Markus Kofler

Early consolidation in human primary motor cortex

Behavioural studies indicate that a newly acquired motor skill is rapidly consolidated from an initially unstable state to a more stable state, whereas neuroimaging studies demonstrate that the brain engages new regions for performance of the task as a result of this consolidation. However, it is not known where a new skill is retained and processed before it is firmly consolidated. Some early aspects of motor skill acquisition involve the primary motor cortex (M1), but the nature of that involvement is unclear. We tested the possibility that the human M1 is essential to early motor consolidation. We monitored changes in elementary motor behaviour while subjects practised fast finger movements that rapidly improved in movement acceleration and muscle force generation. Here we show that low-frequency, repetitive transcranial magnetic stimulation of M1 but not other brain areas specifically disrupted the retention of the behavioural improvement, but did not affect basal motor behaviour, task performance, motor learning by subsequent practice, or recall of the newly acquired motor skill. These findings indicate that the human M1 is specifically engaged during the early stage of motor consolidation.

The auditory startle reaction in parkinsonian disorders.

The auditory startle reaction to an unexpected loud stimulus is regarded as a brainstem reflex originating in the nucleus reticularis pontis caudalis and being distributed up the brainstem and down the spinal cord along slowly conducting pathways. Auditory startle responses (ASR) have been reported absent or reduced in progressive supranuclear palsy (PSP), and delayed in Parkinsons disease (PD), but normal in multiple‐system atrophy (MSA). For the first time we studied ASR in patients fulfilling the clinical criteria of dementia with Lewy bodies (DLB) (n = 8), a neurodegenerative disorder characterized by cortical and subcortical depositions of Lewy bodies resulting in parkinsonism and progressive cognitive decline. For comparison, we also investigated patients with PD (n = 10), MSA (n = 7), PSP (n = 10), and age‐matched healthy controls (n = 10). ASR were elicited by binaural high‐intensity auditory stimuli. Surface electromyographic activity was simultaneously recorded from facial, upper, and lower extremity muscles. For each muscle, we assessed response probability and measured latency, amplitude, duration, and habituation rate. Patients with DLB had fewer and abnormally delayed ASR of low amplitude and short duration in extremity muscles compared to healthy controls. Furthermore, we confirm and extend previous findings of abnormal ASR in PSP and PD, and also demonstrate exaggerated ASR in extremity muscles of MSA patients. The different patterns of ASR abnormalities may reflect distinct types of brainstem dysfunction in DLB, PD, MSA, and PSP. Mov. Disord. 16:62–71, 2001.

Suppression of cortical myoclonus by levetiracetam.

A 16‐year‐old boy suffered severely disabling posthypoxic myoclonus. Neurophysiological investigation showed cortical but not reticular reflex myoclonus. Add‐on therapy with levetiracetam significantly improved the patients clinical condition, suppressed cortical myoclonus‐associated spikes, and enabled further neurorehabilitation.

The impact of intrathecal baclofen on gastrointestinal function

Intrathecal baclofen (ITB) application has become the first choice in the management of otherwise intractable generalized spasticity. The mechanism whereby ITB alleviates increased skeletal muscle tone is generally accepted; however, less is known about its effect on smooth muscles. The authors present two patients who developed a paralytic ileus during ITB infusion for supraspinal spasticity. In addition, they performed a retrospective chart analysis of another 12 patients receiving ITB with respect to their intestinal function. They calculated the cumulative sum of days without bowel movements plus the cumulative sum of interventions intended to promote intestinal peristalsis before and during ITB treatment. Intestinal function deteriorated in 10, remained unchanged in one, and improved in three patients compared to baseline, irrespective of concomitant oral baclofen medication. This is the first study addressing a previously unnoticed, but potentially deleterious side effect of ITB treatment. The findings suggest, however, that close observation of intestinal activity in conjunction with the generous use of prokinetic, laxantic or eubiotic drugs may allow for continuation of ITB treatment, even in particularly sensitive patients.

Exaggerated auditory startle responses in multiple system atrophy: a comparative study of parkinson and cerebellar subtypes

OBJECTIVEnAuditory startle responses (ASRs) have recently been reported to be exaggerated in cranial and peripheral nerve supplied muscles of patients with multiple system atrophy (MSA). ASRs displayed increased probability, amplitude and duration, shorter onset latency, and reduced habituation in comparison with healthy subjects. In order to investigate whether certain ASR features may differentiate MSA subtypes, the authors studied ASRs in 21 MSA patients (olivopontocerebellar type, MSA-C: n = 8, striatonigral type, MSA-P: n = 13), and 17 age-matched normal controls.nnnMETHODSnASRs were elicited by binaural high-intensity auditory stimuli which differed randomly in tonal frequency and intensity (250 Hz, 90 db; 500 Hz, 105 db; 750 Hz, 105 db; 1000 Hz, 110 db normal hearing level), presented through tubal insert phones. Reflex electromyographic activity was simultaneously recorded with surface electrodes from masseter, orbicularis oculi, sternocleidomastoid, biceps brachii, abductor pollicis brevis, rectus femoris, tibialis anterior, and soleus muscles.nnnRESULTSnEighteen MSA patients (86%) had exaggerated ASRs as compared to normal subjects. At group level, indices of ASR disinhibition including increased ASR probability (in extremity muscles), shortened onset latency, and enlarged response magnitude were significantly more marked in MSA-P as compared to MSA-C patients. ASR probability showed habituation in normal subjects, less in MSA-P. and none in MSA-C patients. Three MSA-patients had no ASRs except in orbicularis oculi muscle.nnnCONCLUSIONSnAlthough absent ASRs may occur in some MSA patients, most of them exhibit exaggerated ASRs. This finding may reflect disinhibition of lower brainstem nuclei due to the degenerative disorder. ASRs were significantly more disinhibited in MSA-P versus MSA-C. suggesting involvement of different neural structures in the two MSA-subtypes.

Sensory modulation of voluntary and TMS-induced activation in hand muscles

Nociceptive suppression of tonic voluntary electromyographic (EMG) activity in human hand muscles (cutaneous silent period, CSP) is in its functional organization consistent with a spinal protective reflex. Motoneuronal excitability and its modulation may also be investigated by conditioned motor evoked potentials (MEPs). To date, effects of exteroceptive stimuli on tonic EMG and on MEPs have been compared mainly using innocuous stimuli, while noxious stimuli have not been studied in great detail. In ten subjects, we recorded CSPs induced in volitionally activated flexor pollicis brevis muscle (FPB) by noxious digit II (D2) stimulation, and in first dorsal interosseous muscle (FDI) following noxious D2 and digit V (D5) stimulation. Then, transcranial magnetic stimulation (TMS) was used to evoke MEPs in the same hand muscles at rest—conditioned by equal noxious D2 or D5 stimulation and individually delayed—so that the MEPs occurred at times corresponding to immediately before, during, and immediately after the CSP in each subject. Immediately before the CSP, there was no significant difference between nociceptive MEP modulation and tonic EMG modulation in any muscle–finger-combination. In the middle of the CSP, noxious finger stimulation exerted suppression of TMS-induced MEPs in all the three muscle–finger-combinations, but less so as compared to corresponding tonic EMG levels. After the CSP, MEPs remained suppressed when corresponding tonic EMG levels were significantly enhanced. Notably, MEPs were also suppressed in cases when occurring at times corresponding to the excitatory long-loop reflex. Incomplete MEP suppression during the CSP may allow for an “emergency grip” even during noxious stimulation. MEP suppression outlasting the CSP is compatible with a “passive” re-synchronization of volitionally activated motor units rather than an “active” reflex involving recruitment of corticospinal motoneurons. The differences in tonic EMG and MEP modulation favors an effect of noxious digital nerve stimulation on interneurons responsible for presynaptic inhibition rather than a postsynaptic inhibitory effect on the motoneuron pool. The present findings caution against the use of nociceptive MEP modulation at rest to substitute for tonic EMG modulation as tested in CSP studies.

Quantification of clinical scores through physiological recordings in low-responsive patients: a feasibility study

Clinical scores represent the gold standard in characterizing the clinical condition of patients in vegetative or minimally conscious state. However, they suffer from problems of sensitivity, specificity, subjectivity and inter-rater reliability.In this feasibility study, objective measures including physiological and neurophysiological signals are used to quantify the clinical state of 13 low-responsive patients. A linear regression method was applied in nine patients to obtain fixed regression coefficients for the description of the clinical state. The statistical model was extended and evaluated with four patients of another hospital. A linear mixed models approach was introduced to handle the challenges of data sets obtained from different locations.Using linear backward regression 12 variables were sufficient to explain 74.4% of the variability in the change of the clinical scores. Variables based on event-related potentials and electrocardiogram account for most of the variability.These preliminary results are promising considering that this is the first attempt to describe the clinical state of low-responsive patients in such a global and quantitative way. This new model could complement the clinical scores based on objective measurements in order to increase diagnostic reliability. Nevertheless, more patients are necessary to prove the conclusions of a statistical model with 12 variables.

Neurophysiology of the brainstem-structure and function of brainstem circuits.

The brainstem is a small but most important center in the brain. It serves as a central relay station between spinal cord, cerebellum and cerebrum and is intricately involved in functions ranging from motor control, sensorimotor integration and regulation of autonomic functions to consciousness and attention. Brainstem anatomy and physiology of brainstem functions are complex, and pathophysiological mechanisms are often difficult to understand. The BrainStem Society, which was founded in the 1990s, is a club of scientists interested in unraveling some of the unsolved mysteries of brainstem function. Since then five international meetings have been organized: 1998 in Barcelona, Spain; 2001 in Amsterdam, Netherlands; 2004 in Rome, Italy; 2007 in Mainz, Germany; and 2010 in London, United Kingdom. The main focus of the BrainStem Society has always been neurophysiology, but at the same time the club has been open to related specialties. This is reflected in the scientific programs of previous meetings, and also in the selection of articles in this issue. Further information can be found at: www.brainstemsociety.com. In this special section, the following 10 articles are based on invited lectures at the 5th International Meeting of the BrainStem Society, December 09–10, 2010, held at the National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom. They cover a broad spectrum of brainstem anatomy, neurophysiology, neuropharmacology, movement disorders, pain and intraoperative neuromonitoring. The reviews begin with a survey by Prats-Galino et al. (2012) of the functional organization of the main human brainstem centers and circuits, in which novel data from 7-tesla high-resolution magnetic resonance imaging, diffusion tensor imaging, and diffusion tensor tracking in post-mortem material, is complemented by a conventional fiber tracking study of the descending pathways in vivo. A set of fascinating figures and a video accompany this excellent paper. It is followed by a masterly survey of the role of neurophysiology in the study of brainstem functions, with a particular emphasis on methods devoted to measuring excitability of neural circuits. Valls-Solé (2012) describes how changes in brainstem reflex excitability can be evaluated via the blink reflex by single or paired stimuli, or via the startle reaction by single or repeated stimulation and points out that these may reflect dysfunction not only in the reflex arc itself, but also at distant sites, e.g. in the basal ganglia. Furthermore he describes how both reflexes can be modulated by low-intensity stimuli that may induce prepulse inhibition or facilitation. The next paper also deals with the startle reaction and the role of brainstem pathways in motor function. Carlsen et al. (2012) review studies of advance preparation of the motor system during various movement tasks. A startling acoustic stimulus presented during a simple reaction time task results in substantial reduction in response time, suggesting a subcortical mechanism for response triggering. Startling acoustic stimuli applied during voluntary motor tasks can reveal if and when advance motor preparation occurs and whether this process changes with practice. Based on recent data the authors propose an updated model of how a startle reaction may interact with motor system preparation and response initiation. Dreissen et al. (2012) from Marina Tijssen’s group provide an excellent overview about syndromes displaying an exaggerated startle reflex. This response originates in the caudal brainstem following an unexpected stimulus, and comprises an initial bilateral motor reaction and a second orienting response with emotional and voluntary behaviors. The authors distinguish three main categories of clinical syndromes with exaggerated startles: hyperekplexia, stimulus-induced disorders, and neuropsychiatric syndromes. Classification remains challenging, but distinct clinical motor features identified in polymyography may help identify hyperekplexia, while stimulus-induced disorders may require video recordings in addition to careful clinical evaluation. Neuropsychiatric disorders usually have additional behavioral and psychiatric symptoms. Kumru and Kofler (2012) provide a focused overview of recent studies revealing how neurophysiological testing can demonstrate neuronal reorganization in patients with spinal cord injury not only below the lesion and at the cerebral cortex, but also at the brainstem level. They were able to demonstrate and quantify the amount and timing of intrathecal baclofen effects on various brainstem reflexes, and by correlating their findings with clinical changes in muscle tone were able to propose that there are previously disregarded antispastic effects of baclofen at the brainstem level. Findings of altered brainstem reflexes in spinal cord injury and their responsiveness to pharmacological interventions contribute to the understanding of mechanisms underlying functional changes following injury to the central nervous system. Remote pharmacological effects of botulinum toxin are summarized by Palomar and Mir (2012), who provide an extensive review of changes at the spinal, brainstem, and cortical level following botulinum toxin injections for the treatment of focal spasticity or dystonia. Although the primary action of botulinum toxin occurs at the neuromuscular junction where it produces biochemical denervation, remote effects can be demonstrated by refined neurophysiological techniques. Central changes may be due to retrograde transport and transcytosis of the toxin to neurons in the central nervous system. In addition there may be interference with and modification of spinal, brainstem and cortical circuits secondary to altered sensory afferent input from intrafusal fibers of the injected muscle.

Startle reaction evoked by kinematic stimuli

Background Kinematic stimuli are used for both assessment and treatment in neurorehabilitation. A patient’s voluntary or reflex response may be affected by a startle reaction. We therefore explored whether certain kinematic stimuli are able to elicit a startle reaction. Methods Eleven healthy subjects were suspended in a Lokomat system and were exposed to unexpected passive left knee flexion at 3 velocities (6, 60, 240°/s). Subjects were asked to perform a right wrist extension as soon as they felt their leg move (conditions: 6-React, 60-React, 240-React, respectively). In some 240°/s trials movement onset was preceded by a low-intensity electrical pre-pulse to the left index finger (240-Prep-React). We recorded EMG activity from right orbicularis oculi and sternocleidomastoid muscles to assess startle responses, from left quadriceps muscle to obtain stretch reflexes, and from right wrist extensors to assess reaction time. Results Startle responses were present in most 240-Reacttrials, as evidenced by (1) EMG activity in orbicularis oculi and/or sternocleidomastoid, (2) significant reaction time shortening in wrist extensors, and (3) stretch reflex latency shortening in quadriceps, as compared to responses without startle reaction. Only few trials at lower angular velocities resulted in startle responses. In 240-Prep-React trials no startle responses occurred. Conclusions Kinematic stimuli of high angular velocity, used to assess muscle stiffness, may elicit a generalized startle reaction, which in turn may modulate stretch reflex latencies of the muscle tested in a passive movement paradigm.

P20. Botulinum toxin treatment has no influence on auditory startle reaction in primary blepharospasm

paresis by using the House–Brackmann scale (HBS). Results and conclusion: Trigeminal and auditory BR latencies and number of evoked PAMR was similar between the asymptomatic sites of PFP patients and control group. On the symptomatic site PMAR could not be elicited in 21 of 31 responsive PFP patients. R1 could not be elicited in 25 patients on the symptomatic site, R2 in 20 and ABR in 31. All the decrease in responses on the symptomatic site was correlative with the increase in HBS. We concluded that ABR is a sensitive reflex response as BR. PAMR is a useful brain stem reflex, although it sometimes could not be elicited.