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Biomedical subjects

Marco Molinari

Publications and source records attributed to Marco Molinari.

18 recordsLinked to original sources
PubMed2006

Cerebellar damage impairs detection of somatosensory input changes. A somatosensory mismatch-negativity study.

Several recent studies support the view that the cerebellum's contribution to sensory processing is not limited to movement regulation. In a previous paper (Restuccia D, Valeriani M, Barba C, Le Pera D, Capecci M, Filippini V, Molinari M. Functional changes of the primary somatosensory cortex in patients with unilateral cerebellar lesions. Brain 2001; 124: 757-68) we showed that the cerebellum influences somatosensory input processing at very early stages. The present study was aimed at verifying whether an analogous influence is also exerted at higher levels. For some time it has been known that in the auditory modality a specific event-related potential (ERP), that is, mismatch negativity (MMN), reflects preattentive detection of changes in the incoming stimulus by comparing the new stimulus with sensory memory traces. To test the cerebellar influence on the processing of incoming somatosensory stimuli we first verified whether the electrical stimulation of fingers, according to an 'oddball' paradigm within a stimulus-ignored condition, was able to elicit event-related components specifically linked to the preattentive detection of change. We analysed scalp responses obtained from eight healthy volunteers during frequent and rare electrical stimulation of the first and fifth finger of the left hand, respectively. To ensure that responses to deviant stimuli were due to changes in detection mechanisms, rather than to activation of new afferents, we also analysed responses to rare stimulation alone ('standard-omitted' condition). The 'oddball' stimulation was able to elicit a parieto-occipital extra negativity that was different in scalp distribution and latency from the N140 response to the 'standard-omitted' stimulation. We considered that this response was related to changes in detection mechanisms and labelled it somatosensory mismatch negativity (S-MMN). When the same procedure was applied to six patients with unilateral cerebellar lesions we found that the S-MMN was clearly abnormal after stimulation of the affected hand (ipsilateral to the affected cerebellar hemisphere). Earlier ERPs, as well as ERPs elicited during the 'standard-omitted' condition, were fully normal. Present data indicate that cerebellar processing is involved in preattentive detection of somatosensory input changes. In conclusion, this study demonstrates the reliability of S-MMN recordings and indicates that subjects with cerebellar damage may be impaired in the cortical processing of incoming somatosensory inputs.

Adult↗
PubMed2006

P2X2R purinergic receptor subunit mRNA and protein are expressed by all hypothalamic hypocretin/orexin neurons.

Neurophysiologic data suggest that orexin neurons are directly excited by ATP through purinergic receptors (P2XR). Anatomical studies, though reporting P2XR in the hypothalamus, did not describe it in the perifornical hypothalamic area, where orexinergic neurons are located. Here we report the presence of the P2X(2)R subunit in the rat perifornical hypothalamus and demonstrate that hypothalamic orexin neurons express the P2X(2)R. Double immunohistochemistry showed that virtually all orexin-immunoreactive neurons are also P2X(2)R immunoreactive, whereas 80% of P2X(2)R-immunoreactive neurons are also orexin positive. Triple-labeling experiments, combining fluorescence in situ hybridization for P2X(2)R mRNA and P2X(2)R/orexin double immunofluorescence, confirmed these findings. In addition, in situ hybridization demonstrated that P2X(2)R mRNA is localized in cellular processes of orexinergic neurons. The present data support neurophysiologic findings on ATP modulation of orexinergic function and provide direct evidence that the entire population of orexin neurons expresses a P2XR subtype, namely, P2X(2)R. Thus, purinergic transmission might intervene in modulating key functions known to be controlled by the orexinergic system, such as feeding behavior and arousal.

Adenosine Triphosphate↗
PubMed2006

N-arachidonoyl-dopamine tunes synaptic transmission onto dopaminergic neurons by activating both cannabinoid and vanilloid receptors.

In the present study, we used electrophysiological, biochemical, and confocal microscopy techniques, to investigate the functional role of transient receptor potential vanilloid type 1 (TRPV1) and cannabinoid type 1 receptors (CB1-R) in the substantia nigra pars compacta (SNpc) and their stimulation by the endocannabinoid N-arachidonoyl-dopamine (NADA). Liquid chromatography-mass spectrometry analyses revealed that a NADA-like compound is produced in substantia nigra slices, in conditions of hyperactivity. Moreover, the functional role of both TRPV1 and CB1-R in modulating synaptic transmission in this area was suggested by confocal microscopy data, showing TRPV1 and CB1-R immunoreactivity in punctate structures, probably representing synaptic contacts on cell bodies of the SNpc. In patch-clamp recordings from dopamine (DA) neurons of the SNpc, we found that NADA increases or reduces glutamatergic transmission onto DA neurons by activating TRPV1 and CB1 receptors, respectively, whereas it decreases GABAergic transmission via CB1 stimulation. Facilitation of glutamate release through TRPV1 was blocked in the presence of a selective blocker of the putative endocannabinoid membrane transporter (EMT), indicating that NADA needs to be taken up by cells to interact with this receptor. In line with these data, biochemical results demonstrated that NADA selectively acted at CB1-R when its re-uptake was blocked. Altogether these data demonstrate a significant role exerted by the endocannabinoid/endovanilloid NADA in the regulation of synaptic transmission to DA neurons of the SNpc. Moreover, they highlight a key function of the EMT transporter in promoting the stimulation of TRPV1 or CB1-R, thus favoring facilitation or inhibition of glutamate synaptic release.

Animals↗
PubMed2005

Sensorimotor transduction of time information is preserved in subjects with cerebellar damage.

The cerebellar contribution to motor entrainment through rhythmic auditory stimuli was analyzed by comparing rhythmic motor responses in subjects with cerebellar pathologies and in healthy controls. Eleven patients with cerebellar lesions and eight healthy subjects tapped in synchrony with an auditory rhythmic stimulus using a hand-held pencil-shaped electrode connected to a PC. A 60-stimulus sequence was delivered with an ISI of 500 ms and changed at random to a new ISI value with either consciously perceived (+/-50 ms) or unperceived tempo changes (+/-10 ms). Synchronization patterns for both groups were computed based on the timing of inter-response intervals (IRIs) and synchronization errors (SE). Variability of IRI as well as the timing of adaptation patterns after the tempo changes were modeled and analyzed mathematically using a logistic/sigmoid function. Healthy subjects performed with significantly lower IRI variability than cerebellar patients. Patients with focal lesions performed with significantly lower IRI variability than patients with atrophic lesions. Asymptote parameters during isochronous synchronization as well as slope angles and symmetry points of the adaptation curves after tempo perturbation showed no significant differences between groups. Present data indicate that temporal variability of rhythmic motor responses is differentially affected by distinct cerebellar pathologies but that motor entrainment to auditory rhythms is not affected by lesion of the cerebellar circuits.

Acoustic Stimulation↗
PubMed2005

Protective role of hydrogen peroxide in oxygen-deprived dopaminergic neurones of the rat substantia nigra.

Hydrogen peroxide (H2O2) is a reactive oxygen species, responsible for cytotoxic damage through the formation of hydroxyl radicals. Dopamine (DA) neurones of the substantia nigra pars compacta (SNc) are highly sensitive to metabolic stress, and they typically respond to energy deprivation with membrane hyperpolarization, mainly through opening of ATP-dependent K+ channels. Accordingly, H2O2 (3 mM) induced a tolbutamide-sensitive outward current in DA neurones. Conversely, in a hypoxic medium, H2O2 reverted membrane hyperpolarization, which is associated with oxygen deprivation in DA neurones, restored their action potential firing, and reduced the hypoxia-mediated outward current in a concentration-dependent manner, between 0.1 and 3 mM (IC50 0.6+/-0.1 mM). Notably, H2O2 did not counteract membrane hyperpolarization associated with hypoglycaemia, moreover, when catalase was inhibited with 3-amino-1,2,4-triazole (3-AT; 30 mM), H2O2 did not reduce hypoxia-mediated outward current. The counteracting action of H2O2 on hypoxia-mediated effects was further confirmed by single-unit extracellular recordings of presumed DA neurones in acute midbrain slices preparations, using a planar multi-electrode array device. Whilst a prolonged period of hypoxia (40 min) caused firing suppression, which did not recover after perfusion in normoxic conditions, the presence of H2O2 (3 mM) during this prolonged hypoxic period rescued most of the neurones from irreversible firing inhibition. Accordingly, morphological studies showed that H2O2 counteracts the cytochrome c release provoked by prolonged hypoxic treatment. Taken together, our data suggest that H2O2 prevents the metabolic stress of DA neurones induced by hypoxia by serving as a supplementary source of molecular oxygen, through its degradation by catalase.

Action Potentials↗
PubMed2005

Enhanced neurogenesis during trimethyltin-induced neurodegeneration in the hippocampus of the adult rat.

The occurrence of neurogenesis in the hippocampus of the adult rat during trimethyltin (TMT)-induced neurodegeneration was investigated using bromodeoxyuridine (BrdU). Fifteen days after TMT intoxication, BrdU-labeled cells were significantly more numerous in the hippocampus of treated animals, gradually decreasing towards the control value 21 days after intoxication in the dentate gyrus (DG), while in the CA3/hilus region BrdU-labeled cells were still more numerous in TMT-treated rats. In order to investigate the fate of newly-generated cells double labeling experiments using neuronal or glial markers were performed. Colocalization of the neuronal marker NeuN was detected in many BrdU-positive cells in the DG, while in the CA3/hilus region no colocalization of NeuN and BrdU could be observed. No colocalization of BrdU and the astroglial marker GFAP or the microglial marker OX-42 was detected either in the DG and or in the CA3/hilus region. The results indicate an enhancement of endogenous neurogenesis in the hippocampus during TMT-induced neurodegeneration, with the development of a subpopulation of regenerated cells into neurons in the DG, while in the CA3/hilus region the population of newly-generated cells should be regarded as undifferentiated.

Animals↗
PubMed2005

Early versus delayed inpatient spinal cord injury rehabilitation: an Italian study.

OBJECTIVE: To examine what effect the injury-to-rehabilitation interval has on the outcome of spinal cord injury (SCI) rehabilitation. DESIGN: Retrospective study. SETTING: Spinal unit of a large rehabilitation hospital. PARTICIPANTS: Consecutive admissions were divided into groups according to age, sex, and American Spinal Injury Association impairment grade and neurologic level of injury. The patients were matched for these variables and divided into groups according to the interval from injury to admission into acute rehabilitation. This approach resulted in 150 patients with SCI grouped into 50 comparison subgroupings. Interventions Three comparison groups-short (<30 d), medium (31-60 d), and long (>60 d) time to admission (TTA)-were evaluated for rehabilitation outcomes. MAIN OUTCOME MEASURES: Barthel Index, Rivermead Mobility Index, Walking Index for Spinal Cord Injury, and motor scores at admission and discharge were examined. The changes and efficiencies were evaluated. RESULTS: The 3 groups were comparable for all medical and demographic characteristics as well as neurologic recovery. The 3 subgroups differed significantly in activity of daily living outcomes, with the short TTA group exhibiting higher Barthel Index raw discharge scores, score increases, and score efficiencies. CONCLUSIONS: Early rehabilitation seems to be a relevant prognostic factor of functional outcome. Rehabilitation intervention in patients with SCI should begin as soon as possible, in a specialized setting, because delay may adversely affect functional recovery.

Activities of Daily Living↗
PubMed2004

Recovery of forward stepping in spinal cord injured patients does not transfer to untrained backward stepping.

Six spinal cord injured (SCI) patients were trained to step on a treadmill with body-weight support for 1.5-3 months. At the end of training, foot motion recovered the shape and the step-by-step reproducibility that characterize normal gait. They were then asked to step backward on the treadmill belt that moved in the opposite direction relative to standard forward training. In contrast to healthy subjects, who can immediately reverse the direction of walking by time-reversing the kinematic waveforms, patients were unable to step backward. Similarly patients were unable to perform another untrained locomotor task, namely stepping in place on the idle treadmill. Two patients who were trained to step backward for 2-3 weeks were able to develop control of foot motion appropriate for this task. The results show that locomotor improvement does not transfer to untrained tasks, thus supporting the idea of task-dependent plasticity in human locomotor networks.

Adolescent↗
PubMed2004

Distributed plasticity of locomotor pattern generators in spinal cord injured patients.

Recent progress with spinal cord injured (SCI) patients indicates that with training they can recover some locomotor ability. Here we addressed the question of whether locomotor responses developed with training depend on re-activation of the normal motor patterns or whether they depend on learning new motor patterns. To this end we recorded detailed kinematic and EMG data in SCI patients trained to step on a treadmill with body-weight support (BWST), and in healthy subjects. We found that all patients could be trained to step with BWST in the laboratory conditions, but they used new coordinative strategies. Patients with more severe lesions used their arms and body to assist the leg movements via the biomechanical coupling of limb and body segments. In all patients, the phase-relationship of the angular motion of the different lower limb segments was very different from the control, as was the pattern of activity of most recorded muscles. Surprisingly, however, the new motor strategies were quite effective in generating foot motion that closely matched the normal in the laboratory conditions. With training, foot motion recovered the shape, the step-by-step reproducibility, and the two-thirds power relationship between curvature and velocity that characterize normal gait. We mapped the recorded patterns of muscle activity onto the approximate rostrocaudal location of motor neuron pools in the human spinal cord. The reconstructed spatiotemporal maps of motor neuron activity in SCI patients were quite different from those of healthy subjects. At the end of training, the locomotor network reorganized at both supralesional and sublesional levels, from the cervical to the sacral cord segments. We conclude that locomotor responses in SCI patients may not be subserved by changes localized to limited regions of the spinal cord, but may depend on a plastic redistribution of activity across most of the rostrocaudal extent of the spinal cord. Distributed plasticity underlies recovery of foot kinematics by generating new patterns of muscle activity that are motor equivalents of the normal ones.

Adolescent↗
PubMed2004

Neurologic recovery of spinal cord injury patients in Italy.

OBJECTIVE: To evaluate neurologic recovery of spinal cord lesion patients and its relationship to some lesion and patient features. DESIGN: Retrospective review of the charts. SETTING: Rehabilitation hospital in Italy. PARTICIPANTS: A total of 284 consecutive, newly injured patients were included with evaluation of lesion to admission time, etiology, lesion level, associated injury, medical complications and surgical intervention, length of stay, and American Spinal Injury Association (ASIA) impairment grade and motor scores. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: ASIA impairment grade and motor scores. RESULTS: Neurologic recovery was present in 27% of the patients. Most patients who improved and reached a functional status (ASIA class D) had an ASIA class C impairment at admission (71/129), versus ASIA class A (2/84) and ASIA class B (5/19). The lesion-to-admission interval was significantly longer in patients who did not improve (73+/-51.2d vs 47.2+/-38.4d, P=.006). CONCLUSIONS: ASIA impairment designations have prognostic value. Recovery from complete lesions was limited. Patients with ASIA class B impairment at admission had a better prognosis than those with ASIA class A. Patients with ASIA class C at admission had the best neurologic improvement. Finally, ASIA class D patients had lower ASIA grade improvement. Neurologic recovery was negatively associated with patients' age and delayed rehabilitation, but not by other lesion features.

Adolescent↗
PubMed2004

Sex-related differences of rehabilitation outcomes of spinal cord lesion patients.

OBJECTIVES: To evaluate sex-related differences of spinal cord lesion patients. PATIENTS: Two hundred and eighty-one patients were included with evaluation of: lesion to admission time, aetiology, lesion level, associated injury, medical complications and surgical intervention, length of stay, American Spinal Injury Association (ASIA) impairment and motor scores. MAIN OUTCOME MEASURES: ASIA impairment grade and ASIA motor scores; Barthel Index, Rivermead Mobility Index and Walking Index for Spinal Cord Injury. RESULTS: In the entire group female patients had a lower frequency of traumatic lesions, a lower frequency of complications at admission and a higher frequency of incomplete lesions (ASIA impairment C). In the matching cohorts comparison female patients showed the same neurological and functional recovery as male patients. CONCLUSION: Gender does not seems to influence spinal cord rehabilitation outcomes despite the fact that men and women showed significant epidemiological differences. Further studies are needed to evaluate some aspects such as long-term bladder management and complications.

Cohort Studies↗
PubMed2003

Temporal components of the motor patterns expressed by the human spinal cord reflect foot kinematics.

What are the building blocks with which the human spinal cord constructs the motor patterns of locomotion? In principle, they could correspond to each individual activity pattern in dozens of different muscles. Alternatively, there could exist a small set of constituent temporal components that are common to all activation patterns and reflect global kinematic goals. To address this issue, we studied patients with spinal injury trained to step on a treadmill with body weight support. Patients learned to produce foot kinematics similar to that of healthy subjects but with activity patterns of individual muscles generally different from the control group. Hidden in the muscle patterns, we found a basic set of five temporal components, whose flexible combination accounted for the wide range of muscle patterns recorded in both controls and patients. Furthermore, two of the components were systematically related to foot kinematics across different stepping speeds and loading conditions. We suggest that the components are related to control signals output by spinal pattern generators, normally under the influence of descending and afferent inputs.

Adult↗
PubMed2003

A new paradigm to analyze observational learning in rats.

A new paradigm of learning was developed through observational training in which rats repeatedly observed companion rats performing different spatial tasks. Observer animals were separately housed in small cages suspended over a water maze tank. They repeatedly observed companion actor rats performing spatial tasks differing according to the experimental requirements. After the observational training, observer animals were or not surgically hemicerebellectomized. This surgical ablation was performed to block any further acquisition of new behavioral strategies during actual performance of swimming task. When cerebellar symptomatology stabilized, observer animals were actually tested in the Morris Water Maze (MWM) task they had previously only observed. The observer rats displayed exploration abilities that closely matched the previously observed behaviors. The results obtained indicate that it is possible to learn complex behavioral strategies by observation using this new protocol. Furthermore, acquisition of the single facets that form the behavioral repertoire can be separately studied.

Animals↗
PubMed2003

Implicit learning deficit in children with developmental dyslexia.

Several neuropsychological deficits have been reported as characteristic of the cognitive profile of dyslexic children. Phonological and visual processing are often impaired as well as auditory processing, attention and information processing speed. We investigated whether implicit learning, is impaired in dyslexic children and adolescents. Tests of implicit and declarative learning were administered to 18 clinically defined dyslexics and 18 similar age controls. Dyslexics showed a reduced learning rate in the implicit but not in the declarative task, suggesting a specific deficit of implicit learning. Although alternative hypothesis cannot be ruled out, considering that implicit learning is a cognitive function primarily processed by the cerebellum and that recent neurological and physiological data suggest a cerebellar dysfunction in dyslexia, the present results suggest an impairment of cerebellar system in reading disabilities.

Analysis of Variance↗
PubMed2003

Watch how to do it! New advances in learning by observation.

Recent data demonstrate that the cerebellum contributes to the internal representation of action. This representation is used not only to generate motor actions, but also to understand and learn the actions and skills of others by imitation. The cerebellar networks appear to be indispensable for acquiring complex behaviors and procedures. The cerebellar role in the acquisition of procedural competencies is particularly evident in spatial information processing. The cerebellum allows acquiring by observation competencies in exploration behaviors as efficient as the competencies acquired by actually performing the same task. The specificity of the cerebellar role in the acquisition phases of learning by observation is demonstrated by the complete absence of spatial learning when the observational training is performed in presence of a cerebellar lesion. This datum is further corroborated by the evidence that, once acquired, spatial procedures can be efficiently performed even in the presence of cerebellar damage, in agreement with the neuroimaging findings of low cerebellar activation after prolonged practice. The finding that the cerebellum is involved in procedural acquisition and in observational learning allowed us to dissect a complex behavior into single behavioral units forming a complete procedural sequence, demonstrating that such behavioral units do exist and can be independently acquired.

Animals↗
PubMed2003

Neurobiology of rhythmic motor entrainment.

Timing is extremely important for movement, and understanding the neurobiological basis of rhythm perception and reproduction can be helpful in addressing motor recovery after brain lesions. In this quest, the science of music might provide interesting hints for better understanding the brain timing mechanism. The report focuses on the neurobiological substrate of sensorimotor transformation of time data, highlighting the power of auditory rhythmic stimuli in guiding motor acts. The cerebellar role of timing is addressed in subjects with cerebellar damage; subsequently, cerebellar timing processing is highlighted through an fMRI study of professional musicians. The two approaches converge to demonstrate that different levels of time processing exist, one conscious and one not, and to support the idea that timing is a distributed function. The hypothesis that unconscious motor responses to auditory rhythmic stimuli can be relevant in guiding motor recovery and modulating music perception is advanced and discussed.

Auditory Perception↗
PubMed2002

Cerebellar input to the posterior parietal cortex in the rat.

The cerebello-thalamo-parietal projections were investigated in rats by means of a multiple anterograde-retrograde tracing technique. Retrograde fluorescent tracers were injected in different loci of the parietal cortex. Injected areas were verified cytoarchitectonically and confirmed by analyzing the retrograde thalamic labeling pattern obtained. Anterograde fluorescent tracers were placed in the intermediate and lateral deep cerebellar nuclei. The topographical overlap between cerebellar terminals and parietal-projecting thalamic neurons was analyzed. In the central lateral (CL) and ventrolateral (VL) thalamic nuclei, cells projecting to anterior somatosensory (S1) and posterior parietal (PPC) cortices were demonstrated to receive direct cerebellar input. In particular, two patterns of organization were revealed. In CL, the PPC- and S1-projecting neurons, both receiving cerebellar fibers, were intermingled. In VL, PPC, and S1-projecting neurons were instead segregated, and the areas containing labeled neurons received separate contingents of cerebellar fibers. These patterns suggest that in CL axons originating from the same or neighboring cerebellar neurons can terminate on both PPC- and S1-projecting neurons, while in VL cerebellar information is funneled to S1 and PPC through two segregated parallel pathways. The significance of the observed organization is discussed comparing findings in other species and in relation with electrophysiological and functional studies on cerebelloparietal interrelationships.

Animals↗