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.

Abnormal intracortical facilitation in early-stage Huntington's disease.

OBJECTIVE: It is known from neuropathological and imaging studies that the neuronal degeneration in Huntington's disease (HD) is already quite severe when the first symptoms of the disease become clinically evident. This study was aimed at detecting neurophysiological changes, as assessed by means of transcranial magnetic stimulation (TMS), involved in the early pathogenesis of the neurodegeneration in HD. METHODS: Motor cortex excitability was examined in 12 patients with HD in the early clinical stage of the disease and in 15 age-matched control subjects, using a range of TMS protocols. Central motor conduction time, resting and active motor threshold, duration of the cortical silent period, the short-interval paired-pulse intracortical inhibition (SICI) and the paired-pulse intracortical facilitation (ICF) were examined. RESULTS: The early-stage HD patients showed a statistically significant reduction in ICF. The other measures did not differ significantly from the control subjects. CONCLUSIONS: Our findings provide neurophysiological evidence that changes in motor function are present in the early HD. Since ICF is thought to depend upon the activity of intracortical glutamatergic excitatory circuits, the results of our study support the theory that altered NMDA receptor function plays an important role in the pathogenesis of HD. SIGNIFICANCE: These findings may provide clues to the underlying pathophysiology of the disease. A more complete understanding of the changes in motor cortex excitability that occur early in the course of HD will lead to a better definition of the disease process and may allow earlier diagnosis and intervention.

Reduced short latency afferent inhibition in patients with Down syndrome and Alzheimer-type dementia.

OBJECTIVE: Adults with Down syndrome (DS) develop progressive cognitive impairment resembling the cognitive profile of Alzheimer's disease (AD). Although the specific neurobiological correlates of cognitive deficits in DS are still not completely understood, it has been proposed that cholinergic dysfunction may contribute to some of these deficits in DS who develop AD. A recently devised test of motor cortex excitability, the short latency afferent inhibition (SAI), has been proven to be helpful in exploring some cholinergic circuits of the human brain. The authors used this test to assess the involvement of the cholinergic transmission in the DS. METHODS: We evaluated the SAI in 12 patients with DS and in 15 healthy subjects. RESULTS: SAI was significantly reduced in DS patients when compared with the controls; the values correlated with the patient's age and the score on Dementia Scale for Down Syndrome. SAI was increased after administration of a single dose of donezepil in a subgroup of 5 patients. CONCLUSIONS: Our findings suggest that, with respect to this putative marker of central cholinergic activity, dementia in aging DS shares pathophysiological similarities to AD in the general population. SIGNIFICANCE: This technique may help to clarify the pathophysiological basis of cognitive dysfunction in DS and may represent an additional tool for the diagnosis of Alzheimer-type dementia in subjects with DS.

Transcranial magnetic stimulation shows impaired transcallosal inhibition in Marchiafava-Bignami syndrome.

A case of Marchiafava-Bignami (MB) syndrome with selective callosal involvement was evaluated by clinical examination and magnetic resonance imaging (MRI) in the acute phase and 6 months after the onset of symptoms; at the same time, the corticospinally and transcallosally mediated effects elicited by transcranial magnetic stimulation (TMS) were investigated. The first MRI study showed the presence of extensive abnormal signal intensity throughout the entire corpus callosum. After high-dose corticosteroid administration her symptoms rapidly resolved, in parallel with the reversion of MRI changes, except for severe cognitive impairment. Follow-up TMS examination revealed persistent transcallosal inhibition (TI) abnormalities. This report indicates that the measurement of TI during the course of MB syndrome is useful for evaluating functional changes to the corpus callosum, including their evaluation with time and after treatment and for elucidating the pathophysiology of MB syndrome.

Polyneuropathy in hypereosinophilic syndrome.

We investigated two patients with the idiopathic hypereosinophilic syndrome and peripheral neuropathy. Clinical, EMG, and pathological findings were consistent with axonal polyneuropathy. Morphologic changes of the nerve biopsies suggested axonal damage secondary to increased endoneurial pressure from leakage of capillaries. We postulate that endothelial cell damage, followed by nerve edema, is the first step in the pathogenesis of peripheral neuropathy in these patients.

Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families.

Spinal and bulbar muscular atrophy (Kennedy disease) is an adult form of X-linked motor neuron disease caused by the expansion of a polymorphic CAG-repeat sequence in the first exon of the androgen receptor gene. We studied clinical and molecular features of 36 patients and 19 heterozygous females. Phenotypic manifestations and disease severity broadly varied among our spinal and bulbar muscular atrophy patients. The size of CAG expansion significantly influences the age of disease onset, but neither clinical features nor disease severity. The majority of carrier women presented signs of chronic denervation at neurophysiological examination and, in three cases, low-amplitude sensory action potentials were recorded. Notably, a few women developed mild signs of bulbar motor neuron impairment later in life. The identification of a large number of patients by the use of the molecular test further supports the hypothesis that Kennedy disease had been previously underdiagnosed, probably because of the great variability of clinical presentation. Although an early diagnosis may not be crucial for treatment, given the lack of effective therapy, the molecular testing can be of great relevance for disease prognosis and genetic counseling.

Changes in motor cortical excitability in humans following orally administered theophylline.

The effects of theophylline on human corticospinal excitability were studied using transcranial magnetic stimulation (TMS) before and after double-blind oral administration of theophylline or placebo in 20 healthy volunteers. TMS measurements included resting and active motor threshold, silent period, intracortical inhibition (ICI), and intracortical facilitation. F-wave and compound muscle action potential (CMAP) were also measured. Theophylline produces a reduction in ICI, while other parameters of corticospinal excitability remained unaffected. Since ICI is thought to depend on GABAA intracortical inhibitory mechanisms, our data suggest that the increase of human motor cortex excitability is the result of a decrease in GABAergic transmission. Our results further support the hypothesis that theophylline might induce convulsions by inhibiting GABAA receptor binding.

Parkinson's disease and lower limb somatosensory evoked potentials: apomorphine-induced relief of the akinetic-rigid syndrome and vertex P37-N50 potentials.

We evaluated brainstem P30, vertex-central P37-N50 and contralateral frontal N37 somatosensory evoked potentials (SEPs) from the tibial nerve in 14 patients affected by Parkinson's disease (PD) with akinetic-rigid syndrome. In seven patients SEPs were recorded after administration of apomorphine. The cortical P37-N50 complex was either absent (five patients, eight tested sides) or significantly smaller in patients as compared to the control group (n = 18). There was a relationship between abnormalities of early vertex potentials and degree of motor impairment. Administration of apomorphine was followed by an increase in amplitude of P37-N50 response, which was maximal after 15-30 min and then progressively returned to basal values in parallel with clinical improvement. Amplitude of brainstem P30 and frontal N37 responses was within normal values and did not vary following drug administration. These results suggest that the P37-N50 complex arises from independent cortical generators, probably located in the pre-rolandic cortex, which may be selectively affected by basal ganglia dysfunction. Amplitude decrease of the P37-50 complex may reflect an abnormal processing of somatosensory inputs within the pre-central cortex due to defective modulation exerted by basal ganglia circuitry on cortical excitability. SEP potentiation following apomorphine, besides indicating that this dysfunction is partly reversible, might suggest objective method to measure therapeutic efficacy.

Inhibitory and excitatory circuits of cerebral cortex after ischaemic stroke: prognostic value of the transcranial magnetic stimulation.

The motor cortex excitatory responses and inhibitory effects after transcranial magnetic stimulation were studied in 20 patients with hemiparesis after ischaemic stroke in the MCA territory within 24 hours from the beginning of the symptomatology, in order to evaluate prognostic utility of these techniques and to compare they with the conventional MEP examination. Central motor conduction time was abnormal in two patient. Ipsilateral cortico-cortical inhibition was decreased after stimulation of the ischaemic motor cortex in all patients; the duration of the silent period was prolonged in 15 patients, whereas the resting threshold for responses to magnetic stimulation was abnormal in 8 patients. Only this last finding was constantly associated with a poor motor recovery; therefore the patients with preserved motor threshold reached a good motor function in the following months. The motor cortex threshold measurement is easily performed and the most sensitive parameter in our group of patients with hemispheric infarct. Our study suggested that the evaluation of the modifications in the intrinsic excitatory properties rather than in the inhibitory cortical circuits may offer a prognostic tool for predicting functional outcome following ischaemic stroke.

Hemiparkinson-hemiatrophy syndrome: a transcranial magnetic stimulation study.

We described the clinical and neuroradiological findings together with a transcranial magnetic stimulation study in two patient with hemiparkinson-hemiatrophy syndrome (HP-HA). In both patients the neuroradiological findings (MRI) and the central motor conduction were normal whereas the functional imaging studies (SPECT) showed asymmetrical perfusion in the basal ganglia; the intracortical inhibition at short interstimulus intervals and the silent period duration in the motor cortex contralateral to hemiparkinsonism were significantly increased only in one of the patient which has a poor response to L-Dopa therapy. These studies suggest that intracortical or thalamo-cortical neuronal inhibition may be increased in HP-HA. The etiopathogenetic considerations, the diagnostic criteria and the prognostic value of our finding to evaluate the clinical evolution of parkinsonism are discussed in the context of current models of basal ganglia-thalamo-cortical connectivity. Transcranial magnetic stimulation will provide valuable information for the differential diagnosis of the parkinsonian disorders and may predict the efficacy of L-Dopa therapy.

Transorbital sonography in acute optic neuritis: a case-control study.

BACKGROUND AND PURPOSE: Acute unilateral optic neuritis is associated with a thickening of the retrobulbar portion of the optic nerve as revealed by transorbital sonography, but no comparison has been made between nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis versus healthy controls. We evaluated optic nerve sheath diameter and optic nerve diameter in patients with acute optic neuritis and healthy controls and compared optic nerve sheath diameter and optic nerve diameter with visual-evoked potentials in patients. MATERIALS AND METHODS: A case-control study was performed in 2 centers. Twenty-one consecutive patients with onset of visual loss during the prior 10 days and established acute noncompressive unilateral optic neuritis were compared with 21 healthy controls, matched for sex and age (±5 years). Two experienced vascular sonographers performed the study by using B-mode transorbital sonography. Visual-evoked potentials were performed on the same day as the transorbital sonography and were evaluated by an expert neurophysiologist. Sonographers and the neurophysiologist were blinded to the status of the patient or control and to clinical information, including the side of the affected eye. RESULTS: The median optic nerve sheath diameter was thicker on the affected side (6.3 mm; interquartile range, 5.9-7.2 mm) compared with the nonaffected side (5.5 mm; interquartile range, 5.1-6.2 mm; P < .0001) and controls (5.2 mm; interquartile range, 4.8-5.5 mm; P < .0001). The median optic nerve diameter was 3.0 mm (range, 2.8-3.1 mm) on the affected side and 2.9 mm (range, 2.8-3.1 mm) on the nonaffected side (P = not significant.). Both sides were thicker than those in controls (2.7 mm; interquartile range, 2.5-2.8 mm; P = .001 and .009). No correlation was found between optic nerve sheath diameter and optic nerve diameter and amplitude and latency of visual-evoked potentials in patients with optic neuritis. CONCLUSIONS: Transorbital sonography is a promising tool to support the clinical diagnosis of acute optic neuritis. Further studies are needed to define its specific role in the diagnosis and follow-up of optic neuritis.

Fixation-off sensitivity.

Fixation-off sensitivity (FOS) is a phenomenon induced by elimination of central vision/fixation, and may either manifest clinically with seizures or only represent an EEG abnormality. FOS is characterized by posterior or generalized epileptiform discharges that consistently occur after closing of the eyes and last as long as the eyes are closed. It is most commonly encountered in patients with idiopathic childhood occipital epilepsies, but may also be observed in cases of symptomatic or cryptogenic focal and generalized epilepsies, as well as in asymptomatic non-epileptic individuals. FOS should be differentiated from pure forms of scotosensitivity, in which EEG discharges or epileptic seizures are elicited by darkness, and from epileptiform discharges triggered by eye closure, which refer to eye closure sensitivity. Although FOS is probably associated with occipital hyperexcitability its intrinsic epileptogenic potential is presumed to be low.

Motor cortex inhibitory circuits in dementia with Lewy bodies and in Alzheimer's disease.

To determine whether a peculiar neurophysiological profile may contribute to characterize dementia with Lewy bodies (DLB) vs. Alzheimer disease (AD), we used transcranial magnetic stimulation to examine the excitability of two different inhibitory systems of the motor cortex, short latency intracortical inhibition (SICI) and short latency afferent inhibition (SAI) in 10 patients with DLB, in 13 patients with AD and in 15 healthy subjects. SICI and SAI were significantly reduced in AD patients, while both were not significantly different from the controls in DLB patients. The differential pattern of SICI and SAI exhibited by AD vs. DLB may have diagnostic significance in discriminating DLB from AD. Furthermore, this technique may help to clarify the pathophysiological entity of DLB; since SAI is a cortical phenomenon that depends on central cholinergic activity, our findings suggest that the mechanisms of cholinergic depletion in DLB may be different from that in AD, while normal SICI may reflect a less pronounced dysregulation of the intracortical GABAergic inhibitory circuitries in DLB.

Isolated oculomotor nerve palsy as the presenting clinical manifestation of a meningeal carcinomatosis: a case report.

We present a previously unreported case of isolated oculomotor nerve palsy as the inaugural clinical sign of meningeal carcinomatosis (MC). Gadolinium-enhanced magnetic resonance images (MRI) were unremarkable. Cerebrospinal fluid (CSF) analysis showed malignant cells consistent with a pulmonary adenocarcinoma; the chest CT revealed a small pulmonary mass in the upper right lobe. This case highlights the importance of considering MC in all patients who develop sudden oculomotor palsy; lumbar punctures should always be performed on patients with normal MRI when other possible causes of oculomotor palsy have been ruled out.

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.

Changes in motor cortex excitability during muscle fatigue in amyotrophic lateral sclerosis.

To further investigate the pathophysiology of amyotrophic lateral sclerosis (ALS), the silent period (SP) evoked by transcranial magnetic stimulation during a fatiguing muscle contraction was evaluated in 15 patients and in 15 healthy subjects. Physiological lengthening of the SP duration was not observed in patients with disease duration of > or = 2 years. Decreased intracortical inhibition, probably secondary to dysfunction of the inhibitory interneurons that modulate the corticomotoneuronal firing, appears in later stages of disease. Normal motor cortex adaptation is impaired and cortical hyperexcitability might be unmasked during fatigue in ALS patients with longer disease duration.

Transient ischaemic attacks in two cases of internal carotid artery hypoplasia.

Congenital anomalies of the internal carotid arteries (ICA) and cerebral arteries have not been frequently reported. Moreover, in the literature there is no clear association between hypoplastic carotid and cerebral vessel systems and the occurrence of cerebral ischaemia. We report two cases of unilateral hypoplasia of the ICA affecting two young patients suffering from an episode of minor stroke and from recurrent transient ischaemic attacks, respectively. Congenital variations in the configuration and size of the carotid and cerebral arteries should not always be considered benign conditions and may predispose to cerebral ischaemia in young adults.

The trigemino-cervical reflex in tension-type headache.

To investigate the pathophysiology of tension-type headache (TTH) with special reference to central mechanisms and to the involvement of the trigeminal system. Short latency responses can be recorded in tonically active sternocleidomastoid muscle after stimulation of the infraorbital branch of the trigeminal nerve (the trigemino-cervical reflex). This brainstem reflex was studied in 15 healthy subjects, in 15 patients with episodic tension-type headache (ETTH) and in 15 patients with chronic tension-type headache (CTTH) outside of the pain attacks. The trigemino-cervical response was abnormal, in the size or latency, in 13 patients with CTTH and in only one patient with ETTH. This finding strongly suggests that only in the CTTH the underlying pathophysiology involves the trigeminal system. The trigemino-cervical reflex is a sensitive method to evaluate the involvement of the trigeminal brainstem neurones in TTH and their assessment may provide useful diagnostic and prognostic information.

Transcranial magnetic stimulation study in hereditary spastic paraparesis.

The motor-evoked potentials and the cortical excitability by transcranial magnetic stimulation (TMS) were studied in a family with chromosome 2p linked (due to mutations in spastin) and in a family with chromosome 16q linked (due to mutations in paraplegin) hereditary spastic paraparesis (HSP), in order to evaluate the utility of these techniques in identifying the subgroups of the disease. Central motor conduction time and motor treshold to TMS were abnormal in some members of both families; the intracortical inhibition was reduced only in the affected members of the family with chromosome 2p linked HSP, even though the neurological symptoms were sometimes similar and also when clinical features reflecting cortical dysfunction were absent. The motor cortex is differentially involved in the often clinically indistinguishable forms of HSP, and TMS may help in the differential diagnosis.