Effects of intermittent theta burst stimulation on cerebral blood flow and cerebral vasomotor reactivity.

OBJECTIVES: To determine whether intermittent theta burst stimulation influences cerebral hemodynamics, we investigated changes induced by intermittent theta burst stimulation on the middle cerebral artery cerebral blood flow velocity and vasomotor reactivity to carbon dioxide (CO(2)) in healthy participants. The middle cerebral artery flow velocity and vasomotor reactivity were monitored by continuous transcranial Doppler sonography. Changes in cortical excitability were tested by transcranial magnetic stimulation. METHODS: In 11 healthy participants, before and immediately after delivering intermittent theta burst stimulation, we tested cortical excitability measured by the resting motor threshold and motor evoked potential amplitude over the stimulated hemisphere and vasomotor reactivity to CO(2) bilaterally. The blood flow velocity was monitored in both middle cerebral arteries throughout the experimental session. In a separate session, we tested the effects of sham stimulation under the same experimental conditions. RESULTS: Whereas the resting motor threshold remained unchanged before and after stimulation, motor evoked potential amplitudes increased significantly (P = .04). During and after stimulation, middle cerebral artery blood flow velocities also remained bilaterally unchanged, whereas vasomotor reactivity to CO(2) increased bilaterally (P = .04). The sham stimulation left all variables unchanged. CONCLUSIONS: The expected intermittent theta burst stimulation-induced changes in cortical excitability were not accompanied by changes in cerebral blood flow velocities; however, the bilateral increased vasomotor reactivity suggests that intermittent theta burst stimulation influences the cerebral microcirculation, possibly involving subcortical structures. These findings provide useful information on hemodynamic phenomena accompanying intermittent theta burst stimulation, which should be considered in research aimed at developing this noninvasive, low-intensity stimulation technique for safe therapeutic applications.

Acute and chronic effects of hypercalcaemia on cortical excitability as studied by 5 Hz repetitive transcranial magnetic stimulation.

We designed the present study to disclose changes in cortical excitability in humans with hypercalcaemia, by delivering repetitive transcranial magnetic stimulation (rTMS) over the primary motor area (M1). In 22 patients with chronic hypercalcaemia related to primary hyperparathyroidism and 22 age-matched healthy subjects 5 Hz-rTMS was delivered at rest and during a sustained voluntary contraction of the target muscle. Changes in the resting motor threshold (RMT), motor evoked potential (MEP) amplitudes and cortical silent period (CSP) duration were measured and compared in patients and healthy controls. Two of the 22 patients were re-tested after parathyroidectomy when serum calcium had normalized. In a subgroup of healthy subjects, changes in the rTMS parameters were tested before and after acute hypercalcaemia. No significant difference between healthy normocalcaemic subjects and chronic hypercalcaemic patients was found in the RMT values and MEP amplitude and CSP duration evoked by the first stimulus of the trains. During the course of 5 Hz-rTMS trains, MEP size increased significantly less in patients with chronic hypercalcaemia than in healthy subjects, whereas the CSP duration lengthened to a similar extent in both groups. In the two patients studied after parathyroidectomy, rTMS elicited a normal MEP amplitude facilitation. Our findings indicate that acute hypercalcaemia significantly decreased the MEP amplitude facilitation. Given that 5 Hz-rTMS modulates cortical excitability through mechanisms resembling short-term synaptic enhancement, the reduction of MEP amplitude facilitation by hypercalcaemia may be related to Ca2+-dependent changes in synaptic plasticity.

Bladder symptoms assessed with overactive bladder questionnaire in Parkinson's disease.

In Parkinson's disease (PD) the urinary dysfunction manifests primarily with symptoms of overactive bladder (OAB). The OAB questionnaire (OAB-q) is a measure designed to assess the impact of OAB symptoms on health-related quality of life. In this study, we quantified the urinary symptoms in a large cohort of PD patients by using the OAB-q short form. Possible correlations between the OAB-q and clinical features were tested. Three hundred and two PD patients were enrolled in the study. Correlations between the OAB-q and sex, age, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), Hoehn-Yahr (H-Y) staging, disease duration, and treatment were analyzed. Data were compared with a large cohort of 303 age-matched healthy subjects. The OAB-q yielded significantly higher scores in PD patients than in healthy subjects. In the group of PD patients, all the variables tested were similar between men and women. Pearson's coefficient showed a significant correlation between mean age, disease duration, mean OAB-q scores, UPDRS-III scores, and H-Y staging. A multiple linear regression analysis showed that OAB-q values were significantly influenced by age and UPDRS-III. No statistical correlations were found between OAB-q scores and drug therapy or the equivalent levodopa dose, whilst the items relating to the nocturia symptoms were significantly associated with the equivalent levodopa dose. Our findings suggest that bladder dysfunction assessed by OAB-q mainly correlates with UPDRS-III scores for severity of motor impairment, possibly reflecting the known role of the decline in nigrostriatal dopaminergic function in bladder dysfunction associated with PD and patients' age. Our study also suggests that the OAB-q is a simple, easily administered test that can objectively evaluate bladder function in patients with PD.

Differences in short-term primary motor cortex synaptic potentiation as assessed by repetitive transcranial magnetic stimulation in migraine patients with and without aura.

To find out more about glutamatergic and gabaergic transmission in migraine, in this study we investigated glutamate-dependent short-term synaptic potentiation and GABA-dependent inhibitory cortical interneuron excitability as assessed by 5Hz-rTMS delivered over primary motor cortex (M1) (motor evoked potential, MEP, amplitude facilitation and cortical silent period, CSP, duration lengthening) in migraine patients with (MA) and without aura (MwoA) and healthy controls. We studied 37 patients with migraine (19 MA and 18 MwoA) and 19 healthy control subjects. 5Hz-rTMS was delivered at 120% resting motor threshold to the hand motor area of the left hemisphere with the target muscle at rest and during contraction. Three of the MA patients were also tested at the end of visual aura during a spontaneous migraine attack. ANOVA showed that the MEP significantly increased in size and CSP significantly lengthened during 5Hz-rTMS in the three groups tested. The 5Hz-rTMS-induced MEP facilitation differed significantly being highest in MA patients. In the three patients tested both ictally and interictally the MEP increased during the interictal session but remained unchanged when the visual aura ended. Our study shows that the neurophysiological feature that differentiates MA patients from MwoA patients and healthy controls is an abnormal M1 susceptibility to 5Hz-rTMS both outside and during the attack suggesting that glutamate-dependent short-term M1 cortical potentiation patterns differ in migraine with and without aura.

Botulinum toxin type A for the treatment of sialorrhoea in amyotrophic lateral sclerosis: a clinical and neurophysiological study.

Botulinum toxin type A (BoNT/A) has been proposed as an alternative treatment for sialorrhoea in patients with amyotrophic lateral sclerosis (ALS). In an open-label prospective study, BoNT/A was injected into the parotid glands bilaterally using anatomic landmarks in 26 ALS patients with bulbar symptoms. Two weeks after injection the severity of sialorrhoea and the related disability were evaluated subjectively and objectively. A group of healthy subjects acted as controls for saliva production. Patients also underwent electrophysiological tests to evaluate possible toxin effects in the nearby non-injected muscles by comparing the amplitude of compound motor action potentials (cMAPs) elicited by electrical stimulation and recorded from the orbicularis oculi and masseter muscles. After BoNT/A injections, of the 26 patients treated, 23 reported that the severity of sialorrhoea improved and the disabling symptoms diminished. Cotton roll weight also decreased after BoNT/A injection, suggesting a reduction in saliva production. Two patients complained of dry mouth. BoNT/A injection left the cMAP amplitude unchanged, suggesting that botulinum toxin does not significantly affect the non-injected facial and masticatory muscles. In conclusion, intraparotid anatomically-guided BoNT/A injection is an effective, easy, and safe treatment for sialorrhoea in patients with bulbar symptoms related to ALS.

Electrical and magnetic repetitive transcranial stimulation of the primary motor cortex in healthy subjects.

Repetitive transcranial magnetic stimulation (rTMS) delivered in short trains at 5Hz frequency and suprathreshold intensity over the primary motor cortex (M1) in healthy subjects facilitates the motor-evoked potential (MEP) amplitude by increasing cortical excitability through mechanisms resembling short-term synaptic plasticity. In this study, to investigate whether rTES acts through similar mechanisms we compared the effects of rTMS and repetitive transcranial electrical stimulation (rTES) (10 stimuli-trains, 5Hz frequency, suprathreshold intensity) delivered over the M1 on the MEP amplitude. Four healthy subjects were studied in two separate sessions in a relaxed condition. rTMS and anodal rTES were delivered in trains to the left M1 over the motor area for evoking a MEP in the right first dorsal interosseous muscle. Changes in MEP size and latency during the course of the rTMS and rTES trains were compared. The possible effects of muscle activation on MEP amplitude were evaluated, and the possible effects of cutaneous trigeminal fibre activation on corticospinal excitability were excluded in a control experiment testing the MEP amplitude before and after supraorbital nerve repetitive electrical stimulation. Repeated measures analysis of variance (ANOVA) showed that rTES and rTMS trains elicited similar amplitude first MEPs and a similar magnitude MEP amplitude facilitation during the trains. rTES elicited a first MEP with a shorter latency than rTMS, without significant changes during the course of the train of stimuli. The MEP elicited by single-pulse TES delivered during muscle contraction had a smaller amplitude than the last MEP in the rTES trains. Repetitive supraorbital nerve stimulation left the conditioned MEP unchanged. Our results suggest that 5 Hz-rTES delivered in short trains increases cortical excitability and does so by acting on the excitatory interneurones probably through mechanisms similar to those underlying the rTMS-induced MEP facilitation.

Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis.

Although clinical studies show that cannabinoids improve central pain in patients with multiple sclerosis (MS) neurophysiological studies are lacking to investigate whether they also suppress these patients' electrophysiological responses to noxious stimulation. The flexion reflex (FR) in humans is a widely used technique for assessing the pain threshold and for studying spinal and supraspinal pain pathways and the neurotransmitter system involved in pain control. In a randomized, double-blind, placebo-controlled, cross-over study we investigated cannabinoid-induced changes in RIII reflex variables (threshold, latency and area) in a group of 18 patients with secondary progressive MS. To investigate whether cannabinoids act indirectly on the nociceptive reflex by modulating lower motoneuron excitability we also evaluated the H-reflex size after tibial nerve stimulation and calculated the H wave/M wave (H/M) ratio. Of the 18 patients recruited and randomized 17 completed the study. After patients used a commercial delta-9-tetrahydrocannabinol (THC) and cannabidiol mixture as an oromucosal spray the RIII reflex threshold increased and RIII reflex area decreased. The visual analogue scale score for pain also decreased, though not significantly. Conversely, the H/M ratio measured before patients received cannabinoids remained unchanged after therapy. In conclusion, the cannabinoid-induced changes in the RIII reflex threshold and area in patients with MS provide objective neurophysiological evidence that cannabinoids modulate the nociceptive system in patients with MS.

Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study.

OBJECTIVES: To study possible psychopathological symptoms and cognitive deficits, abuse induction, as well as general tolerability and effects on quality of life, fatigue and motor function in cannabis-naïve patients with multiple sclerosis (MS) treated with a free-dose cannabis plant extract (Sativex). METHODS: In an 8-week, randomized, double-blind, placebo-controlled, parallel group crossover trial, 17 cannabis-naïve patients with MS were assessed at baseline and at the end of the cannabis and placebo phases of the trial (each of 3 weeks) by means of Symptom Checklist-90 Revised, Self-rating Anxiety Scale, Multiple Sclerosis Functional Composite (of which 1 dimension is the Paced Auditory Serial Additional Test that was used to evaluate cognition), Visual Analogue Scale on health-related quality of life, Multiple Sclerosis Impact Scale-29, and Fatigue Severity Scale. RESULTS: Postplacebo versus postcannabinoid scores showed that no significant differences could be detected on all the variables under study. A significant positive correlation was found between Delta-9-tetrahydrocannabinol blood levels and scores at the General Symptomatic Index and at the "interpersonal sensitivity," "aggressive behaviour," and "paranoiac tendencies" subscales of the Symptom Checklist-90 Revised. No serious adverse events, abuse tendencies, or direct withdrawal symptoms were reported. Increased desire for Sativex with secondary depression was reported in 1 subject. CONCLUSIONS: Cannabinoid treatment did not induce psychopathology and did not impair cognition in cannabis-naïve patients with MS. However, the positive correlation between blood levels of Delta-9-tetrahydrocannabinol and psychopathological scores suggests that at dosages higher than those used in therapeutic settings, interpersonal sensitivity, aggressiveness, and paranoiac features might arise, although greater statistical power would be necessary to confirm this finding.

Asymmetric responses to repetitive transcranial magnetic stimulation (rTMS) over the left and right primary motor cortex in a patient with lateralized progressive limb-kinetic apraxia.

Repetitive transcranial magnetic stimulation (5 Hz-rTMS, 10 stimuli, 120% resting motor threshold intensity, RMT) produces in healthy subjects a progressive facilitation of motor-evoked potential (MEP) amplitude probably through a short-term enhancement of cortical excitatory interneurones. We had the opportunity to investigate the effect of 5 Hz-rTMS delivered over the right and left primary motor cortex (M1) in a patient with limb-kinetic apraxia of the left hand and fingers and reduced cerebral perfusion in the fronto-parietal cortex of the right hemisphere documented by single-photon emission computed tomography scans. Changes in the MEP size during the trains and the RMT were measured and compared between the hemispheres. 5 Hz-rTMS was also delivered in a group of healthy subjects over both hemispheres in order to compare changes in the MEP size from the right and left M1. In the patient, 5 Hz-rTMS delivered over the left hemisphere elicited normal MEPs that progressively increased in size during the trains whereas 5 Hz-rTMS delivered over the right affected hemisphere failed to facilitate the MEP size. RMT was similar in both hemispheres. In healthy subjects, 5 Hz-rTMS delivered over either hemisphere elicited a similar, significant MEP size facilitation. Despite the limitations of a single case, our findings suggest an altered response to 5 Hz-rTMS over the M1 of the affected hemisphere. This asymmetric response correlated with the altered perfusion in the right hemisphere and the patient's lateralized clinical manifestations of apraxia.

Influence of the corticospinal tract on the cutaneous silent period: a study in patients with pyramidal syndrome.

The cutaneous silent period (CSP) is a brief transient suppression of the voluntary muscle contraction that follows a noxious cutaneous nerve stimulation. In this study we investigated the influence of the corticospinal tract on this spinal inhibitory reflex. In patients with pyramidal syndrome and in a group of healthy subjects we delivered painful electrical finger stimulation during sustained contraction of the ipsilateral abductor digiti minimi muscle. The CSP latency and duration and the background electromyographic (EMG) activity were measured and compared between-groups. The compound motor action potential amplitude and F-wave latency were also measured after electrical stimulation of the ulnar nerve at the wrist. The CSP latency was significantly longer in patients than in healthy subjects. None of the other variables differed in patients and healthy subjects. Our findings suggest that corticospinal projections influence the CSP latency probably by modulating the balance of excitability in the underlying circuits.