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Simple and complex movement-associated functional MRI changes in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis.

Using functional magnetic resonance imaging (fMRI), we investigated whether movement-associated functional changes of the brain are present in patients who are, most likely, at the earliest stage of multiple sclerosis (MS). Functional MRI exams were obtained from 16 patients at presentation with clinically isolated syndromes (CIS) suggestive of MS and 15 sex- and age-matched healthy volunteers during the performance of three simple and one more complex motor tasks with fully normal functioning extremities. fMRI analysis was performed using statistical parametric mapping (SPM99). Compared to healthy volunteers, CIS patients had increased activations of the contralateral primary sensorimotor cortex (SMC), secondary somatosensory cortex (SII), and inferior frontal gyrus (IFG), when performing a simple motor task with the dominant hand. The increased recruitment of the contralateral primary SMC was also found during the performance of the same motor task with the non-dominant hand and with the dominant foot. In this latter case, an anterior shift of the center of activation of this region was detected. During the performance of a complex motor task with the dominant upper and lower limbs, CIS patients had an increased recruitment of a widespread network (including the frontal lobe, the insula, the thalamus), usually considered to function in motor, sensory, and multimodal integration processing. The comparison of brain activations during the performance of simple vs. complex motor tasks showed that the movement-associated somatotopic organization of the cerebral and cerebellar cortices was retained in patients with CIS. Cortical reorganization occurs in patients at presentation with CIS highly suggestive of MS. Local synaptic reorganization, recruitment of parallel existing pathways, and reorganization of distant sites are all likely to contribute to the observed functional changes. Hum. Brain Mapping 21:106-115, 2004.

Adult↗

A review of recent observations concerning the synaptic organization of the basilar pontine nuclei.

Ultrastructural studies are described that have identified in the basilar pontine nuclei (BPN), the synaptic boutons formed by the corticopontine, cerebellopontine, tectopontine, and dorsal column nuclei-pontine afferent projection systems. In addition, immunocytochemical studies visualized neuronal somata, dendrites, and synaptic boutons that contain immunoreactivity for GABA or the synthesizing enzyme glutamic acid decarboxylase (GAD). Based upon differences in the mode of degeneration and postsynaptic locus of degenerative synaptic boutons in the BPN, it is suggested that two types of cortical neurons and three classes of deep cerebellar nuclear cells project to the BPN. For similar reasons, it appears that two types of neurons in the dorsal column nuclei project to the BPN while only one type of afferent synaptic bouton takes origin from the superior colliculus. Furthermore it appears that the population of BPN neurons projecting to the paramedian lobule receives convergent inputs from the cutaneous periphery and the corresponding region of sensorimotor cortex. Studies employing GAD immunohistochemistry indicate that GABA-ergic neurons and axon terminals are present in the BPN and thus support the suggestion that a local inhibitory interneuron is present within the BPN. Taken together these observations suggest that basilar pontine neurons might play a more active role in the integration of various types of information destined for the cerebellar cortex than has previously been recognized.

Animals↗

Phosphofructokinase in the rat nervous system: regional differences in activity and characteristics of axonal transport.

The distribution of phosphofructokinase (PFK) in gray and white matter regions of the rat nervous system was evaluated. Determinations of PFK activity revealed that cell body enriched regions (sensorimotor cortex) had a significantly higher level of activity than axonal regions (sciatic nerve, dorsal roots, and optic nerve). The level of PFK activity was also significantly higher in central axons (optic nerve) than in peripheral axons (sciatic nerve). Differences in PFK activity could be largely attributed to differences in tissue content of the enzyme rather than to differences in the types of PFK isozymes present. Cortex contained significantly larger amounts of PFK relative to total protein than did peripheral nerve. However, purification of PFK revealed that all three of the PFK isozymes, C (86 kd), A (84 kd), and B (80 kd), were present in both cortex and sciatic nerve. Both SDS/PAGE and immunoblotting studies using PFK isozyme-specific antibodies demonstrated that the relative proportions of the three PFK isozymes were similar in cell body and axonal regions of the nervous system. The PFK-C and PFK-A isozymes each comprised about half the total and only small amounts of the PFK-B isozyme were present in both regions. However, immunoprecipitation experiments suggested that quantitatively different proportions of the possible PFK hybrids (tetramers) may be distributed between axonal and cell body regions. The transport of PFK was examined in this study and PFK was identified in slow component b (SCb) of axonal transport. SCb moves at a rate of 2-4 mm/day in rat axons and is known to contain several other enzymes of intermediary metabolism as well as actin. The finding that PFK, the rate limiting enzyme in glycolysis, is present in SCb lends support to the hypothesis that glycolytic enzymes are not freely diffusing proteins in axons but, instead, are present as organized assemblies that have long-term, yet flexible, associations with structural elements of the cytoplasm.

Animals↗

Small-amplitude cortical myoclonus in Parkinson's disease: physiology and clinical observations.

We studied the occurrence of small-amplitude myo- clonus in 20 idiopathic Parkinson's disease patients who had no evidence of dementia as defined by criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Parkinson's disease was diagnosed by United Kingdom Brain Bank criteria, and clinical assessment was performed with the Unified Parkinson's Disease Rating Scale motor score, Hoehn and Yahr staging, and the Mini-Mental State Examination. Clinical assessment showed a range of mild-to-moderate disease severity. All patients underwent polygraphic electro-encephalographic-electromyographic (EMG) recording with back-averaging, somatosensory evoked potential testing, and attempted elicitation of long-latency EMG responses. Multichannel surface EMG recording during muscle activation showed irregular, multifocal, brief (<50 msec) myoclonus EMG discharges. Back-averaging consistently showed a focal, short-latency, electroencephalographic transient prior to the myoclonus EMG discharge. Cortical somatosensory evoked potential waves were not enlarged, and long-latency EMG responses at rest were not present. The small-amplitude myoclonus in such cases arises from an abnormal discharge from the sensorimotor cortex. The mechanism of this cortical myoclonus in Parkinson's disease has differences from the more common "cortical reflex myoclonus" physiology. Advanced parkinsonism is not a requirement for manifestation of this myoclonus type. Although the myoclonus occurred without dementia in these cases, its relationship to the subsequent development of cognitive impairment remains to be defined.

Aged↗

Impaired heteronymous somatosensory motor cortical inhibition in dystonia.

A typical pathophysiological abnormality in dystonia is cocontraction of antagonist muscles, with impaired reciprocal inhibitory mechanisms in the spinal cord. Recent experimental data have shown that inhibitory interactions between antagonist muscles have also a parallel control at the level of the sensorimotor cortex. The aim of this work was to study heteronymous effects of a median nerve stimulus on the corticospinal projections to forearm muscles in dystonia. We used the technique of antagonist cortical inhibition, which assesses the conditioning effect of median nerve afferent input on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in ipsilateral forearm extensor muscles at rest. Nine healthy subjects and 10 patients with torsion dystonia participated in the study. MEPs and somatosensory evoked potentials were normal in patients. In healthy subjects, median nerve stimulation at 15- to 18-msec intervals inhibited the test MEPs in forearm extensors. In dystonic patients, median nerve stimulation delivered at the same conditioning-test intervals elicited significantly less inhibition of the test MEP. On the whole, these data suggest an impaired sensory-motor integration in dystonia and, more specifically, the decreased antagonistic cortical inhibition could suggest that functional interactions between antagonist muscles are primarily impaired at the cortical level.

Adult↗

Rhythmic cortical myoclonus in a case of HIV-related encephalopathy.

We describe a 66-year-old, HIV-seropositive patient presenting with ataxia and upper limb rhythmic myoclonus activated by postural maintenance. Electromyograph (EMG) recordings of the forearm muscles showed 50-msec bursts, with a frequency of 10 Hz, concurring with frontocentral electroencephalograph (EEG) rhythmic activity. Autoregressive spectral analysis applied to the EEG-EMG traces made it possible to detect significant coherence between the rhythmic EEG discharges and EMG bursts. The amplitude of the middle-latency somatosensory evoked potentials was increased. Long-latency reflexes were enhanced. On the basis of the electrophysiological findings, the movement disorder should be considered a rhythmic variant of cortical myoclonus. In our patient, HIV infection may have caused a dysfunction in the central nervous system pathways involving the cerebellum and sensorimotor cortex, similar to that occurring in genetically determined conditions characterised by cortical myoclonus.

AIDS Dementia Complex↗

Co-occurrence of infantile epileptic seizures and childhood paroxysmal choreoathetosis in one family: clinical, EEG, and SPECT characterization of episodic events.

The co-occurrence of infantile convulsions and childhood paroxysmal choreoathetosis (ICCA syndrome) has recently been reported in several families. The pattern of familial clustering observed is consistent with a single locus mutation which has been mapped onto the pericentromeric region of chromosome 16. We studied the main clinical, electroencephalogram (EEG), and single photon emission computed tomography (SPECT) characteristics of episodic events in a new family presenting clinical features similar to that described in the ICCA syndrome. In the first year of life, a mother and her two daughters suffered from rare afebrile seizures lasting from 30 seconds to 15 minutes. Ictal EEG recording in one daughter at 7 months of age showed bilateral polyspikes with a posterior predominance. In the three patients, epileptic seizures regressed within a few weeks, and never reoccurred. At the age of 7 and 12 years, respectively, the two daughters presented daily brief (20 seconds to 1 minute) involuntary choreoathetotic episodes. In 10 of these attacks, EEG did not show any epileptiform abnormalities. In both sisters, an ictal SPECT was performed during a choreoathetotic episode. Subtracting the ictal SPECT from the interictal SPECT coregistered to magnetic resonance imaging (MRI) revealed significant modifications in the local cerebral perfusion in the sensorimotor cortex, the supplementary motor areas, and pallidum. Carbamazepine completely suppressed paroxysmal dyskinesias. These observations, together with literature data, suggest that in this syndrome, depending on brain maturation, the same genetic abnormality may result in different paroxysmal neurological symptoms.

Athetosis↗

Performing functional magnetic resonance imaging in patients with Parkinson's disease treated with deep brain stimulation.

Deep brain stimulation (DBS) is a relatively novel treatment in advanced Parkinson's disease (PD). Functional magnetic resonance imaging (fMRI) is a useful technique for examining the effects of DBS both within the basal ganglia and its cortical connectivity. There are technical difficulties in imaging patients with PD, and the DBS itself can generate image artifacts. We describe aspects related to optimizing the fMRI acquisition parameters in patients with DBS and the results of sensorimotor activation tasks performed by four PD patients during hand, foot, and tongue movements, both before and after DBS implant. Provided that all safety conditions are followed, it is possible to perform fMRI in patients with PD and DBS. The standard DBS surgical procedure has to be slightly modified in order to reduce image artifacts. The event-related design provided increased power to detect sensorimotor cortex and basal ganglia activation.

Artifacts↗

Synchronized brain network underlying postural tremor in Wilson's disease.

Common neurological manifestation of Wilson's disease (WD) is a postural tremor of the upper extremities. Recently, the primary sensorimotor cortex (S1/M1) has been shown to be involved in WD postural tremor generation. However, neuropathological changes in WD are mostly observed in subcortical structures. We therefore aimed to investigate whether S1/M1 may be functionally interconnected with other brain areas. In five WD patients, we used magnetoencephalography and surface electromyography (EMG) to record simultaneously cerebral neuronal activity and muscular activity during sustained posture of the right forearm. As demonstrated previously, the strongest coupling to tremor EMG was observed in the contralateral S1/M1. This area was taken as reference in order to identify and localize cerebro-cerebral coherence at tremor frequency and its first harmonic. The analysis revealed significant coherence within an oscillatory network including S1/M1, higher cortical motor areas (premotor cortex, PM; supplementary motor area, SMA), posterior parietal cortex (PPC) and thalamus contralateral as well as the cerebellum ipsilateral to the tremor forearm. Flow of information was mainly of bidirectional nature. Taken together, our results indicate that WD postural tremor is generated within a synchronized cerebello-thalamo-cortical network, comprising S1/M1, higher cortical motor areas (SMA, PM), and PPC.

Adult↗

Cortical mechanisms mediating asterixis.

We describe a patient with chronic renal failure who suffered multifocal action-induced jerks. Electromyography (EMG) recorded the typical silence of asterixis. Back-averaging the EEG activity preceding the EMG silent periods in the forearm showed a biphasic wave antedating the asterixis by 23 ms. Somatosensory evoked potentials (SEPs) after median nerve stimulation were pathologically enlarged on both hemispheres. Brain-mapping of the biphasic wave preceding asterixis and the giant SEPs indicated a common origin in the sensorimotor cortex. This observation provides further documentation of a cortical origin for some types of asterixis in humans.

Brain Mapping↗

Corticobasal degeneration: decreased and asymmetrical glucose consumption as studied with PET.

Cerebral energy metabolism was studied by positron emission tomography and [18F]fluorodeoxyglucose in five patients with clinical diagnoses of probable corticobasal degeneration. A reduction in glucose consumption was observed in most cortical and subcortical structures compared to age-matched controls. The reduction was greatest on the side of the brain contralateral to the most affected limbs, as shown by the significantly lower ratios of contralateral to homolateral metabolic rates, in the temporal and sensorimotor cortex of patients compared to controls. A distinct asymmetry between the two hemispheres could be observed in a patient who was examined twice in the course of his illness. Detection of this asymmetrical decrease in brain cortical and subcortical glucose metabolism may prove useful as additional evidence supporting clinical diagnoses of the disease.

Aged↗

A comparison of fast MR scan techniques for cerebral activation studies at 1.5 tesla.

To evaluate the sensitivity of fast, gradient-echo MR scan techniques in their ability to detect blood oxygenation level dependent (BOLD) signal changes in task activation studies, three dedicated fast scan techniques, each with whole-brain coverage, were compared during a 3-min finger tapping paradigm on nine normal volunteers on a clinical 1.5 T scanner. Multislice (2D) single-shot spiral, 3D spiral, and multislice (2D) single-shot EPI scan techniques were done with similar temporal and spatial resolutions on each of the volunteers in random order. After image registration and statistical analysis, the sensitivity to detect activation was evaluated for the techniques by calculating t scores and number of activated voxels in predetermined regions of interest, including the contralateral primary sensorimotor cortex, the premotor region, the parietal region, the supplementary motor area, and the ipsilateral cerebellum. Baseline images acquired with the three techniques were qualitatively comparable and had a similar effective spatial resolution of around 5 x 5 x 5 mm3, as determined from autocorrelation analysis. The anatomical coverage was somewhat reduced (4 less slices per volume) with EPI at the identical temporal resolution of 1.76 s for all techniques. The use of multislice 2D spiral scan for motor cortex fMRI experiments provided for a superior overall temporal stability, and an increased sensitivity compared with multislice 2D EPI, and 3D spiral scan. The difference in sensitivity between multislice 2D spiral and EPI scans was small, in particular in the case of a ramp-sampled version of EPI. The difference in performance is attributed mainly to the difference in scan-to-scan stability.

Brain↗

Somatosensory evoked potential and clinical changes after electrode implant in basal ganglia of parkinsonian patients.

Median nerve somatosensory evoked potentials (SEPs) were recorded in three parkinsonian patients who underwent electrode implant in the subthalamic nucleus and/or globus pallidus for chronic deep brain stimulation (DBS). SEPs were evoked before surgery, in a medication-free condition, and after the functional stereotactic procedure, before beginning DBS. In order to evaluate the timing of the SEP changes after the electrode implant, in three further patients SEPs were recorded within the operating theater, before and immediately after the implantation. Patients' symptoms improved immediately after the electrode implant, and both N20 and N30 amplitudes increased in the postsurgical SEP recording. The clinical and neurophysiological effects observed after surgery, before commencing DBS, can be explained by microdamage in the target nucleus following the electrode implant. They occurred also in the patients studied in the operating theater, thus suggesting that they occur immediately after the stereotactic procedure. Our results suggest that the circuitries between the basal ganglia and the primary sensorimotor cortex may be modified not only by DBS but also by microdamage due to surgery and that they exert an important influence on SEP amplitude.

Basal Ganglia↗

Unilateral ischemic sensorimotor cortical damage induces contralesional synaptogenesis and enhances skilled reaching with the ipsilateral forelimb in adult male rats.

Unilateral damage to the forelimb representation area of the sensorimotor cortex (SMC) results in a compensatory reliance on the unimpaired (ipsilateral to the lesion) forelimb as well as reorganization of neuronal structure and connectivity in the contralateral motor cortex. Recently, male rats with unilateral electrolytic SMC lesions were found to have enhanced skilled reaching performance with the ipsilesional forelimb compared with sham-operated controls. The present study was performed to determine whether these behavioral findings are replicable using an ischemic lesion and whether there is a link between the enhanced learning and synaptogenesis in motor cortical layer V opposite the trained limb and lesion, as assessed using stereological methods for light and electron microscopy. Rats were given a sham operation or an endothelin-1 (ET-1) induced ischemic SMC lesion. They were then trained for 20 days on a skilled reaching task with the unimpaired limb or received control procedures. As with previous findings using electrolytic lesions, rats with unilateral ischemic SMC lesions performed significantly better using the unimpaired forelimb than did sham-operates. Lesions, but not training, significantly increased the total number of motor cortical layer V synapses per neuron as well as the number of perforated and multisynaptic bouton (MSB) synapses per neuron compared with shams. Thus, in addition to a net increase in synapses, the improved reaching ability was coupled with an increase in synapse subtypes that have previously been linked to enhanced synaptic efficacy. The failure to induce synaptogenesis in layer V with reach training alone is in contrast to previous findings and may be related to training intensity.

Age Factors↗

Mapping interactions between dopamine and adenosine A2a receptors using pharmacologic MRI.

Adenosine receptors in the basal ganglia are implicated in regulation of dopamine function and release. We investigated the interactions between dopamine receptors and adenosine receptors in the basal ganglia using pharmacologic MRI (phMRI) in rats. Stimulation of dopamine receptors was achieved using administration of 2 mg/kg of amphetamine. Then we investigated the antagonism of these changes using the selective A2a receptor antagonist 3,7-dimethyl-1-propargylaxanthine (DMPX). Amphetamine alone caused large increases (10-30%) in relative cerebral blood volume (rCBV) in caudate/putamen (CPu), nucleus accumbens (NAcc), thalamus, and frontal and cingulate cortices with changes that persisted for 70-80 min. DMPX alone (5 mg/kg) induced decreases in rCBV (approximately 8-10%) in NAcc, CPu, and olfactory tubercule, with smaller changes in thalamus (-6%) consistent with the regional distribution of A2a receptors. We examined the interactions between amphetamine and DMPX by assessing the effects of DMPX (5 mg/kg) administration 20 min after injection of 3 mg/kg amphetamine. These experiments showed that DMPX immediately decreased the rCBV increase induced by amphetamine in NAcc, CPu, and thalamus but not in cingulate or sensorimotor cortex. Companion microdialysis experiments showed that dopamine release in CPu was decreased in a similar manner. These experiments demonstrate the utility of phMRI for probing, in a noninvasive manner, the temporal and spatial dynamics of neurotransmitter interactions.

Adenosine A2 Receptor Antagonists↗

Increase of GAP-43 in the rat cerebellum following unilateral striatal 6-OHDA lesion.

In order to further characterize synaptic alterations following a severe lesion of the nigrostriatal system, the expression of synaptic marker proteins, synaptophysin and growth-associated protein-43 (GAP-43), was examined in various brain regions of 6-hydroxydopamine (6-OHDA)-treated rats, an animal model of Parkinson's disease. Unilateral nigrostriatal lesioning induced an increase in synaptophysin protein levels by 68% and 106% in the sensorimotor cortex and striatum, respectively, while changes in the level of GAP-43 were not observed. In contrast, 6-OHDA induced a 73% increase in the level of GAP-43 protein in the cerebellum. This increase was also confirmed with immunohistochemistry. The level of synaptophysin in the cerebellum remained unchanged in response to the lesion. These results suggest that a neurotoxic lesion of the nigrostriatal pathway differentially affects the expression of the two synaptic proteins and that plasticity-related changes in this model are not solely restricted to the nigrostriatal system. In addition, these results provide further evidence of the involvement of the cerebellum in the late response to a 6-OHDA lesion.

Animals↗

Long-term potentiation is associated with changes in synaptic ultrastructure in the rat neocortex.

Long-term potentiation (LTP) in the sensorimotor cortex of freely moving rats has been associated with changes in dendritic morphology and dendritic spine density. The current research examined changes in synaptic number and ultrastructure associated with LTP in this cortical region. LTP was induced over a 1 h period and the animals were sacrificed 2 h after the initial stimulation of the LTP group. Synapses within the terminal area of the apical dendrites from layer III pyramidal neurons were quantified by determining the total number of synapses per neuron, the number of excitatory and inhibitory contacts, number of synapses with different curvature subtypes, number of perforated synapses, and synaptic length. Several changes in synaptic morphology of excitatory synapses were revealed but no overall increase in the number of synapses per neuron was evident. Specifically, the induction of LTP was associated with an increased number of excitatory perforated and concave shaped synapses. Increased numbers of perforated concave synapses were also found to be significantly correlated with the degree of potentiation in the LTP animals. These and previous results suggest similar synaptic changes in both the cortex and hippocampus during the early phases of LTP maintenance and distinct synaptic changes during later phases of LTP maintenance.

Analysis of Variance↗

Corticospinal tract plasticity and astroglial reactivity after cervical spinal injury in the postnatal rat.

We have investigated corticospinal (CS) axon growth around cervical spinal injury in the neonatal rat and related this growth to the astroglial reaction occurring at the lesion site. Rats received a high cervical overhemisection (left dorsal funiculotomy, right spinal hemisection) and a right cortical ablation on Postnatal Days (PNDs) 0, 3, 6, 12, and 21 to 24 (weanlings). In chronic operates the remaining CS projection from the left sensorimotor cortex was then assayed using wheat germ agglutinin-horseradish peroxidase as an anterograde tracer. In other operates the formation of the astroglial scar at the spinal lesion site was studied using a monoclonal antibody to glial fibrillary acidic protein. In PNDs 0-6 operates labeled axons extend through the intact left hemicord to bypass the lesion. The labeled axons travel to the edge of the lesion, cross the midline, and pass lateral to the lesion within the dorsal and intermediate gray and dorsal lateral white matter. Axons project bilaterally to normal areas of CS termination in PND 0 operates for a distance of 2.5 to 4 spinal segments caudal to the lesion which decreases to 1.5 to 2 segments in PND 6 operates. In PND 12 and weanling operates labeled fibers do not grow around the lesion but instead are retracted rostrally. There is an astrocytic reaction to injury at all ages by 3 days postoperatively (p.o.) that becomes greater with age and p.o. survival time. A more complicated cystic scar forms in 6-day and older operates. These data show that there is an age-related change in the ability of CS axons to grow around spinal injury which ends near the time CS elongation and gliogenesis is complete in the spinal cord.

Aging↗