Prospective evaluation of Globus pallidus internus deep brain stimulation in Huntington's disease.

INTRODUCTION: Pharmacological treatment of chorea in Huntington's disease (HD) is often limited by poor efficacy or side effects. Pallidal deep brain stimulation (DBS) has been considered in these patients but experience is so far limited. METHODS: We prospectively evaluated the effects of bilateral DBS of the Globus pallidus internus (GPi) over one year in six severely affected HD patients with treatment refractory chorea in an advanced stage of the disease. Primary endpoint of the study was improvement in chorea. Additionally, we evaluated the effects of GPi DBS on the motor part of the Unified Huntington's Disease Rating Scale (UHDRS), bradykinesia, dystonia, functional impairment, psychiatric and cognitive symptoms. Side effects were systematically assessed. RESULTS: The chorea subscore was significantly reduced postoperatively (-47% six months, -40% twelve months postoperatively). The UHDRS total motor score was significantly reduced at six months postoperatively (- 17%) but the effect was not sustained twelve months after the operation (- 5%). Pallidal DBS did not improve other motor symptoms or functional impairment. There was no effect on psychiatric symptoms or cognition. A number of side effects were noted, especially spasticity in three of the patients. CONCLUSIONS: Pallidal DBS is a treatment option for HD patients with severe pharmacologically refractory chorea. Further studies are needed to define optimal candidates for this procedure.

Involvement of obliquus capitis inferior muscle in dystonic head tremor.

INTRODUCTION: Head tremor is a common feature in cervical dystonia (CD) and often less responsive to botulinum neurotoxin (BoNT) treatment than dystonic posturing. Ultrasound allows accurate targeting of deeper neck muscles. METHODS: In 35 CD patients with dystonic head tremor the depth and thickness of the splenius capitis (SPL), semispinalis capitis and obliquus capitis inferior muscles (OCI) were assessed using ultrasound. Ultrasound guided EMG recordings were performed from the SPL and OCI. RESULTS: Burst-like tremor activity was present in both OCI in 25 and in one in 10 patients. In 18 patients, tremor activity was present in one SPL and in 2 in both SPL. Depth and thickness of OCI, SPL and semispinalis capitis muscles were very variable. CONCLUSION: Muscular activity underlying tremulous CD is most commonly present in OCI. Due to the variability of muscle thickness, we suggest ultrasound guided BoNT injections into OCI.

[Diagnostic nerve ultrasonography]. / Diagnostische Nervensonographie.

CLINICAL/METHODICAL ISSUE: For the diagnostics of nerve lesions an imaging method is necessary to visualize peripheral nerves and their surrounding structures for an etiological classification. STANDARD RADIOLOGICAL METHODS: Clinical neurological and electrophysiological investigations provide functional information about nerve lesions. The information provided by a standard magnetic resonance imaging (MRI) examination is inadequate for peripheral nerve diagnostics; however, MRI neurography is suitable but on the other hand a resource and time-consuming method. METHODICAL INNOVATIONS: Using ultrasonography for peripheral nerve diagnostics. PERFORMANCE: With ultrasonography reliable diagnostics of entrapment neuropathies and traumatic nerve lesions are possible. The use of ultrasonography for neuropathies shows that a differentiation between different forms is possible. ACHIEVEMENTS: Nerve ultrasonography is an established diagnostic tool. In addition to the clinical examination and clinical electrophysiology, structural information can be obtained, which results in a clear improvement in the diagnostics. Ultrasonography has become an integral part of the diagnostic work-up of peripheral nerve lesions in neurophysiological departments. PRACTICAL RECOMMENDATIONS: Nerve ultrasonography is recommended for the diagnostic work-up of peripheral nerve lesions in addition to clinical and electrophysiological investigations. It should be used in the clinical work-up of entrapment neuropathies, traumatic nerve lesions and spacy-occupying lesions of nerves.

Normalization of sensorimotor integration by repetitive transcranial magnetic stimulation in cervical dystonia.

Previous studies indicated that sensorimotor integration and plasticity of the sensorimotor system are impaired in dystonia patients. We investigated motor evoked potential amplitudes and short latency afferent inhibition to examine corticospinal excitability and cortical sensorimotor integration, before and after inhibitory 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex in patients with cervical dystonia (n = 12). Motor evoked potentials were recorded from the right first dorsal interosseous muscle after application of unconditioned transcranial magnetic test stimuli and after previous conditioning electrical stimulation of the right index finger at short interstimulus intervals of 25, 30 and 40 ms. Results were compared to a group of healthy age-matched controls. At baseline, motor evoked potential amplitudes did not differ between groups. Short latency afferent inhibition was reduced in cervical dystonia patients compared to healthy controls. Inhibitory 1 Hz sensory cortex repetitive transcranial magnetic stimulation but not motor cortex repetitive transcranial magnetic stimulation increased motor evoked potential amplitudes in cervical dystonia patients. Additionally, both 1 Hz repetitive transcranial magnetic stimulation over primary sensory and primary motor cortex normalized short latency afferent inhibition in these patients. In healthy subjects, sensory repetitive transcranial magnetic stimulation had no influence on motor evoked potential amplitudes and short latency afferent inhibition. Plasticity of sensorimotor circuits is altered in cervical dystonia patients.

Effects of dopaminergic treatment on functional cortico-cortical connectivity in Parkinson's disease.

Interactions between dorsal premotor cortex (PMd) and primary motor cortex (M1) and interhemispheric inhibition (IHI) between M1 are impaired in Parkinson's disease (PD). We used dual-site transcranial magnetic stimulation to compare effects of first-time levodopa application with chronic dopaminergic therapy on these interactions in PD. Twelve untreated PD patients were studied before and after their first-ever intake of levodopa. The effects of chronic dopaminergic medication were evaluated in 11 patients who had received regular dopaminergic medication for approximately 3 years. Nine of these patients were also measured after overnight withdrawal of medication. For IHI, conditioning stimuli (CS) were applied to left M1 followed by test stimuli (TS) over right M1 and vice versa in separate blocks at interstimulus intervals (ISI) of 6-10 ms. Next, CS were applied to left PMd at subthreshold intensity followed by TS over left M1 at ISIs of 4 and 6 ms. Results were compared to 17 age- and gender-matched controls. In de novo PD patients, levodopa reduced left-to-right IHI, but did not alter PMd-M1 connectivity. In contrast, inhibitory PMd-M1 connectivity was present in early disease patients under chronic dopaminergic stimulation, but not in de novo PD patients at low stimulus intensities at an ISI of 4 ms. First-time exposure to levodopa exerts different effects on cortico-cortical pathways than chronic dopaminergic stimulation in PD, suggesting a change in the responsiveness of cortico-cortical circuits during the course of PD.

Accumulation of non-compressive fascicular lesions underlies NF2 polyneuropathy.

A distinct polyneuropathy (PNP) syndrome affects up to 66 % of patients with neurofibromatosis II (NF2). Whether this is primarily a diffuse PNP or due to single, surgically amenable mass lesions has not yet been conclusively demonstrated. We aimed to solve this question by investigating the pathomorphological MR imaging correlate of this rare disorder. Eight patients with NF2-PNP were characterized by clinical examination, electrophysiological studies, and genetic analysis. All patients additionally underwent extended peripheral nerve imaging by a novel protocol of large-coverage high-resolution MRI. Quantitative analyses were performed by separately evaluating cross-sectional images, and by categorizing lesions into non-compressive fascicular microlesions (<2 mm), intermediate lesions (2-5 mm), and compressive macrolesions (>5 mm). The predominant imaging findings were non-compressive fascicular microlesions and intermediate lesions. Proximal-to-distal cumulative lesion burden of these lesions correlated strongly with the severity of clinical symptoms of NF2-PNP. In contrast, compressive macrolesions were not found at all in several symptomatic extremities. We conclude that proximal-to-distal accumulation of non-compressive fascicular lesions instead of compressive mass lesions predominantly underlies the clinical manifestation and severity of NF2-associated PNP. Diagnostic management may now be assisted by large-coverage high-resolution imaging of plexus and peripheral nerves. Additionally, the results underscore the feasibility of this new method, which may open up new diagnostic and investigative possibilities for other disseminated disorders of the peripheral nervous system.

Motor pathway excitability in ATP13A2 mutation carriers: a transcranial magnetic stimulation study.

OBJECTIVE: To describe excitability of motor pathways in Kufor-Rakeb syndrome (PARK9), an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration caused by a mutation in the ATP13A2 gene, using transcranial magnetic stimulation (TMS). METHODS: Five members of a Chilean family with an ATP13A2 mutation (one affected mutation carrier (MC) with a compound heterozygous mutation, 4 asymptomatic MC with a single heterozygous mutation) and 11 healthy subjects without mutations were studied. We measured motor evoked potentials (MEP), the contralateral silent period (cSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), short latency afferent inhibition (SAI) as markers of intracortical intrahemispheric inhibition/facilitation and the ipsilateral silent period (iSP) and paired-pulse interhemispheric inhibition (IHI) to probe interhemispheric motor interactions. RESULTS: CSP duration was increased in the symptomatic ATP13A2 MC. The iSP measurements revealed increased interhemispheric inhibition in both the compound heterozygous and the heterozygous MC. CONCLUSION: A compound heterozygous mutation in the ATP13A2 gene is associated with increased intracortical inhibition. In addition, some aspects of interhemispheric inhibition are increased in the presence of a single ATP13A2 mutation.

Inhibitory and facilitatory connectivity from ventral premotor to primary motor cortex in healthy humans at rest--a bifocal TMS study.

OBJECTIVE: In macaques, intracortical electrical stimulation of ventral premotor cortex (PMv) can modulate ipsilateral primary motor cortex (M1) excitability at short interstimulus intervals (ISIs). METHODS: Adopting the same conditioning-test approach, we used bifocal transcranial magnetic stimulation (TMS) to examine intrahemispheric connectivity between left PMv and M1 in humans. A conditioning stimulus (CS) was applied to PMv at intensities of 80% and 90% of active motor threshold (AMT) and 90% and 110% of resting motor threshold (RMT). A supra-threshold test stimulus (TS) was given 2, 4, 6, 8 and 10 ms after the CS and the amplitude of the motor evoked potential (MEP) was measured to probe corticospinal excitability. RESULTS: The CS facilitated corticospinal excitability in ipsilateral M1 when PMv was stimulated with 80% AMT 4 or 6 ms before the TS. At the same ISIs, the CS suppressed corticospinal excitability when the stimulus intensity was increased to 90% RMT. Conditioning effects were site-specific because conditioning the dorsal premotor cortex (PMd) at three different sites produced different effects. Using neuronavigated TMS the PMv site where applied CS produced changes in ipsilateral M1 excitability was located at the border between ventral Brodmann area (BA) 6 and BA 44, the human homologue of monkey's PMv (area F5). CONCLUSION: We infer that the corticospinal motor output from M1 to contralateral hand muscles can be facilitated or inhibited by a CS over ipsilateral PMv. SIGNIFICANCE: The fact that conditioning effects following PMd stimulation differ from those after PMv stimulation supports the concept that inputs from premotor cortices to M1 are functionally segregated.

Sensory afferent inhibition within and between limbs in humans.

OBJECTIVE: To examine the distribution and inter-limb interaction of short-latency afferent inhibition (SAI) in the arm and leg. METHODS: Motor evoked potentials (MEPs) in distal and proximal arm, shoulder and leg muscles induced with ranscranial magnetic stimulation (TMS) were conditioned by painless electrical stimuli applied to the index finger (D2) and great toe (T1) at interstimulus intervals (ISIs) of 15, 25-35, 80 ms (D2) and 35, 45, 55, 65 and 100 ms (T1) in 27 healthy human subjects. TMS was delivered over primary motor cortex (M1) arm and leg areas. Electrical stimulus intensities were varied between 1 and 3 times the sensory perception thresholds. We also tested effects of posterior cutaneous brachial nerve (PCBN) stimulation on MEPs in arm muscles at ISIs of 18 and 28 ms. RESULTS: D2 but not PCBN electrical conditioning reduced MEP amplitudes in upper limb muscles at ISIs of 25 and 35 ms. SAI was more pronounced in distal as compared to proximal arm muscles. Also, SAI following D2 stimulation increased with higher conditioning intensities. D2 stimulation did not change lower limb muscles MEPs. In contrast, T1 stimulation did not induce SAI in any muscles but caused MEP facilitation in a foot muscle at an ISI of 55 ms and in upper limb muscles at ISIs of 35 and 55 ms. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were not affected by electrical T1 conditioning. CONCLUSION: D2 stimulation causes segmental SAI in upper limb muscles with a distal to proximal attenuation without affecting leg muscles. In contrast, toe stimulation facilitates motor output both in foot and upper arm muscles. SIGNIFICANCE: Our data suggest that cutaneo-motor pathways in arms and legs are functionally organized in a different way with cutaneo-motor interactions induced by toe stimulation probably relayed at a thalamic level. Abnormal cutaneo-motor interactions following electrical toe stimulation may serve as an electrophysiological marker of thalamic dysfunction, e.g. in neurodegenerative diseases.

Sensorimotor integration is abnormal in asymptomatic Parkin mutation carriers: a TMS study.

BACKGROUND: In patients with Parkinson disease (PD), transcranial magnetic stimulation (TMS) studies have consistently demonstrated a reduced inhibitory tone in the sensorimotor cortex. It remains unclear whether this is related to motor symptoms or represents adaptive compensatory changes to degeneration of dopaminergic neurons. Here we used short-interval afferent inhibition after digital stimulation (dSAI) and intracortical paired-pulse inhibition and facilitation to probe intracortical sensorimotor excitability in clinically asymptomatic carriers of a single mutant Parkin allele who have a latent nigrostriatal dopaminergic dysfunction. METHODS: Nine heterozygous mutation carriers and nine healthy controls were investigated. For dSAI testing, electrical pulses were applied to the right index finger followed by TMS pulses over the left motor cortex at interstimulus intervals (ISI) of 25, 30, and 40 msec. Intracortical paired-pulse excitability was tested at ISIs of 2 to 15 msec. RESULTS: dSAI was reduced at an ISI of 25 msec in carriers of a single mutant Parkin allele, whereas paired-pulse TMS was normal. CONCLUSION: The relative decrease in sensorimotor inhibition may be a direct consequence of the Parkin mutation or represent adaptive changes at the cortical level in response to a subcortical dysfunction, but is not caused by motor symptoms.

Do simple intransitive finger movements consistently activate frontoparietal mirror neuron areas in humans?

The posterior inferior frontal gyrus (pIFG) and anterior inferior parietal lobule (aIPL) form the core regions of the human "mirror neuron system" that matches an observed movement onto its internal motor representation. We used event-related functional MRI to examine whether simple intransitive finger movements evoke "mirror activity" in the pIFG and aIPL. In separate sessions, participants either merely observed visuospatial stimuli or responded to them as quickly as possible with a spatially compatible finger movement. A picture of a relaxed hand with static dots on the tip of the index and little finger was continuously presented as high-level baseline. Four types of stimuli were presented in a pseudorandom order: a color change of a dot, a moving finger, a moving dot, or a simultaneous finger-dot movement. Dot movements were spatially and kinematically matched to finger movements. Participants were faster at imitating a finger movement than performing the same movement in response to a moving dot or a color change of a dot. Though imitative responses were facilitated, fMRI revealed no additional "mirror activity" in the pIFG and aIPL during the observation or imitation of finger movements as opposed to observing or responding to a moving dot. Mere observation of a finger movement alone failed to induce significant activation of the pIFG and aIPL. The lack of a signature of "mirror neuron activity" in the inferior frontoparietal cortex is presumably due to specific features of the task which may have favored stimulus-response mapping based on common spatial coding. We propose that the responsiveness of human frontoparietal mirror neuron areas to simple intransitive movements critically depends on the experimental context.

Laterality of interhemispheric inhibition depends on handedness.

There is some evidence that handedness is related to lateralisation of excitability in the motor system. We investigated lateralisation of interhemispheric inhibition (IHI), motor thresholds and short interval intracortical inhibition (SICI) and facilitation (SICF) in relation to handedness in 12 right (RH) and 13 left handed (LH) subjects. Because there is some controversy as to the optimal localisation to produce IHI we also compared IHI induced by conditioning the dorsal premotor cortex (dPM) versus primary motor cortex (M1) in ten RH. IHI was stronger following conditioning the motor dominant as compared to the motor non-dominant hemisphere in RH and LH. Motor thresholds were higher when elicited over the right hemisphere than over the left in both RH and LH, while SICI and SICF showed no differences between hemispheres or dependency from handedness. We hypothesize that IHI is a function of handedness perhaps reflecting predominant usage of the dominant hand, while lateralisation of thresholds and intracortical excitability are determined by other factors.

Observation of a finger or an object movement primes imitative responses differentially.

Behavioural advantages for imitation of human movements over movements instructed by other visual stimuli are attributed to an 'action observation-execution matching' (AOEM) mechanism. Here, we demonstrate that priming/exogenous cueing with a videotaped finger movement stimulus (S1) produces specific congruency effects in reaction times (RTs) of imitative responses to a target movement (S2) at defined stimulus onset asynchronies (SOAs). When contrasted with a moving object at an SOA of 533 ms, only a human movement is capable of inducing an effect reminiscent of 'inhibition of return' (IOR), i.e. a significant advantage for imitation of a subsequent incongruent as compared to a congruent movement. When responses are primed by a finger movement at SOAs of 533 and 1,200 ms, inhibition of congruent or facilitation of incongruent responses, respectively, is stronger as compared to priming by a moving object. This pattern does not depend on whether S2 presents a finger movement or a moving object, thus effects cannot be attributed to visual similarity between S1 and S2. We propose that, whereas both priming by a finger movement and a moving object induces processes of spatial orienting, solely observation of a human movement activates AOEM. Thus, S1 immediately elicits an imitative response tendency. As an overt imitation of S1 is inadequate in the present setting, the response is inhibited which, in turn, modulates congruency effects.

Hemispheric asymmetry and somatotopy of afferent inhibition in healthy humans.

A conditioning electrical stimulus to a digital nerve can inhibit the motor-evoked potentials (MEPs) in adjacent hand muscles elicited by transcranial magnetic stimulation (TMS) to the contralateral primary motor cortex (M1) when given 25-50 ms before the TMS pulse. This is referred to as short-latency afferent inhibition (SAI). We studied inter-hemispheric differences (Experiment 1) and within-limb somatotopy (Experiment 2) of SAI in healthy right-handers. In Experiment 1, conditioning electrical pulses were applied to the right or left index finger (D2) and MEPs were recorded from relaxed first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles ipsilateral to the conditioning stimulus. We found that SAI was more pronounced in right hand muscles. In Experiment 2, electrical stimulation was applied to the right D2 and MEPs were recorded from ipsilateral FDI, extensor digitorum communis (EDC) and biceps brachii (BB) muscles. The amount of SAI did not differ between FDI, EDC and BB muscles. These data demonstrate inter-hemispheric differences in the processing of cutaneous input from the hand, with stronger SAI in the dominant left hemisphere. We also found that SAI occurred not only in hand muscles adjacent to electrical digital stimulation, but also in distant hand and forearm and also proximal arm muscles. This suggests that SAI induced by electrical D2 stimulation is not focal and somatotopically specific, but a more widespread inhibitory phenomenon.

Motor cortex excitability and fatigue in multiple sclerosis: a transcranial magnetic stimulation study.

We investigated electrophysiological correlates of fatigue in patients with multiple sclerosis (MS). Transcranial magnetic stimulation (TMS) was used to explore motor excitability in three groups of subjects: MS patients with fatigue (MS-F), MS patients without fatigue (MS-NF) and healthy control subjects. All participants had to perform a fatiguing hand-grip exercise. TMS was performed prior to and after the exercise. Prior to the motor task, MS-F patients had less inhibition in the primary motor cortex compared to both other groups. Postexercise, intracortical inhibition was still reduced in the MS-F patients compared to the MS-NF patients. In MS-F patients the postexercise time interval for normalization of the motor threshold was correlated with the fatigue severity. We conclude that MS patients with fatigue have an impairment of inhibitory circuits in their primary motor cortex. The results also indicate that fatigue severity is associated with an exercise-induced reduction of membrane excitability.

Abnormal excitability of premotor-motor connections in de novo Parkinson's disease.

The dorsal premotor cortex (PMd) is abnormally active in patients with idiopathic Parkinson's disease. This has been interpreted as a functional correlate of adaptive plasticity within the motor system to compensate for deficient activation of striato-mesial-frontal projections in these patients. Whether abnormal PMd activity influences excitability in the primary motor cortex (M1) in untreated Parkinson's disease patients and how this premotor-motor interaction might be altered by l-dopa is unclear. To this end, we studied the effects of 1 Hz premotor repetitive transcranial magnetic stimulation (rTMS) on M1 excitability in 10 previously untreated non-tremulous Parkinson's disease patients before (day 1) and after (day 8) their first ever l-dopa treatment and compared the results with those of a group of nine age- and sex-matched healthy controls. In each rTMS session, 1200 pulses of 1 Hz rTMS were applied at an intensity of 80% active motor threshold (AMT) to the PMd contralateral to the clinically more affected side in Parkinson's disease patients and to the left PMd in healthy controls. Intracortical paired pulse excitability of ipsilateral M1 was probed using a TMS paired pulse paradigm where subthreshold conditioning pulses (80% of AMT) were given 2-15 ms prior to a suprathreshold test pulse. In Parkinson's disease patients, abnormal baseline intracortical excitability at an interstimulus interval (ISI) of 5 ms was normalized by premotor rTMS. In contrast, rTMS led to an increased excitability at an ISI of 5 ms in healthy controls. Premotor rTMS effects lasted longer (for at least a week) in patients. These results show that the modifiability of premotor-motor connections is abnormal in untreated Parkinson's disease. A single dose of l-dopa reversed, i.e. normalized, the direction of excitability changes in M1 following premotor rTMS in Parkinson's disease patients, suggesting that dopamine depletion directly or indirectly influences premotor-motor interactions in Parkinson's disease. The rTMS conditioning approach described here provides a promising tool to delineate further the excitability changes in frontal motor areas in response to progressive degeneration of nigrostriatal dopaminergic neurons and also to chronic l-dopa treatment in Parkinson's disease.

Motor cortex excitability after cerebellar infarction.

BACKGROUND AND PURPOSE: The cerebellum has an influence on motor excitability. We investigated if the location of a cerebellar infarction was crucial for changes of motor cortex excitability and if the electrophysiological findings were correlated with motor performance. METHODS: Transcranial magnetic stimulation was applied to study intracortical inhibition (ICI), intracortical facilitation (ICF), motor thresholds, and corticospinal excitability. Dexterity as a measure of motor performance was tested with the Nine-Hole-Peg Test (9HPT). Ratios (affected/unaffected) were also calculated. RESULTS: ICI and ICF ratios were negatively correlated with 9HPT ratios in all patients (n=9). Compared with an age-matched control group, patients with lesions in the territory of the superior cerebellar artery (SCA) (n=3) or a lesion rostral of the dentate nucleus (n=1) had abnormally enhanced ICI and a loss of ICF (3 patients). Dexterity was impaired in all 4 patients. Motor excitability and motor performance normalized over the subsequent weeks. Patients with an infarct either in the territory of the anterior inferior cerebellar artery (n=2) or in the territory of the posterior inferior cerebellar artery (n=3) displayed motor excitability and motor performance within the normal range. CONCLUSIONS: The superior part of the cerebellum has a strong influence on motor cortex excitability. We suggest that the enhancement of motor inhibition and reduction of motor facilitation is mediated by an impairment of the deep cerebellar nuclei.