Effects of low frequency and low intensity repetitive paired pulse stimulation of the primary motor cortex.

OBJECTIVE: Following a previous report [Bestmann et al. Clin Neurophysiol 2004;115:755-64] that pairs of subthreshold pulses of transcranial magnetic stimulation (TMS) can show temporal summation, we explored whether repeated application of pairs of stimulation could produce long-lasting after effects on the excitability of the human motor cortex. METHODS: Twelve healthy subjects received 25 min repetitive paired pulse magnetic stimulation (paired rTMS) given at a frequency of about 0.6 Hz over the left primary motor cortex (500 paired stimuli in total). The interval between the paired stimuli was 3 ms and the intensity of both stimuli was 80% of active motor threshold. The resting and active motor threshold, MEP recruitment curve, short interval intracortical inhibition (SICI) and facilitation, and the duration of the cortical silent period (SP) were tested for the right first interosseous muscle (FDI) before and two times after the end of 25 min paired rTMS. RESULTS: Prolonged subthreshold paired rTMS produced a significant decrease in excitability in the corticospinal projection to FDI: resting motor threshold was significantly increased and MEP recruitment was significantly decreased, SICI was significantly increased at 2 and 4 ms and the SP was significantly increased in duration. CONCLUSIONS: Prolonged low frequency paired rTMS at subthreshold intensity can modulate cortical excitability by producing inhibitory effects that outlast the period of stimulation.     

Depressed intracortical inhibition after long trains of subthreshold repetitive magnetic stimuli at low frequency

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability. These effects outlast the rTMS train, and range from inhibition to facilitation according to the variables used for rTMS. Several studies have demonstrated short and long-term effects on motor evoked potential (MEP) size, whereas the effects on intracortical inhibition (ICI) and facilitation (ICF) are still unclear. We investigated short- (1-15 min), intermediate- (16-30 min), and long-term (6 h) effects on intracortical excitability. METHODS: Fourteen healthy subjects were stimulated with rTMS trains of 900 pulses (1 Hz, 90% resting motor threshold (rMTh)), delivered over the primary motor cortex and the occipital area. MTh, MEP size, silent period, intracortical inhibition at short (ICI) and long inter-stimulus intervals, and ICF were tested before and after rTMS. RESULTS: ICI was reduced 16-30 min after 1 Hz rTMS trains over the primary motor area, whereas the other response variables remained unchanged. The ICI reduction at 16-30 min was reproducible on different days in the same subjects; it was absent at 6 h and after stimulation of the occipital area. CONCLUSIONS: Subthreshold 1 Hz rTMS decreases ICI by reducing the excitability of intracortical inhibitory interneurones or by altering the electrical properties of the facilitatory chain of neurons responsible for the I waves.     

Effects of subthalamic nucleus stimulation on motor cortex excitability in Parkinson's disease

BACKGROUND: Transcranial magnetic stimulation (TMS) studies have found abnormalities in several excitatory and inhibitory circuits in the motor cortex in PD. These include motor evoked potential (MEP) recruitment curve, silent period duration (SP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI). METHODS: The authors studied the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on these circuits in 12 patients with PD treated with STN DBS. Data from nine patients who completed the study were analyzed. Patients remained on their usual medications. The stimulators were set at the optimal parameters (ON), half the optimal amplitude (HALF), and switched off (OFF) in random order. RESULTS: The Unified PD Rating Scale motor scores were significantly lower in the ON compared to the HALF and OFF conditions. Resting SICI, studied with paired-pulse TMS at interstimulus interval of 2 ms, was reduced in the OFF and HALF conditions compared to normal subjects. STN stimulation restored SICI to normal levels. STN stimulation had no effect on motor threshold, MEP recruitment curve, SP, active SICI, ICF, and LICI. CONCLUSIONS: Although restoration of short-interval intracortical inhibition by STN stimulation is similar to the effects of dopaminergic drugs, it has no effect on silent period duration and long-interval intracortical inhibition, which are also influenced by dopaminergic drugs. A previous study found that internal globus pallidus (GPi) stimulation reduced SP but did not change SICI. Thus, GPi and STN stimulation may affect different circuits in the motor cortex.     

Long-lasting increase in corticospinal excitability after 1800 pulses of subthreshold 5 Hz repetitive TMS to the primary motor cortex.

OBJECTIVE: To study the after effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) on corticospinal excitability. METHODS: Eight healthy volunteers received either 150 or 1800 stimuli of 5 Hz rTMS on two separate days in a counterbalanced order. rTMS was given over the 'motor hot spot' of the right first dorsal interosseus (FDI) muscle using an intensity of 90% of resting motor threshold (referred to as subthreshold rTMS). We evaluated the amplitude of the motor-evoked potential (MEP), short-latency intracortical inhibition (SICI), short-latency intracortical facilitation (SICF), and cortical silent period (CSP) before and for about 30 min after rTMS. MEPs were recorded from the right FDI muscle and abductor digiti minimi (ADM) muscle. RESULTS: 1800 stimuli induced an increase in MEP amplitude in the relaxed FDI muscle, but not in the relaxed ADM muscle. This facilitatory after effect was stable for at least 30 min. Prolonged 5 Hz rTMS had no effect on the relative magnitude of SICI and SICF. 150 stimuli caused no lasting modulation of MEP amplitudes in either muscle. In a subgroup of 5 subjects, 900 conditioning stimuli caused only a short-lived MEP facilitation. 5 Hz rTMS did not modify the duration of the CSP during tonic contraction. CONCLUSIONS: A single session of subthreshold 5 Hz rTMS to the M1 can induce a long-lasting and muscle-specific increase in resting corticospinal excitability. However, a sufficient number of conditioning stimuli is necessary to produce persistent corticospinal facilitation.     

Abnormal cortical excitability with preserved brainstem and spinal reflexes in sialidosis type I.

OBJECTIVE: To examine neurophysiological evidence of functional involvement of the brainstem and spinal cord and motor cortical excitability in sialidosis type I, a rare inherited neurodegenerative disorder caused by mutations in the NEU1 gene. METHODS: We investigated particular pathways in the brainstem, spinal cord and motor cortex in 12 genetically proven cases of sialidosis type I by assessing blink reflex recovery cycle (BR), spinal reciprocal inhibition (RI), input-output curves (I/O), short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and silent period (SP). RESULTS: The BR and RI were normal. The slope of I/O was significantly increased, and SICI and the duration of SP were reduced in sialidosis patients. CONCLUSIONS: Despite reports of pathology involving brainstem and anterior horn neurones, there were no obvious abnormalities in spinal and brainstem reflexes in the present patients, suggesting that the major clinical effects may be caused by changes at a level above the brainstem. SIGNIFICANCE: For the first time, the integrity of certain brainstem and spinal cord reflexes in addition to motor cortical facilitatory and inhibitory circuits has been assessed in genetically proven type I sialidosis. This provides new data to aid in understanding of the pathophysiology of motor system dysfunction in this condition.     

Primary motor cortex hyperexcitability in Fabry’s disease

ObjectiveInvolvement of pyramidal cells and/or changes in excitability of brain areas remote from an ischemic stroke has been demonstrated. Since in Fabry disease (FD), specific cerebrovascular lesions are present, we thought to investigate motor cortex excitability, using transcranial magnetic stimulation.MethodsResting (RMT) and active (AMT) motor threshold, input–output curve (IN–OUT), central motor conduction time (CMCT), cortical silent period (cSP), short and long interval intracortical inhibition (SICI and LICI), intracortical facilitation (ICF), short interval intracortical facilitation (SICF) and short afferent inhibition (SAI) were measured in the cortical representation of the right first dorsal interosseous muscle in 11 patients with FD and 11 sex- and age matched healthy subjects.ResultsFD patients showed a significant increase of steepness in IN–OUT, ICF and SICF curves. RMT, AMT, CMCT, SICI, LICI and SAI were normal.ConclusionsOur data documented an increased activity of motor cortex glutamatergic excitatory circuits in FD, evident also in patients without brain MRI lesions. Following enzyme replacement treatment, this abnormality was partly reversed.SignificanceWe suggest that our findings are expression of subtle “biochemical brain lesions”, due to an early involvement of neurons and/or astrocytes by the cascade of pathologic events leading to brain damage in FD.     

Altered response to rTMS in patients with Alzheimer's disease.

OBJECTIVE: In this study, we tested the excitability of cortical motor areas in patients with Alzheimer's disease. Because repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability, possibly by inducing a short-term increase in synaptic efficacy, we used rTMS to investigate motor cortex excitability in patients with Alzheimer's disease. METHODS: We tested the changes in the size and threshold of motor evoked potential (MEP) and cortical silent period (CSP) duration evoked by focal rTMS delivered in 10 trains of 10 stimuli at 5Hz frequency and 120% rMth intensity in a group of patients with Alzheimer's disease, and age-matched controls. In a further session, rTMS was also delivered at 1Hz frequency (trains of 10 stimuli, 120% rMth). RESULTS: Whereas in control subjects, 5Hz-rTMS elicited normal MEPs that progressively increased in size during the train, in patients, it elicited MEPs that decreased in size. The increase in the duration of the CSP was similar in patients and healthy controls. One hertz rTMS left the MEP amplitude unchanged in patients and healthy controls. CONCLUSIONS: The lack of MEP facilitation reflects an altered response to 5Hz-rTMS in patients with Alzheimer's disease. SIGNIFICANCE: Our rTMS findings strongly suggest an altered cortical plasticity in excitatory circuits within motor cortex in patients with Alzheimer's disease.     

Motor cortical excitability studied with repetitive transcranial magnetic stimulation in patients with Huntington's disease.

OBJECTIVE: TMS techniques have provided controversial information on motor cortical function in Huntington's disease (HD). We investigated the excitability of motor cortex in patients with HD using repetitive transcranial magnetic stimulation (rTMS). METHODS: Eleven patients with HD, and 11 age-matched healthy subjects participated in the study. The clinical features of patients with HD were evaluated with the United Huntington's Disease Rating Scale (UHDRS). rTMS was delivered with a Magstim Repetitive Magnetic Stimulator through a figure-of-8 coil placed over the motor area of the first dorsal interosseus (FDI) muscle. Trains of 10 stimuli were delivered at 5 Hz frequency and suprathreshold intensity (120% resting motor threshold) with the subjects at rest and during voluntary contraction of the target muscle. RESULTS: In healthy subjects at rest, rTMS produced motor evoked potentials (MEPs) that increased in amplitude over the course of the trains. Conversely in patients, rTMS left the MEP size almost unchanged. In both groups, during voluntary contraction rTMS increased the silent period (SP) duration. CONCLUSIONS: Because rTMS modulates motor cortical excitability by activating cortical excitatory and inhibitory interneurons these findings suggest that in patients with HD the excitability of facilitatory intracortical interneurones is decreased. SIGNIFICANCE: We suggest that depressed excitability of the motor cortex in patients with HD reflects a disease-related weakening of cortical facilitatory mechanisms.     

Motor cortical physiology in patients and asymptomatic carriers of parkin gene mutations

Autosomal recessive parkin (PARK2) gene‐related parkinsonism may be phenotypically and pathophysiologically distinct from idiopathic Parkinson's disease (PD). Furthermore, asymptomatic subjects carrying a single parkin mutation (“parkin carriers”) may show striatal dopaminergic dysfunction and increased cortical movement‐related activation. Here, we used transcranial magnetic stimulation (TMS) to study corticospinal and intracortical excitability in manifesting parkin patients and asymptomatic carriers. We studied resting and active motor thresholds (RMT/AMT), central motor conduction time (CMCT), active recruitment curves, short‐interval intracortical inhibition (SICI) and facilitation (ICF), SICI recruitment curve, and cortical silent period (CSP) in 8 patients “off” medication, 7 carriers, and two groups of age‐matched controls (n = 21). Patients had longer CMCTs compared to controls with a significant negative correlation between CMCT duration and onset age (r = ?0.83, P = 0.04). Carriers had increased RMT/AMT; the time course of SICI/ICF and the duration of CSP were normal in both patients and carriers; however slight abnormalities in the recruitment of SICI were found in the carriers. Prolonged CMCT and normal cortical inhibitory mechanisms in parkin patients may be of value in the differentiation from idiopathic PD. The subclinical electrophysiological abnormalities found in carriers may represent underlying compensatory mechanisms. © 2008 Movement Disorder Society     

Modulation of motor cortex excitability in obsessive-compulsive disorder: An exploratory study on the relations of neurophysiology measures with clinical outcome

Low-frequency repetitive transcranial magnetic stimulation (rTMS) to supplementary motor area (SMA) showed clinical benefit in obsessive-compulsive disorder (OCD). Here we tested whether clinical improvement was associated with enhanced cortical inhibition as measured by single and paired-pulse TMS variables. In 18 OCD patients receiving 4 weeks of either active or sham rTMS in a double-blind randomized trial, we assessed bilateral resting and active motor thresholds (RMT and AMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We tested correlations between changes in Yale-Brown Obsessive Compulsive Scale-Self-report (Y-BOCS-SR), Clinical Global Impression-Severity subscale (CGI-S) and cortical excitability measures. Active rTMS increased right hemisphere RMT whose change correlated with Y-BOCS-SR improvement. Baseline RMT hemispheric asymmetry, defined as the difference between left and right hemispheres RMT, and its normalization after active rTMS correlated with Y-BOCS-SR and CGI-S improvements. Active rTMS also increased right hemisphere SICI whose change correlated with Y-BOCS-SR and CGI-S at week 4, and with normalization of baseline RMT hemispheric asymmetry. Treatment-induced changes in cortical excitability measures are consistent with an inhibitory action of SMA rTMS on dysfunctional motor circuits in OCD. Correlations of neurophysiology measures with therapeutic outcome are supportive of the role of SMA in the modulation of OCD symptoms.     

Functional repetitive transcranial magnetic stimulation increases motor cortex excitability in survivors of stroke

ObjectiveTo determine if repetitive transcranial magnetic stimulation (rTMS) applied to the motor cortex with simultaneous voluntary muscle activation, termed functional-rTMS, will promote greater neuronal excitability changes and neural plasticity than passive-rTMS in survivors of stroke.MethodsEighteen stroke survivors were randomized into functional-rTMS (EMG-triggered rTMS) or passive-rTMS (rTMS only; control) conditions. Measures of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), force steadiness (coefficient of variation, CV) at 10% of maximum voluntary contraction, and pinch task muscle activity were assessed before and after rTMS. Functional-rTMS required subjects to exceed a muscle activation threshold to trigger each rTMS train; the passive-rTMS group received rTMS while relaxed.ResultsSignificant interactions (time × condition) were observed in abductor pollicis brevis (APB) SICI, APB ICF, CV of force, and APB muscle activity. Functional-rTMS decreased APB SICI (p < 0.05) and increased ICF (p < 0.05) after stimulation, whereas passive-rTMS decreased APB muscle activity (p < 0.01) and decreased CV of force (p < 0.05). No changes were observed in FDI measures (EMG, ICF, SICI).Conclusion(s)Functional-rTMS increased motor cortex excitability, i.e., less SICI and more ICF for the APB muscle. Passive stimulation significantly reduced APB muscle activity and improved steadiness.SignificanceFunctional-rTMS promoted greater excitability changes and selectively modulated agonist muscle activity.     

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.     

Non-homogeneous effect of levodopa on inhibitory circuits in Parkinson's disease and dyskinesia

IntroductionLevodopa-induced dyskinesia in patients with Parkinson's disease (PD) has been shown to be associated with an abnormal plasticity in the motor cortex. We investigated whether changes in the excitability of inhibitory and excitatory motor circuits could underlie maladaptive mechanisms associated with dyskinesia.MethodsUsing single and paired transcranial magnetic stimulation (TMS), we studied motor threshold, silent period (SP) duration, intracortical facilitation (ICF), short intracortical inhibition (SICI) and low- and high-intensity long intracortical inhibition (LICI) in 10 dyskinetic and 10 non-dyskinetic patients, matched for disease and treatment duration, before (OFF state) and after (ON state) levodopa, and in 10 healthy controls.ResultsIn the OFF state, the two groups of patients showed similar motor cortex excitability with a reduced SICI compared to controls. LICI was weaker and increasing stimulation intensity had a lower effect on SP duration in dyskinetic patients than in controls. In dyskinetic patients, in contrast to non-dyskinetic patients, levodopa failed to increase SICI and SP duration, and potentiated to a lesser extent the effect of increasing the stimulation intensity on LICI. Although levodopa improved motor symptoms to a similar extent in both dyskinetic and non-dyskinetic patients, it failed to activate effectively the excitability of the inhibitory systems in dyskinetic patients.DiscussionThese findings suggest that dyskinesia is associated with an abnormal effect of levodopa on cortical motor inhibitory circuits.     

Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer's cramp

OBJECTIVE: To study the short-term effects of slow repetitive transcranial magnetic stimulation (rTMS) of the motor cortex on cortical excitability and handwriting in patients with writer's cramp. BACKGROUND: Cortical excitability of the primary motor cortex is abnormally enhanced in patients with writer's cramp. Therefore, reducing cortical excitability by low-frequency rTMS of the motor cortex might result in beneficial effects on handwriting in writer's cramp. DESIGN/METHODS: We studied the effects of subthreshold 1-Hz rTMS on motor threshold and cortico-cortical excitability using the paired-pulse technique in seven patients and seven controls. In another 16 patients and 11 age-matched controls we evaluated changes in cortical excitability by measuring the stimulus-response curve and the postexcitatory silent period before and after subthreshold 1-Hz rTMS. In addition, we analyzed the handwriting before and 20 minutes after 1-Hz rTMS. RESULTS: In the first experiment, low-frequency rTMS resulted in a normalization of the deficient cortico-cortical inhibition in the patients without affecting motor threshold. In the second experiment, 1-Hz rTMS resulted in a significant prolongation of the postexcitatory silent period without affecting the stimulus-response curve in the patient group. Moreover, the dystonic patients showed a significant reduction of mean writing pressure after subthreshold 1-Hz rTMS that was associated with clear but transient improvement in six patients. CONCLUSIONS: In some patients 1-Hz rTMS can reinforce deficient intracortical inhibition and may improve handwriting temporarily. Our data support the notion that reduced intracortical inhibition plays a part in the pathophysiology of focal dystonia.     

Restoration of motor inhibition through an abnormal premotor‐motor connection in dystonia

To clarify the rationale for using rTMS of dorsal premotor cortex (PMd) to treat dystonia, we examined how the motor system reacts to an inhibitory form of rTMS applied to the PMd in healthy subjects and in a group of patients with focal hand dystonia and DYT1 gene carriers. Continuous theta burst transcranial magnetic stimulation (cTBS) with 300 and 600 pulses (cTBS300 and cTBS600) was applied to PMd, and its after‐effects were quantified by measuring the amplitude of MEPs evoked by single pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1), short interval intracortical inhibition/facilitation (SICI/ICF) within M1, the third phase of spinal reciprocal inhibition (RI), and writing tests. In addition, in DYT1 gene carriers, the effects of cTBS300 over M1 and PMd on MEPs were studied in separate experiments. In healthy subjects, cTBS300 and cTBS600 over PMd suppressed MEPs for 30 min or more and cTBS600 decreased SICI and RI. In contrast, neither form of cTBS over PMd had any significant effect on MEPs, while cTBS600 increased effectiveness of SICI and RI and improved writing in patients with writer's cramp. NMDYT1 had a normal response to cTBS300 over left PMd. We suggest that the reduced PMd to M1 interaction in dystonic patients is likely to be due to reduced excitability of PMd‐M1 connections. The possible therapeutic effects of premotor rTMS may therefore involve indirect effects of PMd on SICI and RI, which this study has shown can be normalised by cTBS. © 2010 Movement Disorder Society     

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 plastic brain responses in schizophrenia: a transcranial magnetic stimulation study

BACKGROUND: Abnormalities in brain plasticity, possibly related to abnormal cortical inhibition (CI), have been proposed to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation (TMS) provides a dynamic method for non-invasive study of plastic processes in the human brain. We aimed to determine whether patients with schizophrenia would exhibit an abnormal response to repetitive TMS (rTMS) applied to the motor cortex and whether this would relate to deficient cortical inhibition. METHODS: Measures of motor cortical excitability and cortical inhibition were made before and after a single 15-min train of 1-Hz rTMS applied to the motor cortex in medicated and unmedicated patients with schizophrenia as well as healthy controls. RESULTS: All three groups had equal motor cortical excitability prior to rTMS, although both patient groups had a shorter cortical silent period (CSP) and less cortical inhibition than the control group. Cortical excitability, as assessed by motor threshold levels, did not reduce in both medicated and unmedicated patients in response to rTMS as was seen in the control group. Significant differences were also seen between the groups in response to the rTMS for motor-evoked potential (MEP) size and cortical silent period duration. CONCLUSIONS: Both medicated and medication free patients with schizophrenia demonstrated reduced brain responses to rTMS and deficits in cortical inhibition.     

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.     

GABA-ergic tone hypothesis in hepatic encephalopathy – Revisited

ObjectiveThe GABA hypothesis of hepatic encephalopathy (HE) proposes an increased cerebral GABA-ergic tone in HE but has not been investigated in vivo in HE-patients yet. Cortical GABA-ergic and glutamatergic neurotransmission in HE-patients were evaluated using transcranial magnetic stimulation.MethodsTwenty-one patients with HE grade 1 and 2 and age matched controls participated in the study. GABA-ergic (short- and long-interval intracortical inhibition (SICI and LICI)) and glutamatergic (intracortical and short-interval intracortical facilitation (ICF and SICF)) excitability of the primary motor cortex (M1) and global corticospinal excitability (motor threshold, motor evoked potential recruitment curve (MEP-RC) were compared between the groups. SICI and ICF were correlated to the critical flicker frequency (CFF) as measure for disease severity.ResultsIn HE-patients, the slope of MEP-RC was significantly shallower compared to healthy controls. SICI was significantly reduced in patients with HE grade 2 compared to healthy controls. In HE-patients, SICI and ICF was significantly correlated to CFF.ConclusionAlthough global corticospinal excitability was reduced in HE-patients, GABA-ergic inhibition was reduced in M1 depending on HE severity. Moreover CFF related alteration of GABAergic and glutamatergic neurotransmission in patients with HE could support the notion of a severity dependent alteration of cortical excitability.SignificanceThe decrease of cortical GABA-ergic tone challenges the classical GABA hypothesis in HE.     

Caffeine has no effect on measures of cortical excitability.

OBJECTIVE: To assess the effect of caffeine on motor thresholds, short interval intra-cortical inhibition (SICI), intra-cortical facilitation (ICF) and cortical silent periods in a placebo controlled double-blinded trial. METHODS: In eleven healthy non-smoking subjects the following parameters were measured using transcranial magnetic stimulation (TMS): motor thresholds (rest, RMT and active, AMT), SICI and ICF at different conditioning stimulus intensities (60, 70, 80, 90% AMT), cortical silent periods at 130, 150 and 175% AMT, and size of motor evoked potential at rest at 110, 125 and 150% RMT. Measurements were repeated after one cup of decaffeinated coffee. On another day, measurements were obtained before and after one cup of decaffeinated coffee that contained caffeine (3 mg/kg bodyweight). Caffeine concentrations were measured in serum before and after experiments. Experiments were conducted and data were evaluated blinded to the experimental condition. RESULTS: The results of repeated measurements of all parameters were similar comparing experiments on each day, or when comparing the caffeine arm of the study with the placebo arm. CONCLUSIONS: Caffeine in a concentration similar to that in a strong cup of coffee does not have a major effect on TMS measures of motor cortex excitability. SIGNIFICANCE: In healthy controls, the design of TMS experiments that investigate the parameters assessed in this TMS study does not need to control for caffeine.