afferent inhibition as a marker of cholinergic dysfunction.ConclusionsThe results of this systematic review indicate a general alteration in motor cortical inhibition in mental illness, rather than disease-specific changes. Changes in motor cortical excitability provide insight that can advance understanding of the pathophysiology underlying various psychiatric disorders. Further investigations are needed to improve the diagnostic application of these parameters.     

Unilateral cortical hyperexcitability in congenital hydrocephalus: A TMS study

Introduction: Changes in cortical excitability are considered to play an important role in promoting brain plasticity both in healthy people and in neurological diseases. Hydrocephalus is a brain development disorder related to an excessive accumulation of cerebrospinal fluid (CSF) in the ventricular system. The functional relevance of cortical structural changes described in this disease is largely unexplored in human. We investigated cortical excitability using multimodal transcranial magnetic stimulation (TMS) in a case of congenital hydrocephalus with almost no neurological signs. Methods: A caucasian 40 years old, ambidextrous and multilingual woman affected by occult spina bifida and congenital symmetrical hydrocephalous underwent a TMS study. The intracortical and interhemispheric paired pulse paradigms were used, together with the mapping technique. Results: No significant differences were found in the resting motor thresholds between the two hemispheres. Instead, the intracortical excitability curves were statistically different between the two hemispheres (with short intracortical inhibition (SICI) being strongly reduced and intracortical facilitation (ICF) enhanced in the right one), and the interhemispheric curves showed a general hyper-excitability on the right hemisphere (when conditioned by the left one) and a general hypo-excitability in the left hemisphere (when conditioned by the right one). It is noteworthy that an asymmetric right hemisphere (RH) change of excitability was observed by means of mapping technique. Conclusion: We hypothesize that in this ambidextrous subject, the observed RH hyper-excitability could represent a mechanism of plasticity to preserve functionality of specific brain areas possibly devoted to some special skills, such as multilingualism.     

Modulating cortical excitability in acute stroke: a repetitive TMS study.

OBJECTIVE: Changes in cerebral cortex excitability have been demonstrated after a stroke and are considered relevant for recovery. Repetitive transcranial magnetic stimulation (rTMS) of the brain can modulate cerebral cortex excitability and, when rTMS is given as theta burst stimulation (TBS), LTP- or LTD-like changes can be induced. The aim of present study was to evaluate the effects of TBS on cortical excitability in acute stroke. METHODS: In 12 acute stroke patients, we explored the effects of facilitatory TBS of the affected hemisphere and of inhibitory TBS of the unaffected hemisphere on cortical excitability to single-pulse transcranial magnetic stimulation (TMS) on both sides. The effects produced by TBS in patients were compared with those observed in a control group of age-matched healthy individuals. RESULTS: In patients, both the facilitatory TBS of the affected motor cortex and the inhibitory TBS of the unaffected motor cortex produced a significant increase of the amplitude of MEPs evoked by stimulation of the affected hemisphere. The effects observed in patients were comparable to those observed in controls. CONCLUSIONS: Facilitatory TBS over the stroke hemisphere and inhibitory TBS over the intact hemisphere in acute phase enhance the excitability of the lesioned motor cortex. SIGNIFICANCE: TBS might be useful to promote cortical plasticity in stroke patients.     

Motor cortex excitability in restless legs syndrome

BACKGROUND AND PURPOSE: A review of the literature shows that the transcranial magnetic stimulation (TMS) is a useful neurophysiological tool to investigate the pathophysiology of the restless legs syndrome (RLS). In this study we used TMS to define motor cortical excitability in RLS subjects. PATIENTS AND METHODS: Six RLS patients and two healthy control subjects underwent TMS (single and paired) examination using two protocols: (1) the evaluation of motor cortical excitability changes occurring at various times after a repetitive finger movement task; (2) the evaluation of the time course of intracortical motor activity tested with pairs of magnetic stimuli applied at inter-stimulus intervals of 1-6 ms. RESULTS: Subjects affected by RLS do not show the normal fluctuations of motor cortical excitability usually found after a bimanual finger movement task. The intracortical inhibition was reduced in RLS subjects. CONCLUSIONS: These results compared with the other studies suggest a modification in the central circuits and suppose a reduction or alteration in the cortical plasticity.     

Transcranial magnetic stimulation: applications in neurology

INTRODUCTION: Transcranial magnetic stimulation (TMS) was first applied to assess conduction time along the corticospinal tract, namely by recording motor evoked potentials. STATE OF ART: At present, TMS techniques include cortical excitability and mapping studies using single or paired-pulse paradigms on the one hand, and repetitive TMS to induce cortical plasticity and to modify brain function on the other hand. TMS is a valuable, non-invasive tool in the diagnosis and the pathophysiological assessment of cortical dysfunction involved in various neurological diseases (multiple sclerosis, myelopathy, amyotrophic lateral sclerosis, movement disorders, epilepsy, stroke). PERSPECTIVES AND CONCLUSION: In the near future, repetitive TMS could have therapeutic applications in neurology (epilepsy, stroke rehabilitation program) as is already the case in some psychiatric diseases. However, most of the new indications for treatment with cortical stimulation will be based on surgically-implanted neuromodulation procedures.     

Motor and phosphene thresholds: a transcranial magnetic stimulation correlation study

Objective: To investigate the stability of visual phosphene thresholds and to assess whether they correlate with motor thresholds. Background: Currently, motor threshold is used as an index of cortical sensitivity so that in transcranial magnetic stimulation (TMS) experiments, intensity can be set at a given percentage of this value. It is not known whether this is a reasonable index of cortical sensitivity in non-motor and hence whether it should be used in experiments where other cortical areas are targeted. Previous studies have indicated that phosphene threshold might be a suitable alternative in TMS studies of the visual system. Method: Using single pulse TMS visual phosphene and motor thresholds were measured in 15 subjects. Both thresholds were retested in seven of these subjects a week later. Result: Visual phosphene thresholds, though stable within subjects across the two sessions, showed greater variability than motor thresholds. There was no correlation between the two measures. Conclusion: TMS motor thresholds cannot be assumed to be a guide to visual cortex excitability and by extension are probably an inappropriate guide to the cortical excitability of other non-motor areas of the brain. Phosphene thresholds are proposed as a potential standard for inter-individual comparison in visual TMS experiments.     

Paired-associative stimulation can modulate muscle fatigue induced motor cortex excitability changes

The aim of this study was to examine whether the changes of the motor cortex excitability induced by muscle fatigue could be affected by prior or subsequent intervention protocol supposed to induce opposing excitability changes. For this purpose we used paired associative stimulation (PAS) method, where peripheral nerve stimuli were associated with transcranial magnetic stimulation (TMS) of the motor cortex at a fixed interstimulus interval of 25 ms. The PAS protocol used is known to produce a long lasting, long-term potentiation (LTP) like change of cortical plasticity manifested by significant increase in motor evoked potentials (MEPs) amplitude. In this study, we confirmed significant MEP size reduction following fatigue, which had been already reported in the literature. When PAS was applied either immediately before or after muscle fatigue protocol, the excitability changes were largely occluded and MEP sizes remained close to baseline levels. However, in spite of the effects on cortical excitability, conditioning with PAS did not cause any change in target fatigue measure, the endurance point, which remained the same as when fatiguing protocol was applied alone. The present results demonstrate that fatigue-related changes in cortical excitability can be modulated by either prior or subsequent excitability promoting activity. They also suggest that muscle fatigue associated changes in motor cortical excitability probably represent non-specific activity-related plasticity, rather than a direct expression of the so-called central fatigue.     

Intracortical motor inhibition and facilitation in adults with attention deficit/hyperactivity disorder

Using transcranial magnetic stimulation (TMS), disturbed facilitatory and inhibitory motor functions were recently found to correlate with motor hyperactivity in children with ADHD. Since hyperactivity seems to become reduced in ADHD during the transition to adulthood, a normalization of motor cortical excitability might be assumed. Therefore, we investigated the same inhibitory and facilitatory TMS paradigms in ADHD adults as we had previously examined in children. Motor cortical excitability was tested with TMS paired-pulse protocols in 21 ADHD adults and 21 age- and gender-matched healthy controls. In contrast to our results in ADHD children, no group-specific differences in amplitude changes of motor evoked potentials for inhibitory inter-stimulus intervals (ISI) (3, 100, 200 and 300 ms) or for facilitatory ISIs (13, 50 ms) could be detected. In ADHD adults, disturbed facilitatory and inhibitory motor circuits as found in ADHD children could not be shown, probably due to a development-dependent normalization of motor cortical excitability.     

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.     

Intravenous clomipramine decreases excitability of human motor cortex. A study with paired magnetic stimulation

Several recent reports suggest the possibility of monitoring pharmacological effects on brain excitability through transcranial magnetic stimulation (TMS). In these studies, paired magnetic stimulation has been used in normal subjects and on patients who were taking different antiepileptic drugs. The aim of our study was to investigate motor area excitability on depressed patients after intravenous administration of a single dose of clomipramine, a tricyclic antidepressant. Motor cortex excitability was studied by single and paired transcranial magnetic stimulation (TMS) before and after 4, 8 and 24 h from intravenous administration of 25 mg of clomipramine. Cortical excitability was measured using different TMS parameters: motor threshold (MT), motor evoked potential (MEP) amplitude, duration of cortical silent period (CSP), intracortical inhibition (ICI) and intracortical facilitation (ICF). Spinal excitability and peripheral nerve conduction was measured by F response and M wave. A temporary but significant increase of motor threshold and intracortical inhibition and a decrease of intracortical facilitation were observed 4 h following drug administration. MEP amplitude, cortical silent period, F response and M wave were not significantly affected by drug injection. Our findings suggest that a single intravenous dose of clomipramine can exert a significant but transitory suppression of motor cortex excitability in depressed patients. TMS represents a useful research tool in assessing the effects of motor cortical excitability of neuropsychiatric drugs used in psychiatric disease.     

Elevated motor threshold in drug-free, cocaine-dependent patients assessed with transcranial magnetic stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) provides a noninvasive method of examining cortical inhibitory and excitatory processes and cortical excitability in awake subjects. There is evidence from clinical and electroencephalographic (EEG) data that cortical excitability may be abnormal in some psychiatric populations. Chronic cocaine abuse influences a number of neurotransmitters that are involved in the excitatory/inhibitory balance of the cerebral cortex. This pilot study was conducted to ascertain the possible utility of TMS in examining cortical excitability in a population of chronic cocaine abusers. METHODS: The right and left motor thresholds of ten cocaine-dependent subjects, according to DSM-IV, and ten normal control subjects were examined using single pulse TMS. RESULTS: The resting motor thresholds resulting from stimulation of the right or the left motor cortical regions were significantly elevated in cocaine-dependent subjects compared with matched control subjects. CONCLUSIONS: These pilot data suggest that chronic cocaine use significantly alters cortical excitability in the direction of increased inhibition or decreased excitability. We hypothesize that this observation reflects adaptation to those effects of cocaine intoxication that promote cortical excitability and seizures.