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Effect of sensory discrimination training on structure and function in patients with focal hand dystonia: a case series.

OBJECTIVE: To measure the effects of sensorimotor training based on the principles of neuroplasticity for patients with focal hand dystonia. DESIGN: Case series of 3 subjects with focal hand dystonia of the left hand, compared with age-matched normative controls. SETTING: Outpatient clinic. PARTICIPANTS: Three consecutive clinic patients-musicians with focal hand dystonia-who described a history of repetitive practice and performance (2 women; ages, 23 y and 35 y; 1 man; age, 24 y). INTERVENTION: Subjects were asked to stop performing the tasks that caused the abnormal movements, to participate in a wellness program (aerobics, postural exercises, stress free hand use), and to carry out supervised, attended, individualized, repetitive sensorimotor training activities at least once week for 12 weeks and reinforced daily at home. MAIN OUTCOME MEASURES: Standard tests documenting somatosensory hand representation, target-specific hand control, and clinical function. RESULTS: On the affected side, the 3 subjects improved an average of 86.8% on somatosensory hand representation, 117% on target-specific performance, 23.9% on fine motor skills, 22.7% on sensory discrimination, 31.9% on musculoskeletal skills, and 32.3% on independence. All 3 subjects improved 10% or more on 90% of the subtests with 20% improvement on 50% of the subtests. CONCLUSION: Individuals with focal hand dystonia who have a history of repetitive hand use can improve cortical somatosensory responses and clinical motor function after individualized sensorimotor training consistent with the principles of neural adaptation.

Adult↗

Sensorimotor gating and schizophrenia. Human and animal model studies.

Human and animal model studies of sensorimotor gating allow us to understand the functional significance of attentional abnormalities and monoaminergic alterations in patients with schizophrenic disorders. Clinically, schizophrenic patients report oversensitivity to sensory stimulation that theoretically correlates with stimulus overload and leads to cognitive fragmentation. Paradigms using cortical event-related potentials and the prepulse inhibition of startle responses show that schizophrenic patients also have impaired central nervous system inhibition (sensorimotor gating). Animal model studies demonstrate that increased systemic aminergic activity and increased nucleus accumbens dopamine tone causes sensorimotor gating failure, similar to that seen in schizophrenic patients. The time course of the observed schizophrenic and animal model deficits is compatible with the "temporal map" of monoaminergic neuron functions (le, several hundred milliseconds). Studies of sensorimotor gating allow investigators to comment on the spatial and temporal mapping of neurons, trait and state deficits, and vulnerability factors in the schizophrenic spectrum of disorders. By translating attentional theories into testable hypotheses, the neurobiology of schizophrenic disorders becomes clearer.

Animals↗

Functional coupling of the stabilizing gaze reflexes during vertical linear motion in the alert cat.

Eye-head coordination is mainly achieved by means of stabilizing reflexes (VOR, VCR, OKR) and orienting movements (eye-neck surgery) underlying the close cooperation of the visual and vestibular systems in gaze stabilization. The functional coupling of these different sensorimotor subsystems has been principally analysed using rotatory stimulation of the whole body and/or of the visual surround. The aim of the present study was to investigate the dynamic properties of these stabilizing gaze reflexes and their coupling during linear motion in the vertical plane. These investigations were performed in the alert cat under open-loop conditions (head fixed). Otolith stimulation consisted of vertically translating the cat in total darkness using sinusoidal linear motion (0.025 Hz-1.39 Hz; 290 mm peak-to-peak amplitude). Optokinetic stimulation was provided by sinusoidally moving a pseudo-random visual pattern in front of the cat and in the vertical plane, with identical kinematic parameters. Normal visual-otolith interaction was performed by translating the cat in front of the stationary visual surround while conflicting interaction was provided by moving the animal and the visual pattern in phase and at the same velocity (visual stabilization). Results showed that the vertical otolith-neck reflex is very poorly developed or absent in the low frequency range of motion (0.025 Hz-0.25 Hz) while consistent EMG activity is found during pure optokinetic stimulation. EMG responses are in phase with the visual surround velocity in the upward direction and with the upward OKR velocity. A close correlation is observed between the EMG gain and the OKR gain, which both decrease in this low frequency range, indicating that gaze stabilization would be mainly ensured by the OKR and a functional oculo-collic coupling or eye-neck surgery in the vertical plane. On the contrary, gaze stabilization is principally achieved by way of the otolith-neck reflex in the higher frequency range of motion (above 0.25 Hz). EMG responses recorded during otolith stimulation exhibit a relatively constant gain and a phase lead with respect to motion velocity which progressively reduces as the stimulus frequency increases up to 1.39 Hz. When present, EMG responses evoked during the optokinetic stimulation show strong gain attenuation and phase lag. Normal visual-otolith interaction induces neck muscle activity which parallels the optokinetic and the otolith responses in the low and high frequency ranges, respectively. The motor responses are however improved in terms of gain and phase values in the whole frequency range when both sensory inputs are combined.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Functional imaging of the brain in the evaluation of drug response and its application to the study of aging.

Functional neuroimaging techniques including single photon emission computerised tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (FMRI) can provide insight into the functional connectivity of the human brain in both health and disease, including the effects of aging and drugs on brain function. Neuroimaging measurement techniques can either be direct, using radio-specific ligands, or indirect, using the neurophysiological consequences of pharmacological interventions. Both approaches can be combined with sensorimotor or cognitive activation to examine the interaction between the targeted receptor function and the sensorimotor or cognitive process implicit in the study design. Using radionuclides, PET can provide absolute measurement of cerebral blood flow to regions of interest and can measure changes in cerebral metabolism using labelled fluorodeoxyglucose. PET offered the first opportunity to image brain activation caused by a variety of stimuli and hence to measure the effect of drugs on brain activation. PET also enables the study of drug disposition within the brain. SPECT has been used to study relative changes in cerebral blood flow associated with disease processes and also receptor occupancy. FMRI, by contrast, does not involve ionising radiation and has better spatial and temporal resolution. It is still a relatively new technique and limited by its ability to only measure haemodynamic changes through the blood oxygen level-dependent (BOLD) signal. The effects of aging on drug responsiveness and the effects of drug treatment of diseases associated with old age are relatively unexplored areas of functional neuroimaging research.

Aging↗

[Habituation and effects of protein synthesis blockers on neuronal activity in the cerebral sensorimotor cortex in rabbits].

The investigation of brain functions has been for many years an exciting and at the same time a very complex and enigmatic domain of research. In our experiments we followed the occurrence of habituation, a simple form of learning, during a peripheral light stimulation, in sensorimotor cortex neurons of rabbits. In the majority of the mature neurons habituation occurred with repeated light stimulations with same features, while in immature rabbits it was less frequently observed and was slower. Since in basic patterns of habituation and learning, cell protein plays a significant role, we followed the effects of protein synthesis blockers in the process of training and electrogenesis. Microiontophoretic application of actinomycin D and cyclohexamide compromised the occurrence of habituation in high number of registered neurons, while the application of a neurotransmitter, acetyl choline, promoted habituation in the sensorimotor brain cortex neurons of immature experimental animals.

Acetylcholine↗

Thalamic projections to sensorimotor cortex in the newborn macaque.

In the present experiments thalamocortical projections to different functional areas of the newborn (or prematurely delivered) macaque's sensorimotor cortex were labeled using retrogradely transported fluorescent dyes. Several dyes were used in each animal to (1) enable the direct comparison of the soma distributions of different thalamocortical projections within thalamic space, and (2) identify by double labeling neurons shared between these distributions. The projection patterns in the newborn macaque were compared with those of the mature animal reported by Darian-Smith et al. (J. Comp. Neurol. 1990;298:000-000). The main observations were (1) all thalamocortical projections to the sensorimotor cortex of the mature macaque are well established by embryonic days 146-150, as was shown by labeling these pathways in infants delivered by cesarean section, (2) a significant number of thalamocortical neurons in the newborn were double-labeled following dye injections into different pre- or postcentral areas, and where the margins of the dye uptake zones were separated by 3-8 mm, and (3) extensive projections from the anterior pulvinar nucleus to the motor and premotor cortex, and to the supplementary motor cortex were labeled in the newborn macaque. Both the exuberant terminal arborizations, and the precentral pulvinar projections were diminished by the 6th postnatal month, and absent in the mature macaque. The role of epigenetic determinants of these postnatal events is briefly considered.

Afferent Pathways↗

Competitive NMDA and strychnine-insensitive glycine-site antagonists disrupt prepulse inhibition.

Prepulse inhibition (PPI) is thought to reflect the operation of a sensorimotor gating system in the brain. Sensorimotor gating abnormalities have been identified in schizophrenic patients, and various neural systems are involved in this function. To study the modulation of the sensorimotor gating system by the N-methyl-D-aspartate (NMDA) receptor channel complex, the effects of noncompetitive and competitive NMDA antagonists on PPI were examined in rats. PPI was not disrupted by CGS 19755, a competitive NMDA antagonist, at 30 min after subcutaneous (s.c.) administration. However, CGS 19755 (40 mg/kg s.c.) decreased PPI at 120 min after administration with a marked decrease of startle amplitude. Late onset of the effect of CGS 19755 was also observed in the increase of spontaneous locomotor activity (SLA). On the other hand, phencyclidine, a noncompetitive NMDA antagonist, disrupted PPI at 30 min after administration and increased SLA from 20 min after administration. PPI was also disrupted by bilateral intracerebroventricular administration of 5,7-dichlorokyn urenate (10 and 20 micrograms/side X 2), an antagonist at the strychnine-insensitive glycine receptor, which is an allosteric binding site in the NMDA receptor-channel complex. It is concluded that the NMDA receptor-channel complex plays an important role in regulation of PPI.

Acoustic Stimulation↗

Frequencies contributing to functional connectivity in the cerebral cortex in "resting-state" data.

BACKGROUND AND PURPOSE: In subjects performing no specific cognitive task ("resting state"), time courses of voxels within functionally connected regions of the brain have high cross-correlation coefficients ("functional connectivity"). The purpose of this study was to measure the contributions of low frequencies and physiological noise to cross-correlation maps. METHODS: In four healthy volunteers, task-activation functional MR imaging and resting-state data were acquired. We obtained four contiguous slice locations in the "resting state" with a high sampling rate. Regions of interest consisting of four contiguous voxels were selected. The correlation coefficient for the averaged time course and every other voxel in the four slices was calculated and separated into its component frequency contributions. We calculated the relative amounts of the spectrum that were in the low-frequency (0 to 0.1 Hz), the respiratory-frequency (0.1 to 0.5 Hz), and cardiac-frequency range (0.6 to 1.2 Hz). RESULTS: For each volunteer, resting-state maps that resembled task-activation maps were obtained. For the auditory and visual cortices, the correlation coefficient depended almost exclusively on low frequencies (<0.1 Hz). For all cortical regions studied, low-frequency fluctuations contributed more than 90% of the correlation coefficient. Physiological (respiratory and cardiac) noise sources contributed less than 10% to any functional connectivity MR imaging map. In blood vessels and cerebrospinal fluid, physiological noise contributed more to the correlation coefficient. CONCLUSION: Functional connectivity in the auditory, visual, and sensorimotor cortices is characterized predominantly by frequencies slower than those in the cardiac and respiratory cycles. In functionally connected regions, these low frequencies are characterized by a high degree of temporal coherence.

Adult↗

Brain activation patterns during imagined stance and locomotion in functional magnetic resonance imaging.

Posture and gait are sensorimotor actions that involve peripheral, spinal, and supraspinal structures. To investigate brain activity during stance and locomotion, 13 healthy subjects were asked to stand, walk, run, and lie down; subsequently, they were trained to imagine standing, walking, running, and lying [imagined lying as rest condition in functional magnetic resonance imaging (fMRI)]. Separate and distinct activation/deactivation patterns were found for the three imagined conditions: (1) standing imagery was associated with activation in the thalamus, basal ganglia, and cerebellar vermis; (2) walking imagery was associated with activation in the parahippocampal and fusiform gyri (areas involved in visuospatial navigation), occipital visual areas, and in the cerebellum; (3) running imagery caused a predominantly cerebellar activation in the vermis and adjacent hemispheres (six times larger than during imagination of walking or standing), but activations in the parahippocampal and fusiform gyri were smaller than during walking. Deactivations were found for walking and running, but not for standing imagery. They were located in the vestibular (posterior insula, superior temporal gyrus, supramarginal gyrus) and somatosensory (postcentral gyrus) cortex with right-hemispheric dominance. These findings support the concept of a hierarchical organization of posture and locomotion. Automated locomotion, for example, running, is based on spinal generators whose pace is driven by the cerebellar locomotor region. Deactivation in the vestibular and somatosensory cortex prevents adverse interactions with the optimized spinal pattern and sensory signals; this confirms earlier findings of a multisensory inhibition during unhindered locomotion. During slow walking, spatial navigation, mediated by the parahippocampal cortex, becomes more important. Postural control during standing involves a low intensity cerebellar activity and sensorimotor control via the thalamus and basal ganglia.

Adult↗

Effect of cefepime on startle amplitude and prepulse inhibition of startle reflex in rats: manipulation of GABAA receptor function with midazolam.

Disruption of prepulse inhibition (PPI) of startle response is manifested in schizophrenia and Huntington's disease among other neuropsychiatric disorders characterized by sensorimotor gating deficit. Antagonism of GABAA receptor function was documented to reduce PPI response. However, whether GABAA antagonism reduces PPI response is yet to be established because of contradicting reports. Cefepime is one of the fourth-generation cephalosporins documented to antagonize GABAA receptor function. This study investigated the effect of intramuscular injection of cefepime (45 and 90 mg/kg) twice daily for three consecutive days on both PPI of acoustic startle response and acoustic startle amplitude in rats. The effect of administration of the GABAA receptor agonist midazolam (1 mg/kg, i.p.) in conjunction with cefepime on PPI response and startle amplitude was also investigated. Results showed that administration of both dose levels of cefepime caused PPI deficit. Treatment of animals with midazolam in conjunction with cefepime reversed the effect of the lower dose, but not the higher one, on PPI of startle response without affecting startle amplitude in both dose levels. Results of this study, therefore, support the view that GABAA antagonism reduces PPI response. It is also concluded that antagonism of GABAergic transmission may be involved in the effect of the lower dose of cefepime on PPI response. Other mechanisms may mediate the effect of the higher dose of cefepime on PPI response. Clinical investigations are needed to determine the consequence of using cefepime in disorders of sensorimotor gating.

Animals↗

Adapting to aging losses: do resources facilitate strategies of selection, compensation, and optimization in everyday functioning?

Previous cross-sectional research has shown that older people who are rich in sensorimotor-cognitive and social-personality resources are better functioning in everyday life and exhibit fewer negative age differences than resource-poor adults. Longitudinal data from the Berlin Aging Study was used to examine these findings across a 4-year time interval and to compare cross-sectional indicators of adaptive everyday functioning among survivors and nonsurvivors. Apart from their higher survival rate, resource-rich older people (a) invest more social time with their family members, (b) reduce the diversity of activities within the most salient leisure domain, (c) sleep more often and longer during daytime, and (d) increase the variability of time investments across activities after 4 years. Overall, findings suggest a greater use of selection, compensation, and optimization strategies in everyday functioning among resource-rich older adults as compared with resource-poor older adults.

Activities of Daily Living↗

Presurgical functional localization of primary somatosensory cortex by dipole tracing method of scalp-skull-brain head model applied to somatosensory evoked potential.

The aim of the present study was to explore the utility of dipole tracing (DT) of a scalp-skull-brain (SSB) head model in preoperative functional localization of the human brain. Nine patients who underwent surgery of mass lesions around the central sulcus (CS) were employed. By using SSB/DT, dipole source location of early cortical components of the somatosensory evoked potential (SEP) was estimated before surgery. Motor cortex, CS and primary somatosensory cortex were determined by cortical SEP during surgery. After surgery precise functional mapping was reproduced in MRI, and the accuracy of DT was evaluated by measuring the distance between estimated dipole source and the posterior bank of the CS. We defined this distance as localization error of DT. In 4 cases without structural change around the sensorimotor cortex, localization error ranged from 1 to 4 mm with an average of 2 mm. In 5 cases with structural alteration of sensorimotor cortex, localization error ranged from 6 to 10 mm with an average of 8 mm. The difference in localization error between the two groups was statistically significant, and may have been caused by changes of conductance near sensorimotor cortex in the latter group. Functional localization by DT was accurate and useful. But localization error could not be ignored in cases with structural alteration in the sensorimotor cortex.

Aged↗

Expression of the melanin-concentrating hormone (MCH) receptor mRNA in the rat brain.

The melanin-concentrating hormone (MCH) system is thought to be an important regulator of food intake. Recently the orphan G protein-coupled receptor SLC-1 was identified as the MCH receptor (MCHR). Preliminary analyses of MCHR mRNA distribution have supported a role for the MCH system in nutritional homeostasis. We report here a complete anatomical distribution of the MCHR mRNA. We have found high levels of expression of MCHR mRNA in most anatomical areas implicated in control of olfaction, with the exception of the main olfactory bulb. Dense labeling was also detected in the hippocampal formation, subiculum, and basolateral amygdala, all of which are important in learning and memory, and in the shell of the nucleus accumbens, a substrate for motivated behavior and feeding. Within the hypothalamus, MCHR mRNA was moderately expressed in the ventromedial nucleus, arcuate nucleus, and zona incerta, all of which serve key roles in the neuronal circuitry of feeding. In the brainstem, strong expression was observed in the locus coeruleus, which is implicated in arousal, as well as in nuclei that contribute to orofacial function and mastication, including the facial, hypoglossal, motor trigeminal, and dorsal motor vagus nuclei. In most regions there was a good correspondence between MCHR mRNA distribution and that of MCH-immunoreactive fibers. Taken together, these data suggest that MCH may act at various levels of the brain to integrate various aspects of feeding behavior. However, the extensive MCHR distribution throughout the brain suggests that this receptor may play a role in other functions, most notably reinforcement, arousal, sensorimotor integration, and autonomic control.

Amygdala↗

Neurochemical compartmentalization of the globus pallidus in the rat: an immunocytochemical study of calcium-binding proteins.

The globus pallidus external segment forms a major target center of the mammalian striatum which is characterized by neurochemically distinct compartments. The present study was undertaken to determine if a corresponding compartmentalization exists within the globus pallidus external segment in the rat. Immunocytochemical examination of the calcium-binding proteins parvalbumin and calbindin D28kDa, which are present in neurons of the striatal matrix compartment, was employed. The results indicate three neurochemically distinct compartments within the globus pallidus external segment: 1) an area in the medial aspect of the entire length of the globus pallidus that contains dense immunoreactivity for calbindin D28kDa; 2) a narrow rim at the striatopallidal junction in the rostral two-thirds of the globus palidus that contains calbindin D28kDa immunoreactivity designated as the "border zone" of the globus pallidus; and 3) an area between these two zones showing very poor immunoreactivity for calbindin D28kDa but containing parvalbumin immunoreactive neurons. The calbindin D28kDa immunoreactive border zone corresponds to the area of the globus pallidus where striatal inputs converge extensively, whereas the rest of the nucleus is involved in segregated, topographically organized pathways. Parvalbumin-containing neurons are involved in the propagation of striatal output related to striosomal and sensorimotor aspects of basal ganglia function. The present results also indicate that calbindin D28kDa immunoreactivity is completely absent from striosomal neurons and is therefore a useful marker for striatal compartments.

Animals↗

Volume transmission of dopamine over large distances may contribute to recovery from experimental parkinsonism.

Administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to cats results in a parkinsonian syndrome that spontaneously recovers by 6 weeks after induction. Striatal dopamine depletions in these animals are heterogenous with more extensive damage dorsolaterally than ventromedially. Measures of extracellular dopamine levels by in vivo microdialysis showed that dopamine released from a relatively preserved ventral striatal innervation can diffuse over a distance of 5.5 mm to 7.0 mm to the more extensively denervated dorsolateral striatum, where it may influence sensorimotor activities and contribute to functional recovery. Diffusion of dopamine through a large volume of striatal tissue was observed in cats 6 weeks after an MPTP-induced lesion and in normal cats with pharmacologically induced dopamine reuptake inhibition, but not in normal animals without reuptake inhibition. In cats recovered from MPTP-induced parkinsonism, a greater amount of dopamine was recovered from the extracellular fluid in the dorsolateral caudate following stimulated release of dopamine from the ventromedial striatum than after stimulated release locally in the dorsolateral caudate. These results suggest volume transmission of dopamine over large distances is possible and perhaps an important contributor to functional recovery from a large dopamine-depleting lesion. These results may also form the basis for understanding how limited reinnervation of the striatum by grafts or trophic factor therapies may lead to significant functional improvement.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Striatal dopamine after cortical injury: a reexamination.

We reevaluated the effects of unilateral sensorimotor cortex ablation on dopamine and dihydroxyphenylacetic acid concentration in the left and right neostriatum. We found no evidence for an asymmetry of either dopamine or dihydroxyphenylacetic acid in control or sham-operated animals and cortical ablation had no effect on dopamine or dihydroxyphenylacetic acid concentrations. These results suggest that the influence of sensorimotor cortex lesions on extrapyramidal function does not involve changes in striatal dopamine concentrations or turnover.

3,4-Dihydroxyphenylacetic Acid↗

Ethanol's effect on selective gating of somatic sensory inputs to single cortical neurons.

The effect of alcohol intoxication was tested on sensory responses of single units in the somatosensory (SI) cortex of awake, freely moving rats. We have previously shown that transmission of cutaneous sensory information from the paw to the cortex during movement is subject to a time varying pattern of sensory suppression which selectively "gates in" sensory information to particular categories of cortical neurons during certain phases of the locomotor step cycle. In the period of 5-20 minutes after alcohol administration (when the rats became hyperactive) the afferent inhibition producing this selective gating was reduced or abolished, depending on the ethanol dose (between 0.75 and 1.5 g/kg). This indicates that the selective suppression of "irrelevant" inputs to certain cortical cells, which is normally seen during movement, is absent during alcohol intoxication. This paradigm may provide a model for study of the neurophysiologic mechanism by which alcohol disturbs higher cognitive functions involving cortical management of sensorimotor tasks.

Animals↗

Mental state inference using visual control parameters.

Although we can often infer the mental states of others by observing their actions, there are currently no computational models of this remarkable ability. Here we develop a computational model of mental state inference that builds upon a generic visuomanual feedback controller, and implements mental simulation and mental state inference functions using circuitry that subserves sensorimotor control. Our goal is (1) to show that control mechanisms developed for manual manipulation are readily endowed with visual and predictive processing capabilities and thus allows a natural extension to the understanding of movements performed by others; and (2) to give an explanation on how cortical regions, in particular the parietal and premotor cortices, may be involved in such dual mechanism. To analyze the model, we simulate tasks in which an observer watches an actor performing either a reaching or a grasping movement. The observer's goal is to estimate the 'mental state' of the actor: the goal of the reaching movement or the intention of the agent performing the grasping movement. We show that the motor modules of the observer can be used in a 'simulation mode' to infer the mental state of the actor. The simulations with different grasping and non-straight line reaching strategies show that the mental state inference model is applicable to complex movements. Moreover, we simulate deceptive reaching, where an actor imposes false beliefs about his own mental state on an observer. The simulations show that computational elements developed for sensorimotor control are effective in inferring the mental states of others. The parallels between the model and cortical organization of movement suggest that primates might have developed a similar resource utilization strategy for action understanding, and thus lead to testable predictions about the brain mechanisms of mental state inference.

Cerebral Cortex↗