Stefano Tamburin

Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral sclerosis

OBJECTIVES Different physiological approaches demonstrated motor system hyperexcitability in amyotrophic lateral sclerosis (ALS), probably reflecting excitotoxic mechanisms. Transcranial magnetic stimulation (TMS) showed that both increased excitability of corticomotoneurons and reduced intracortical inhibition (ICI) contribute to motor cortex hyperexcitability, but the importance of these factors in inducing this cortical dysfunction is unknown. The aim of the study was to establish how different mechanisms interact to promote motor system hyperexcitability in ALS in relation to clinical features. METHODS The resting motor threshold (RMT), the motor evoked potential (MEP) recruitment curve and the cortical silent period (CSP) to single-pulse TMS were evaluated in 35 patients with ALS. Early ICI and intracortical facilitation (ICF) and late ICI were evaluated by paired TMS. RESULTS The main abnormal TMS findings were: (a) a steeper MEP recruitment curve associated with a lowering of the RMT; (b) reduced or even absent early and late ICI; (c) reduced CSP lengthening with increasing TMS intensity. ICF was not affected. RMT increased and the MEP recruitment curve became less steep with longer disease duration, but they did not correlate with the motor deficit, the type of motoneuron affection and the decrease of ICI. Impairment of early and late ICI were significantly correlated to each other, to disease severity and to clinical evidence of upper motor neuron involvement. CONCLUSIONS Different and partially independent mechanisms contribute to motor cortex hyperexcitability in ALS. The increased gain in MEP recruitment with a lowering of the RMT appears to be a primary event reflecting an increase in the strength of corticospinal projections, probably related to changes in the ion-channel permeability of the neuronal membrane. On the other hand, inhibitory functions linked to multiple neurotransmitter systems decline with disease progression. Both depletion of specific subpopulations of intracortical GABAergic neurons and mechanisms involved in motor cortex reorganization following progressive neuronal loss have been considered to account for the impaired inhibition. The clarification of the importance of these factors in the pathogenesis of ALS may have diagnostic and therapeutic implications.

Hyperexcitable cortical responses in progressive myoclonic epilepsy A TMS study

Objective: Transcranial magnetic stimulation (TMS) has allowed investigators to study intracortical inhibition and facilitation and sensorimotor integration in motor disorders and epilepsy. The authors used TMS to elucidate the pathophysiology of reflex myoclonus with giant somatosensory evoked potentials (SEP). Methods: The authors studied four patients with progressive myoclonic epilepsy. All patients had giant SEP elicited by mixed and digital nerve stimulation. They studied the response to paired-pulse TMS at interstimulus intervals (ISI) ranging from 1 to 15 ms and the conditioning effect of digital electrical stimulation at ISI ranging from 10 to 100 ms on the motor evoked potential amplitude to TMS. Results: Digital stimulation markedly facilitated conditioned motor evoked potentials at ISI ranging from 25 to 40 ms in all patients. This pattern was significantly different from the inhibition observed in controls (n = 12) at the same ISI. In the patients, paired-pulse TMS showed a decrease in intracortical inhibition in the motor cortex in comparison with controls. Conclusions: These findings suggest cortical and subcortical components of abnormal sensorimotor integration in addition to hyperexcitability of the sensory and motor cortex in our myoclonic patients.

Changes in motor cortex inhibition over time in patients with amyotrophic lateral sclerosis.

Abstract. Abnormal balance between intracortical inhibitory and excitatory mechanisms has been found to contribute to the genesis of motor cortex hyperexcitability in amyotrophic lateral sclerosis (ALS), but data are lacking on the role of these abnormalities in the pathophysiology of the disease. We evaluated the resting motor threshold (RMT), the cortical silent period (CSP) to single-pulse transcranial magnetic stimulation (TMS), early intracortical inhibition (ICI), early intracortical facilitation (ICF) and late ICI to paired-pulse TMS in 40 patients with ALS. These parameters were correlated with disease duration and clinical features. They were also monitored over time in selected patients.The main abnormal TMS findings were: (a) reduced or even absent early and late ICI; six out of 9 patients, with normal early ICI at the first recording, developed abnormal ICI after several months; (b) reduced cortical silent period duration with increasing TMS intensity. ICF and RMT were not affected. Impairment of early and late ICI correlated significantly with disease duration, the diagnostic categories and the clinical evidence of upper motor neuron involvement.The alteration of different cortical inhibitory functions seems to take place with disease progression, rather than being the primary event in the pathogenesis of ALS. The impaired inhibition is considered as being due to both depletion of specific subpopulations of intracortical GABAergic neurons and mechanisms involved in motor cortex reorganization following progressive neuronal loss. Clarification of the importance of these factors in the pathogenesis of the disease may have diagnostic and therapeutic implications.

Extra-median spread of sensory symptoms in carpal tunnel syndrome suggests the presence of pain-related mechanisms.

Abstract Patients with carpal tunnel syndrome (CTS) may complain of sensory symptoms outside the typical median nerve distribution. The study is aimed to understand which clinical features are associated with the extra‐median distribution of symptoms in CTS. We recruited 241 consecutive CTS patients. After selection, 103 patients (165 hands) were included. The symptoms distribution was evaluated with a self‐administered hand symptoms diagram. Patients underwent objective evaluation, neurographic study and a self‐administered questionnaire on subjective complaints. No clinical or electrodiagnostic signs of ulnar nerve involvement were found in the 165 hands. Median distribution of symptoms was found in 60.6% of hands, glove distribution in 35.2% and ulnar distribution in 4.2%. Objective measures of median nerve lesion (tactile hypaesthesia and thenar muscles hypasthenia) and neurographic involvement were significantly more severe in median hands than in the other groups. Subjective complaints (nocturnal pain, numbness and tingling sensations) were significantly more severe in glove hands. Neurophysiological and objective measures were not correlated with subjective complaints. The severity of the objective examination and neurographic involvement and the intensity of sensory complaints appear to be independent factors that influence the symptoms distribution. Extra‐median spread of sensory symptoms was associated with higher levels of pain and paresthesia. We suggest that central nervous system mechanisms of plasticity may underlie the spread of symptoms in CTS.

Central sensitization in carpal tunnel syndrome with extraterritorial spread of sensory symptoms

&NA; Extraterritorial spread of sensory symptoms is frequent in carpal tunnel syndrome (CTS). Animal models suggest that this phenomenon may depend on central sensitization. We sought to obtain psychophysical evidence of sensitization in CTS with extraterritorial symptoms spread. We recruited 100 unilateral CTS patients. After selection to rule out concomitant upper‐limb causes of pain, 48 patients were included. The hand symptoms distribution was graded with a diagram into median and extramedian pattern. Patients were asked on proximal pain. Quantitative sensory testing (QST) was performed in the territory of injured median nerve and in extramedian territories to document signs of sensitization (hyperalgesia, allodynia, wind‐up). Extramedian pattern and proximal pain were found in 33.3% and 37.5% of patients, respectively. The QST profile associated with extramedian pattern includes: (1) thermal and mechanic hyperalgesia in the territory of the injured median nerve and in those of the uninjured ulnar and radial nerves and (2) enhanced wind‐up. No signs of sensitization were found in patients with the median distribution and those with proximal symptoms. Different mechanisms may underlie hand extramedian and proximal spread of symptoms, respectively. Extramedian spread of symptoms in the hand may be secondary to spinal sensitization but peripheral and supraspinal mechanisms may contribute. Proximal spread may represent referred pain. Central sensitization may be secondary to abnormal activity in the median nerve afferents or the consequence of a predisposing trait. Our data may explain the persistence of sensory symptoms after median nerve surgical release and the presence of non‐anatomical sensory patterns in neuropathic pain.

Neuropathic pain: diagnosis and treatment

Neuropathic pain (NP) develops as a consequence of a lesion or disease affecting the somatosensory pathways in the peripheral or central nervous system, and occurs in many neurological diseases (eg, peripheral neuropathy, radiculopathy, spinal cord injury, stroke and multiple sclerosis). It affects 6%–8% of the general population and its impact on quality of life, mood and sleep exceeds the burden of its causative pathology. A peculiar feature of NP is the coexistence of negative and positive symptoms and signs, reflecting loss-of-function and gain-of-function of the somatosensory system, respectively. NP has long been considered a difficult clinical issue because of the lack of a diagnostic gold standard and the unsatisfactory response to treatment. In recent years, a redefinition, diagnostic algorithm, and some guidelines on diagnosis and treatment of NP have been published. This review offers an updated overview on the definition, pathophysiology, clinical evaluation, diagnosis and treatment of NP and focuses on some of the most frequent NP conditions. We intend to help overcome uncertainties on NP and bridge the gap between evidence based medicine and the real clinical world.

Task-dependent modulation of excitatory and inhibitory functions within the human primary motor cortex

We evaluated motor evoked potentials (MEPs) and duration of the cortical silent period (CSP) from the right first dorsal interosseous (FDI) muscle to transcranial magnetic stimulation (TMS) of the left motor cortex in ten healthy subjects performing different manual tasks. They abducted the index finger alone, pressed a strain gauge with the thumb and index finger in a pincer grip, and squeezed a 4-cm brass cylinder with all digits in a power grip. The level of FDI EMG activity across tasks was kept constant by providing subjects with acoustic-visual feedback of their muscle activity. The TMS elicited larger amplitude FDI MEPs during pincer and power grip than during the index finger abduction task, and larger amplitude MEPs during pincer gripping than during power gripping. The CSP was shorter during pincer and power grip than during the index finger abduction task and shorter during power gripping than during pincer gripping. These results suggest excitatory and inhibitory task-dependent changes in the motor cortex. Complex manual tasks (pincer and power gripping) elicit greater motor cortical excitation than a simple task (index finger abduction) presumably because they activate multiple synergistic muscles thus facilitating corticomotoneurons. The finger abduction task probably yielded greater motor cortical inhibition than the pincer and power tasks because muscles uninvolved in the task activated the cortical inhibitory circuit. Increased cortical excitatory and inhibitory functions during precision tasks (pincer gripping) probably explain why MEPs have larger amplitudes and CSPs have longer durations during pincer gripping than during power gripping.

Motor Responses to Afferent Stimulation in Juvenile Myoclonic Epilepsy

Summary:  Purpose: To document whether the mechanisms responsible for myoclonic jerks in juvenile myoclonic epilepsy (JME) are similar to those causing other forms of myoclonus.

Hyperalgesia and laser evoked potentials alterations in hemiparkinson: Evidence for an abnormal nociceptive processing

A number of patients with Parkinsons Disease (PD) complain of painful sensations that might be related not only to peripheral factors (muscle spasms, postural abnormalities) but also to an abnormal processing of nociceptive inputs in the Central Nervous System (CNS). To test this hypothesis, we recorded scalp CO(2) laser evoked potentials (LEPs) to foot skin stimulation in 11 pain-free treated PD patients affected by hemiparkinson (during the off state), in 6 pain-free drug-naïve hemiparkinsonian patients and in 11 healthy subjects. After each LEP recording, both patients and controls were asked to rate pain due to laser stimuli. In all subjects, CO(2) laser stimulation gave rise to a main negative N2 potential followed by a positive P2 response at vertex peaking at a latency of about 250 and 350 ms respectively which are thought to originate from several brain structures devoted to nociceptive input processing, including the cingulate gyrus and insula. ANOVA showed that the N2/P2 amplitude was significantly lower and pain rating significantly increased in treated PD patients than in controls in both the affected and unaffected sides, while in drug-naïve PD patients the reduction of the N2/P2 amplitude and the increase in pain rating were observed only in the affected side. These results suggest that in pain-free PD patients there is an abnormal nociceptive input processing that may be independent of the clinical expression of parkinsonian motor signs.

Proximal pain in patients with carpal tunnel syndrome: a clinical-neurophysiological study.

Abstract  Patients with carpal tunnel syndrome (CTS) usually complain of pain and paresthesia in the hand or wrist, but pain proximally to the wrist has been frequently reported in this condition. This study was aimed at understanding which clinical features are associated with the presence of proximal pain (PP) in the upper limb of CTS patients. We recruited 250 patients with clinical and neurophysiological evidence of CTS. After thorough selection to rule out concomitant upper limb painful conditions, 112 patients (175 hands) were included. PP was defined as the presence of pain in the upper limb proximally to the wrist (neck excluded) in association with sensory complaints in the hand. Patients were asked about the presence and severity of proximal sensory complaints, the distribution of sensory complaints in the hand, and underwent an objective evaluation and neurographic study. Thenar muscle strength was significantly larger, the neurophysiological measures were significantly less severe, and hand paresthesia was significantly greater in patients with PP. The neurographic score and the measures of median nerve damage were inversely correlated with the severity of PP. PP was related to extramedian spread of symptoms in the hand. None of the objective/neurographic variables was related to severity of sensory complaints restricted to the hand. PP may be found in a consistent number of CTS patients. PP may represent a clinical marker of mild median nerve damage. The presence of proximal complaints might be related to peripheral or central nervous system mechanisms.