Esteban A. Fridman

Detection of Helicobacter pylori in Human Carotid Atherosclerotic Plaques

Background and Purpose — Several lines of evidence point toward a relationship between infection and atherosclerotic vascular disease. Thus, infection and inflammation often precede ischemic neurological events. Transient alterations in coagulation and direct arterial invasion by certain microorganisms have been reported. Helicobacter pylori infection is the major cause of peptic ulcer disease and appears to be a risk factor for ischemic cerebrovascular disease. However, in contrast to other chronic infectious agents, H pylori has not been consistently isolated from atherosclerotic lesions. Methods — We investigated the presence of H pylori in 38 atherosclerotic plaques obtained at carotid endarterectomy by using morphological and immunohistochemical techniques and a highly sensitive polymerase chain reaction method. We performed immunohistochemical detection of intercellular adhesion molecule-1, a marker related to inflammatory cell response. We also examined 7 carotid arteries obtained at autopsy from subjects without carotid atherosclerosis. Results — H pylori DNA was found in 20 of 38 atherosclerotic plaques. Ten of the H pylori DNA–positive plaques also showed morphological and immunohistochemical evidence of H pylori infection. None of 7 normal carotid arteries was positive for H pylori. Intercellular adhesion molecule-1 was expressed in 75% of H pylori–positive plaques and in 22% of H pylori–negative plaques. The presence of the microorganism was associated with male sex but was independent of age, vascular risk factor profile, and prior neurological symptoms. Conclusions — H pylori is present in a substantial number of carotid atherosclerotic lesions and is associated with features of inflammatory cell response. This study provides additional evidence of the relationship between H pylori infection and atherosclerotic disease.

The role of the dorsal stream for gesture production

Skilled gestures require the integrity of the neural networks involved in storage, retrieval, and execution of motor programs. Premotor cortex and/or parietal cortex lesions frequently produce deficits during performance of gestures, transitive more than intransitive. The dorsal stream links object information with object action, suggesting that mechanical knowledge of tool use is stored focally in the brain. Using event-related fMRI, we explored activity during instructed-delay transitive and intransitive hand gestures. The comparison between planning-preparation and execution of gestures demonstrated a temporal rostral to caudal gradient of activation in the ventral premotor cortex (PMv) and inferior to superior gradient of activation in the posterior parietal cortex (PPc). Comparison between transitive and intransitive gestures established a functional specificity within the dorsal stream for mechanical knowledge. Results demonstrate that not only PPc but also the PMv acts in the processing of sensorimotor information during gestures. This might be the substrate underlying selective deficits in ideomotor apraxia patients.

The neural substrate of gesture recognition

Previous studies have linked action recognition with a particular pool of neurons located in the ventral premotor cortex, the posterior parietal cortex and the superior temporal sulcus (the mirror neuron system). However, it is still unclear if transitive and intransitive gestures share the same neural substrates during action-recognition processes. In the present study, we used event-related functional magnetic resonance imaging (fMRI) to assess the cortical areas active during recognition of pantomimed transitive actions, intransitive gestures, and meaningless control actions. Perception of all types of gestures engaged the right pre-supplementary motor area (pre-SMA), and bilaterally in the posterior superior temporal cortex, the posterior parietal cortex, occipitotemporal regions and visual cortices. Activation of the posterior superior temporal sulcus/superior temporal gyrus region was found in both hemispheres during recognition of transitive and intransitive gestures, and in the right hemisphere during the control condition; the middle temporal gyrus showed activation in the left hemisphere when subjects recognized transitive and intransitive gestures; activation of the left inferior parietal lobe and intraparietal sulcus (IPS) was mainly observed in the left hemisphere during recognition of the three conditions. The most striking finding was the greater activation of the left inferior frontal gyrus (IFG) during recognition of intransitive actions. Results show that a similar neural substrate, albeit, with a distinct engagement underlies the cognitive processing of transitive and intransitive gestures recognition. These findings suggest that selective disruptions in these circuits may lead to distinct clinical deficits.

Synchronization of parietal and premotor areas during preparation and execution of praxis hand movements

OBJECTIVE We sought to determine temporal patterns of functional connectivity between the parietal, premotor, and motor cortices during preparation and execution of praxis hand movements. METHODS Normal subjects were instructed to perform six transitive (tool use) and intransitive (communicative gesture) self-paced pantomimes with the right hand while recording 64-channel electroencephalography (EEG) and electromyography (EMG) from right thumb and forearm flexors. Focusing on corticocortical coherence, we explored the time-course of synchronously active parietal and premotor circuits involved in these motor tasks. Trials were marked for EMG onset and averaged across subjects to determine changes in coherence relative to baseline between parietal, premotor, and motor areas. RESULTS Coherence of homologous electrode pairs was similar when comparing transitive and intransitive movements. During preparation, beta band (18-22 Hz) coherence was maximal between electrodes over the left parietal lobe and left premotor electrodes. Additionally during preparation, the premotor area showed high coherence to the motor hand area and the parietal cortex. Electrodes over the supplementary motor area also showed coherence to the motor and parietal, but not the premotor area. Before and during execution, a second peak of high coherence increase was present in each area that demonstrated coherence increases during preparation. There was no coherence increase between parietal and motor areas. Coherence rapidly diminished 1.5-2.0 s after movement onset. CONCLUSIONS Patterns of increased corticocortical coupling within a parietal, premotor, and motor network are present during preparation and execution of praxis movements. SIGNIFICANCE This study adds to evidence that parietofrontal networks may be critical for integrating preparatory and motor-related activity for praxis movements.

Preservation of electroencephalographic organization in patients with impaired consciousness and imaging‐based evidence of command‐following

Standard clinical characterization of patients with disorders of consciousness (DOC) relies on observation of motor output and may therefore lead to the misdiagnosis of vegetative state or minimally conscious state in patients with preserved cognition. We used conventional electroencephalographic (EEG) measures to assess a cohort of DOC patients with and without functional magnetic resonance imaging (fMRI)‐based evidence of command‐following, and correlated the findings with standard clinical behavioral evaluation and brain metabolic activity.

Gesture Subtype-Dependent Left Lateralization of Praxis Planning: An Event-Related fMRI Study.

Ideomotor apraxia is a disorder mainly of praxis planning, and the deficit is typically more evident in pantomiming transitive (tool related) than intransitive (communicative) gestures. The goal of the present study was to assess differential hemispheric lateralization of praxis production using event-related functional magnetic resonance imaging. Voxel-based analysis demonstrated significant activations in posterior parietal cortex (PPC) and premotor cortex (PMC) association areas, which were predominantly left hemispheric, regardless of whether planning occurred for right or left hand transitive or intransitive pantomimes. Furthermore, region of interest-based calculation of mean laterality index (LI) revealed a significantly stronger left lateralization in PPC/PMC clusters for planning intransitive (LI = -0.49 + 0.10, mean + standard deviation [SD]) than transitive gestures (-0.37 + 0.08, P = 0.02, paired t-tests) irrespective of the hand involved. This differential left lateralization for planning remained significant in PMC (LI = -0.47 + 0.14 and -0.36 + 0.13, mean + SD, P = 0.04), but not in PPC (-0.56 + 0.11 and -0.45 + 0.12, P = 0.11), when both regions were analyzed separately. In conclusion, the findings point to a left-hemispheric specialization for praxis planning, being more pronounced for intransitive gestures in PMC, possibly due to their communicative nature.

Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain

Significance Establishing consciousness in the human brain requires an ensemble activity of multiple cortical and subcortical structures. Following severe brain injuries, widespread deafferentation and neuronal death alter function across the corticothalamic system and its projections to the basal ganglia. In this paper, we test a theoretical model of a mesocircuit mechanism likely to arise in all severe brain injuries. Specifically, reduction of resting glucose metabolism within the central thalamus, striatum, and frontoparietal cortices and concomitant increases in metabolism within the globus pallidus as a result of disinhibition are proposed to arise across etiologies of injury. Here we verify this prediction and demonstrate a reversal of metabolic profile of central thalamus and globus pallidus that characterizes and indexes the patients’ behavioral level. Although disorders of consciousness (DOCs) demonstrate widely varying clinical presentations and patterns of structural injury, global down-regulation and bilateral reductions in metabolism of the thalamus and frontoparietal network are consistent findings. We test the hypothesis that global reductions of background synaptic activity in DOCs will associate with changes in the pattern of metabolic activity in the central thalamus and globus pallidus. We compared 32 [18F]fluorodeoxyglucose PETs obtained from severely brain-injured patients (BIs) and 10 normal volunteers (NVs). We defined components of the anterior forebrain mesocircuit on high-resolution T1-MRI (ventral, associative, and sensorimotor striatum; globus pallidus; central thalamus and noncentral thalamus). Metabolic profiles for BI and NV demonstrated distinct changes in the pattern of uptake: ventral and association striatum (but not sensorimotor) were significantly reduced relative to global mean uptake after BI; a relative increase in globus pallidus metabolism was evident in BI subjects who also showed a relative reduction of metabolism in the central thalamus. The reversal of globus pallidus and central thalamus profiles across BIs and NVs supports the mesocircuit hypothesis that broad functional (or anatomic) deafferentation may combine to reduce central thalamus activity and release globus pallidus activity in DOCs. In addition, BI subjects showed broad frontoparietal metabolic down-regulation consistent with prior studies supporting the link between central thalamic/pallidal metabolism and down-regulation of the frontoparietal network. Recovery of left hemisphere frontoparietal metabolic activity was further associated with command following.

Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury

Background: The prognosis of long-term severe disorders of consciousness due to traumatic brain injury is discouraging. There is little definitive evidence of the underlying mechanisms, but a deficiency of the dopaminergic system may be involved. Methods: In a prospective open-labelled clinical study, the feasibility, relative efficacy and safety of continuous subcutaneous (s.c.) administration of apomorphine in Vegetative State (VS) or Minimally Conscious State (MCS) patients due to severe traumatic brain injury (TBI) was tested. Apomorphine was administered to eight patients. Outcome measures were the Coma Near-Coma Scale (CNCS) and Disability Rating Scale (DRS). Results: Drug management was implemented without any problems. There was improvement in the primary outcomes for all patients. Awakening was seen as rapidly as within the first 24 hours of drug administration and as late as 4 weeks. Seven of the patients had completely recovered consciousness. All improvements were sustained for at least 1 year, even after apomorphine was discontinued. Drug-related adverse events were all anticipated and resolved after the dose was reduced. Conclusion: Based on this open-label pilot study, continuous s.c. apomorphine infusion appears to be feasible, safe and potentially effective in improving consciousness in patients in VS and MCS due to severe TBI.

Cortico-cortical networks in patients with ideomotor apraxia as revealed by EEG coherence analysis.

We sought to determine whether coherent networks which circumvent lesioned cortex are seen in patients with ideomotor apraxia (IMA) while performing tool-use pantomimes. Five normal subjects and five patients with IMA (three patients with corticobasal degeneration and two with left hemisphere stroke) underwent 64-channel EEG recording while performing three tool-use pantomimes with their left hand in a self-paced manner. Beta band (20-22 Hz) coherence indicates that normal subjects have a dominant left hemisphere network responsible for praxis preparation, which was absent in patients. Corticobasal degeneration patients showed significant coherence increase between left parietal-right premotor areas. Left hemisphere stroke patients showed significant coherence increases in a right parietofrontal network. The right hemisphere appears to store useable praxis representations in IMA patients with left hemisphere damage.

Fast awakening from minimally conscious state with apomorphine

Background: Traumatic brain injury (TBI) can induce long-term severe disorders of consciousness. Evidence suggests an underlying dopaminergic deficit. Dopamine agonists may therefore play an important role in recovery of consciousness. Objective: To explore the response to continuous subcutaneous administration of apomorphine in a patient who had remained in minimally conscious state for 104 days and to evaluate the anatomical substrate of the effect. Design: A prospective, open-label, daily treatment, dose-escalation single case clinical study, with retrospective diffusion tensor image (DTI) evaluation. Results: On the fist day of treatment, the patient was able to move his limbs on command and answer yes/no questions which had not been the case prior to apomorphine administration. Subsequently there was a full recovery of consciousness and substantial functional recovery that was sustained even after apomorphine discontinuation. At the highest dose, mild dyskinesias were observed. These resolved with a lowering of the dose. DTI demonstrated a decrease of thalamocortical and corticothalamic projections in this MCS patient compared to normal volunteers. Conclusion: Although this is an open-label single-patient case report, the data are consistent with the theory that a dopaminergic deficit underlies MCS and that it may be overcome with apomorphine administration.