Giampietro Zanette

Reversible changes of motor cortical outputs following immobilization of the upper limb

We mapped the cortical representations of the abductor pollicis brevis, flexor carpi radialis, biceps and deltoid muscles in six subjects with unilateral wrist fractures, immediately after the removal of the splint. This was repeated 1 month later in three out of the six subjects. Duration of immobilization was 1 month. Muscle maps were obtained by delivering four focal magnetic pulses for each scalp position (1 cm apart with reference to Cz) over the contralateral hemisphere. Motor evoked potentials (MEPs) were averaged off-line and expressed as a percentage of the motor action potential evoked by supramaximal peripheral nerve stimulation. Volume, area and threshold of the motor maps showed no significant hemispheric differences within each muscle in 10 control subjects. In the first recording session the volume of each immobilized muscle was distinctly higher when compared to that of controls in terms of absolute value and side-to-side ratio. This finding disappeared 1 month later. Moreover, MEP amplitude difference recorded from hand muscle could be reversed during a small tonic voluntary contraction. Immobilization had no significant effect on the threshold for activation of the target muscles and on the area of the motor map. The increase in MEP amplitudes occurred without changes in spinal excitability as tested by the F wave. These findings suggest that immobilization of the upper limb induces a reversible enhancement of the excitability of structures along the corticomotoneuronal pathway. Sustained restriction of volitional movements and reduction in somatic sensory inputs might promote this functional modulation of the motor system.

Motor Cortical Disinhibition During Early and Late Recovery After Stroke

Background. Functional neuroimaging studies show adaptive changes in areas adjacent and distant from the stroke. This longitudinal study assessed whether changes in cortical excitability in affected and unaffected motor areas after acute stroke correlates with functional and motor recovery. Methods. We studied 13 patients with moderate to severe hemiparesis 5 to 7 days (T1), 30 days (T2), and 90 days (T3) after acute unilateral stroke, as well as 10 healthy controls. We used paired-pulse transcranial magnetic stimulation to study intracortical inhibition and facilitation, recording from the bilateral thenar eminences. F waves were also recorded. Results. At T1, all patients showed significantly reduced intracortical inhibition in the unaffected hemisphere. At T2, in patients whose motor function recovered, intracortical inhibition in the unaffected hemisphere returned to normal. In patients with poor clinical motor recovery, abnormal disinhibition persisted in both hemispheres. At T3, in patients whose motor function progressively recovered, the abnormal disinhibition in the unaffected hemisphere decreased further, whereas in patients whose motor function remained poor, abnormal inhibition in the unaffected hemisphere persisted. No modification of F-wave latency and amplitude were found in patients and controls. Conclusions. During early days after stroke, motor cortical disinhibition involves both cerebral hemispheres. Longitudinal changes in motor disinhibition of the unaffected hemisphere may reflect the degree of clinical motor recovery.

Long-lasting depression of motor-evoked potentials to transcranial magnetic stimulation following exercise

We used transcranial magnetic stimulation to study the modulation of motor cortex excitability after rapid repetitive movements. Eleven healthy subjects aged 24–32 years were evaluated. Serial motor-evoked potential (MEP) recordings were performed from the right thenar eminence every 5 min for a period of 20 min at rest and for a period of 35 min after repetitive abduction-adduction of the thumb at maximal frequency for 1 min. All subjects presented distinct changes in MEP amplitude after exercise with an approximately 55% mean maximal decrease compared with basal conditions and complete recovery 35 min after the end of the exercise. The time course of MEP amplitude changes presented the following trend: (1) a rapid decrease phase within the first 5 min; (2) a maximal depression phase of 10 min duration (from the 5th to the 15th min); and (3) a slow recovery phase. No significant modifications in post-exercise MEP amplitude were found in ipsilateral non-exercised muscles. In order to determine the level where these changes take place, we recorded the M and F waves induced by median nerve stimulation at the wrist (all subjects) and MEPs in response to transcranial electrical stimulation (five subjects) at rest and during the decrease and maximal depression phases. None of these tests were significantly affected by exercise, indicating that the motor cortex was the site of change. Evaluation of maps of cortical outputs to the target muscle, performed in four subjects, showed an approximately 40% spatial reduction in stimulation sites evoking a motor response during the maximal depression phase. These data prove that exercise induces a reversible, long-standing depression of cortical excitability, probably related to intracortical presynaptic modulation, which transitorily reduces the motor representation area.

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.

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.

Transcranial magnetic stimulation selectively impairs interhemispheric transfer of visuo-motor information in humans

Abstract We investigated the cerebral cortical route by which visual information reaches motor cortex when visual signals are used for manual responses. Subjects responded unimanually to photic stimuli delivered to the hemifield ipsilateral or contralateral to the moving hand. On some trials, trans-cranial magnetic stimulation (TMS) was applied unilaterally over the occiput, with the aim of stimulating extrastriate visual areas and thereby modifying transmission of visual input. In association with the side of a visual stimulus and a motor response, TMS could change inter- or intra-hemispheric transmission needed to convey visual information to motor areas. Reaction time differences following TMS suggested that TMS exerted an inhibitory effect only when visuo-motor information had to be transferred interhemispherically. This result reinforces evidence for an extrastriate pathway of interhemispheric transfer of visuomotor information.

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.

Role of HIV in the pathogenesis of distal symmetrical peripheral neuropathy

We report the results of a clinical, electrophysiological and pathological study conducted in 18 AIDS patients presenting a distal symmetrical predominantly sensory polyneuropathy (DSPN) characterized by painful dysesthesias as main complaint. Onset of the neuropathy was at CDC (Center for Disease Control) stage II in 2 patients, at CDC stage III in 5 patients and at CDC stage IV in the remainder. Electrophysiological investigation confirmed the presence of an axonal alteration in the sensory nerves, but also revealed motor involvement in all cases. The neuropathological features of sensory nerves were fiber loss and axonal degeneration with macrophagic activation. The expression of monocyte-macrophage markers and of major histocompatibily complex class II antigens appeared up-regulated in endoneurial ramified cells, while expression of CR3, a complement receptor involved in the process of phagocytosis, was down-regulated. In six nerve biopsy samples and in two out of five DSPN dorsal root ganglia we found HIV-related mRNA and protein located in scattered cells of the endoneurium which we presume to be macrophages. These data suggest that: (a) DSPN may occur early in the course of the disease and is not limited to later stages; (b) DSPN is not a ganglionitis but is actually a sensory-motor neuropathy; (c) the virus enters the peripheral nervous system and induces changes in the immunocompetent cell population with activation of macrophages. Storage of the virus inside macrophages may act both as a reservoir for the virus and as a putative cause of nerve damage, probably through release of cytotoxins and/or interaction with trophic factors.