Guillermo Paradiso

Exploring the connectivity between the cerebellum and motor cortex in humans

Animal studies have shown that cerebellar projections influence both excitatory and inhibitory neurones in the motor cortex but this connectivity has yet to be demonstrated in human subjects. In human subjects, magnetic or electrical stimulation of the cerebellum 5–7 ms before transcranial magnetic stimulation (TMS) of the motor cortex decreases the TMS‐induced motor‐evoked potential (MEP), indicating a cerebellar inhibition of the motor cortex (CBI). TMS also reveals inhibitory and excitatory circuits of the motor cortex, including a short‐interval intracortical inhibition (SICI), long‐interval intracortical inhibition (LICI) and intracortical facilitation (ICF). This study used magnetic cerebellar stimulation to investigate connections between the cerebellum and these cortical circuits. Three experiments were performed on 11 subjects. The first experiment showed that with increasing test stimulus intensities, LICI, CBI and ICF decreased, while SICI increased. The second experiment showed that the presence of CBI reduced SICI and increased ICF. The third experiment showed that the interaction between CBI and LICI reduced CBI. Collectively, these findings suggest that cerebellar stimulation results in changes to both inhibitory and excitatory neurones in the human motor cortex.

Flunarizine- and cinnarizine-induced extrapyramidal reactions.

Cinnarizine and flunarizine are selective calcium blockers that have been used to treat and prevent vertigo. We studied 15 patients who had extrapyrqmidal syndromes after taking these drugs. Eleven patients had parkinsonism, one with persistent akathisia as well; one had an orofacial tremor; one, acute akathisia alone; and one an acute dystonic reaction. All but one improved when the drug therapy was discontinued. Seven patients were also depressed during treatment. Cinnarizine and flunarizine must therefore be added to the list of potentially risky drugs known to induce extrapyramidal reactions and depression.

Involvement of the human subthalamic nucleus in movement preparation

Background: Although it has long been recognized that the basal ganglia play a major role in motor control, their precise functions remain unclear. As patients with Parkinson’s disease (PD) have difficulties initiating movement, the basal ganglia may be involved in movement preparation. The subthalamic nucleus (STN) is particularly suited to play a role in movement preparation because it receives direct input from the supplementary motor area through the corticosubthalamic pathway. Methods: Taking advantage of the electrodes surgically implanted in the STN for deep brain stimulation (DBS) treatment in 13 PD patients, we recorded from the DBS electrodes and the scalp simultaneously while the patients were performing self-paced wrist extension movements. Results: Scalp recordings showed a slow, negative movement-related potential (MRP) in all patients studied (onset 1,690 ± 336 milliseconds before electromyography onset). STN recordings showed premovement MRP in 11 of 13 patients. The STN activity occurred with both ipsilateral and contralateral hand movement. The onset time for STN MRP (contralateral 2,095 ± 1,005 milliseconds, ipsilateral 2,020 ± 920 milliseconds) was not significantly different from that for cortical MRP. Conclusion: The STN or nearby structures are active before self-paced movement in humans.

Involvement of the Basal Ganglia and Cerebellar Motor Pathways in the Preparation of Self-Initiated and Externally Triggered Movements in Humans

The subthalamic nucleus (STN) is part of the cortico-basal ganglia (BG)–thalamocortical circuit, whereas the ventral lateral nucleus of the thalamus (VL) is a relay nucleus in the cerebello-dentato-thalamocortical (CTC) pathway. Both pathways have been implicated in movement preparation. We compared the involvement of the STN and VL in movement preparation in humans by recording local field potentials (LFPs) from seven patients with Parkinsons disease with deep-brain stimulation (DBS) electrodes in the STN and five patients with tremor and electrodes in VL. LFPs were recorded from DBS electrodes and scalp electrodes simultaneously while the patients performed self-paced and externally cued (ready, go/no-go) movements. For the self-paced movement, a premovement-related potential was observed in all patients from scalp, STN (phase reversal, five of six patients), and VL (phase reversal, five of five patients) electrodes. The onset times of the potentials were similar in the cortex, STN, and VL, ranging from 1.5 to 2 s before electromyogram onset. For the externally cued movement, an expectancy potential was observed in all patients in cortical and STN electrodes (phase reversal, six of six patients). The expectancy potential was recorded from the thalamic electrodes in four of five patients. However, phase reversal occurred only in one case, and magnetic resonance imaging showed that this contact was outside the VL. The cortico-BG–thalamocortical circuit is involved in the preparation of both self-paced and externally cued movements. The CTC pathway is involved in the preparation of self-paced but not externally cued movements, although the pathway may still be involved in the execution of these movements.

Subthalamic nucleus stimulation modulates afferent inhibition in Parkinson disease

Background: Peripheral sensory stimulation at the wrist inhibits the motor cortex as measured by transcranial magnetic stimulation at interstimulus intervals of approximately 20 ms (short latency afferent inhibition [SAI]) and 200 ms (long latency afferent inhibition [LAI]). Previous studies suggested that reduced SAI in Parkinson disease (PD) reflects adverse effect of dopaminergic medications and reduced LAI may be related to nondopaminergic manifestations of PD. We hypothesize that subthalamic nucleus (STN) deep brain stimulation (DBS) may correct these deficiencies. Methods: We studied the effects of STN DBS on SAI and LAI in seven PD patients and age-matched controls. PD patients were studied in an off medication followed by an on medication session, with the stimulator switched on or off in random order in each session. Results: In the on medication session, SAI was reduced in the stimulator off condition and was restored by STN DBS. LAI was partially normalized by STN DBS in the medication on condition. Conclusions: Subthalamic nucleus (STN) stimulation improves short latency afferent inhibition, suggesting that it could normalize pathways that are adversely affected by dopaminergic medications. The effect of STN stimulation on long latency afferent inhibition suggests that it may influence nondopaminergic pathways involved in sensorimotor integration.

Representation of facial muscles in human motor cortex

Whether there is a projection from the primary motor cortex (M1) to upper facial muscles and how the facial M1 area is modulated by intracortical inhibitory and facilitatory circuits remains controversial. To assess these issues, we applied transcranial magnetic stimulation (TMS) to the M1 and recorded from resting and active contralateral (C‐OOc) and ipsilateral orbicularis oculi (I‐OOc), and contralateral (C‐Tr) and ipsilateral triangularis (I‐Tr) muscles in 12 volunteers. In five subjects, the effects of stimulating at different scalp positions were assessed. Paired TMS at interstimulus intervals (ISIs) of 2 ms were used to elicit short interval intracortical inhibition (SICI) and ISI of 10 ms for intracortical facilitation (ICF). Long interval intracortical inhibition (LICI) was evaluated at ISIs between 50 and 200 ms, both at rest and during muscle activation. The silent period (SP) was also determined. C‐OOc and I‐OOc responses were recorded in all subjects. The optimal position for eliciting C‐OOc responses was lateral to the hand representation in all subjects and MEP amplitude markedly diminished when the coil was placed 2 cm away from the optimal position. For the I‐OOc, responses were present in more scalp sites and the latency decreased with more anterior placement of the coil. C‐Tr response was recorded in 10 out of 12 subjects and the I‐Tr muscle showed either no response or low amplitude response, probably due to volume conduction. SICI and ICF were present in the C‐OOc and C‐Tr, but not in the I‐OOc muscle. Muscle activation attenuated SICI and ICF. LICI at rest showed facilitation at 50 ms ISI in all muscles, but there was no significant inhibition at other ISIs. There was no significant inhibition or facilitation with the LICI protocol during muscle contraction. The SP was present in the C‐OOc, C‐Tr and I‐OOc muscles and the mean durations ranged from 92 to 104 ms. These findings suggest that the I‐OOc muscle response is probably related to the first component (R1) of the blink reflex. There is M1 projection to the contralateral upper and lower facial muscles in humans and the facial M1 area is susceptible to cortical inhibition and facilitation, similar to limb muscles.

Electrophysiological features of myoclonus-dystonia.

Inherited myoclonus‐dystonia (M‐D) is an autosomal dominant disorder characterized by myoclonus and dystonia that often improves with alcohol. To examine the electrophysiologic characteristics of M‐D, we studied 6 patients from 4 different families and 9 age‐matched healthy subjects. Neurophysiological studies performed include electromyography (EMG)‐electroencephalography (EEG) polygraphy, jerk‐locked back‐averaged EEG, somatosensory evoked potentials (SEP), long‐latency reflex (LLR) to median and digital nerve stimulation, and transcranial magnetic stimulation studies with short‐interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long‐interval intracortical inhibition (LICI). All 6 patients showed myoclonus and dystonia on clinical examination and EMG testing. The EMG burst durations ranged from 30.4 to 750.6 milliseconds (mean, 101.5 milliseconds). Jerk‐locked back‐averaged EEG failed to reveal any preceding cortical correlates. Median nerve SEP revealed no giant potential. No patients had exaggerated LLR to median or digital nerve stimulation. There was no significant difference in SICI, ICF, and LICI between M‐D patients and normal subjects. Myoclonus in inherited M‐D is likely of subcortical origin. Normal intracortical inhibition and facilitation suggest that the GABAergic circuits in the motor cortex are largely intact and that the mechanisms of myoclonus and dystonia are different from those for cortical myoclonus and other dystonic disorders.

Dopa-responsive dystonia masquerading as idiopathic kyphoscoliosis

A 19-year-old girl with a long-standing history of kyphoscoliosis misdiagnosed as idiopathic was offered corrective surgery on several occasions but fortunately refused, since neurological examination later found evidence of mild dystonic posturing in the neck and right leg. Symptoms worsened toward evening but improved with rest. Treatment with low doses of levodopa led to total remission within a month. Our case illustrates that dopa-responsive dystonia can manifest spinal curvature as the major symptom and warrants its inclusion in the differential diagnoses of idiopathic kyphoscoliosis.

Involvement of Subcortical Structures in the Preparation of Self-Paced Movement

Abstract Although it has long been suggested that the basal ganglia and thalamus are involved in movement planning and preparation, there was little direct evidence in humans to support this hypothesis. Deep brain stimulation (DBS) is a well-established treatment for movement disorders such as Parkinsons disease, tremor, and dystonia. In patients undergoing DBS surgery, we recorded simultaneously from scalp contacts and from electrodes surgically implanted in the subthalamic nucleus (STN) of 13 patients with Parkinsons disease and in the “cerebellar” thalamus of 5 patients with tremor. The aim of our studies was to assess the role of the cortico-basal ganglia-thalamocortical loop through the STN and the cerebello-thalamocortical circuit through the “cerebellar” thalamus in movement preparation. The patients were asked to perform self-paced wrist extension movements. All subjects showed a cortical readiness potential (RP) with onset ranging between 1.5 to 2s before the onset of movement. Subcortical RPs ...

Familial bulbospinal neuronopathy with optic atrophy : a distinct entity

A 61 year old woman and her 58 year old brother presented with the clinical picture of late onset progressive bulbar and spinal muscular atrophy with family history of involvement in successive generations. The sister also had optic neuropathy and the brother developed diabetes mellitus and sex hormone abnormalities. Neurophysiological and histopathological studies showed a pattern of motor and sensory neuronopathy. There was no abnormal expansion of CAG repeats in the androgen receptor gene. This family seems to have a previously unrecognised entity with the bulbospinal neuronopathy phenotype.