Biomedical subjects

Abbas F Sadikot

Publications and source records attributed to Abbas F Sadikot.

At least 19 recordsLinked to original sources

PubMed2006

Bradykinesia in patients with essential tremor.

We compared the level of bradykinesia during rapid alternating movements (RAM) in patients with essential tremor (ET) with that of patients with Parkinson's disease (PD) having either the "tremor dominant" or "akinetic-rigid" form of PD, and 10 healthy controls. We found an increase of pronation-supination cycle duration in the PD and ET group, suggestive of bradykinesia. RAM range was, however, similar between groups. The akinetic-rigid group showed a distinct increase in RAM amplitude fluctuation, suggesting that rigidity modified the characteristics of the observed bradykinesia. In conclusion, slow movements should then be considered as part of the ET symptomatology.

Adult↗

PubMed2006

The neural response to transcranial magnetic stimulation of the human motor cortex. II. Thalamocortical contributions.

Beta oscillations (15-30 Hz) constitute an important electrophysiological signal recorded in the resting state over the human precentral gyrus. The brain circuitry involved in generating the beta oscillations is not well understood but appears to involve both cortical and subcortical structures. We have shown that single pulses of transcranial magnetic stimulation (TMS) applied over the primary motor cortex consistently elicit a brief beta oscillation. Reducing the local cortical excitability using low-frequency repetitive TMS does not change the amplitude of the induced beta oscillation (Van Der Werf and Paus in Exp Brain Res DOI 10.1007/s00221-006-0551-2). Here, we investigated the possible involvement of the thalamus in the cortically expressed beta response to single-pulse TMS. We included eight patients with Parkinson's disease who had undergone unilateral surgical lesioning of the ventrolateral nucleus of the thalamus. We administered 50 single pulses of TMS, at an intensity of 120% of resting motor threshold, over the left and right primary motor cortex and, at the same time, recorded the electroencephalogram (EEG) using a 60-electrode cap. We were able to perform analyses on seven EEG data sets and found that stimulation of the unoperated hemisphere (with thalamus) resulted in higher amplitudes of the single-trial induced beta oscillations than in the operated hemisphere (with thalamotomy). The beta oscillation obtained in response to pulses applied over the unoperated hemisphere was also higher than that obtained in healthy controls. We suggest that (1) the beta oscillatory response to pulses of TMS applied over the primary motor cortex is higher in Parkinson's disease patients, (2) thalamotomy serves to reduce the abnormally high TMS-induced beta oscillations, and (3) the motor thalamus facilitates the cortically generated oscillation, through cortico-subcortico-cortical feedback loops.

Aged↗

PubMed2006

The creation of a brain atlas for image guided neurosurgery using serial histological data.

Digital and print brain atlases have been used with success to help in the planning of neurosurgical interventions. In this paper, a technique presented for the creation of a brain atlas of the basal ganglia and the thalamus derived from serial histological data. Photographs of coronal histological sections were digitized and anatomical structures were manually segmented. A slice-to-slice nonlinear registration technique was used to correct for spatial distortions introduced into the histological data set at the time of acquisition. Since the histological data were acquired without any anatomical reference (e.g., block-face imaging, post-mortem MRI), this registration technique was optimized to use an error metric which calculates a nonlinear transformation minimizing the mean distance between the segmented contours between adjacent pairs of slices in the data set. A voxel-by-voxel intensity correction field was also estimated for each slice to correct for lighting and staining inhomogeneity. The reconstructed three-dimensional (3D) histological volume can be viewed in transverse and sagittal directions in addition to the original coronal. Nonlinear transformations used to correct for spatial distortions of the histological data were applied to the segmented structure contours. These contours were then tessellated to create three-dimensional geometric objects representing the different anatomic regions in register with the histological volumes. This yields two alternate representations (one histological and one geometric) of the atlas. To register the atlas to a standard reference MR volume created from the average of 27 T1-weighted MR volumes, a pseudo-MRI was created by setting the intensity of each anatomical region defined in the geometric atlas to match the intensity of the corresponding region of the reference MR volume. This allowed the estimation of a 3D nonlinear transformation using a correlation based registration scheme to fit the atlas to the reference MRI. The result of this procedure is a contiguous 3D histological volume, a set of 3D objects defining the basal ganglia and thalamus, both of which are registered to a standard MRI data set, for use for neurosurgical planning.

Algorithms↗

PubMed2005

The impact of ventrolateral thalamotomy on tremor and voluntary motor behavior in patients with Parkinson's disease.

A preferred target for parkinsonian tremor alleviation is the ventrolateral (VL) thalamus. The goal of the present study is to determine how lesions involving the presumed cerebellar and pallidal recipient areas of the "motor" thalamus would alter the tremor and motor behavior of ten patients with Parkinson's disease (PD). Tremor amplitude, power dispersion (a measure of sharpness of the power spectrum of tremor), and power distribution were quantified using a laser displacement sensor prior to, and a week after, VL thalamotomy. As well, the impact of surgery on tremor seen during movement was quantified in a manual-tracking (MT) task. Tremor-induced noise (a measure of the amount of tremor present during movement) and ERROR (difference between subject's performance and target) were quantified. Finally, bradykinesia was assessed with a rapid alternating movement (RAM) task. Duration, range, and amplitude irregularity of wrist pronation-supination cycles were computed. Both motor tasks were quantified using a highly sensitive forearm rotational sensor. Healthy age-matched control subjects were also tested. Magnetic resonance images with an integrated atlas of thalamic nuclei were used to confirm lesion location. Results show that the lesions were centered upon the posterior portion of the ventral lateral (VLp) nucleus of the thalamus, included the posterior part of the ventral lateral anterior nucleus (VLa), and extended posteriorly to encroach upon the most rostral sector of the sensory ventral posterior nucleus (VPLa). VL thalamotomy significantly decreased tremor amplitude in all cases. Power dispersion was increased significantly so that it became similar to that of control subjects. Changes in power distribution indicate that thalamotomy selectively targeted PD tremor oscillations. Tremor detected during the MT task was also markedly decreased, becoming similar to that of controls. Patients also showed significant decrease in ERROR during MT. RAM duration and range were not significantly modified by the surgery, and patients' performance remained impaired compared to healthy control subjects. Collectively, these results suggest that lesions involving the presumed "cerebellar" and "pallidal" recipient sectors of the motor thalamus do not worsen bradykinesia, suggesting that neural circuits other than the pallido-thalamo-cortical loop may be involved in slowness of movement in PD. A review of alternate pathways is presented.

Aged↗

PubMed2005

Flow-based fiber tracking with diffusion tensor and q-ball data: validation and comparison to principal diffusion direction techniques.

In this study, we evaluate the performance of a flow-based surface evolution fiber tracking algorithm by means of a physical anisotropic diffusion phantom with known connectivity. We introduce a novel speed function for surface evolution that is derived from either diffusion tensor (DT) data, high angular resolution diffusion (HARD) data, or a combined DT-HARD hybrid approach. We use the model-free q-ball imaging (QBI) approach for HARD reconstruction. The anisotropic diffusion phantom allows us to compare and evaluate the performance of different fiber tracking approaches in the presence of real imaging artifacts, noise, and subvoxel partial volume averaging of fiber directions. The surface evolution approach, using the full diffusion tensor as opposed to the principal diffusion direction (PDD) only, is compared to PDD-based line propagation fiber tracking. Additionally, DT reconstruction is compared to HARD reconstruction for fiber tracking, both using surface evolution. We show the potential for surface evolution using the full diffusion tensor to map connections in regions of subvoxel partial volume averaging of fiber directions, which can be difficult to map with PDD-based methods. We then show that the fiber tracking results can be improved by using high angular resolution reconstruction of the diffusion orientation distribution function in cases where the diffusion tensor model fits the data poorly.

Algorithms↗

PubMed2005

Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease.

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo.

Aged↗

PubMed2005

The impact of ventrolateral thalamotomy on high-frequency components of tremor.

OBJECTIVE: The present study assessed the impact of ventrolateral (VL) thalamotomy on the high-frequency components of tremor in patients with Parkinson's disease (PD). METHODS: Tremor was recorded prior to, and 7 days post-surgery using a laser displacement sensor. In addition, tremor was recorded in 10 age-matched patients with PD showing low amplitude tremor (named PD controls) and in 10 age-matched control subjects. Tremor recordings in patients were performed after a 12h withdrawal from anti-Parkinsonian drugs. Tremor characteristics such as amplitude, median power frequency (MPF) and power dispersion (a measure of concentration of power in the frequency domain) were assessed for all groups (i.e. controls, PD controls, pre-surgery and post-surgery). RESULTS: All tremor characteristics were similar between controls and PD controls. Tremor amplitude was significantly reduced post-surgery, to become statistically similar to that of controls and PD controls. However, MPF and power dispersion remained lower post-surgery, indicating that although there was normalization of tremor amplitude, tremor showed systematically slower oscillations after the surgical procedure. In order to eliminate amplitude as a possible confounding factor, epochs of post-surgical tremor (5s in duration) were paired for equal amplitude with 5s tremor epochs from matched controls. Results show once again that MPF and power dispersion were lower post-surgery compared to controls. In addition, when amplitude of power was compared within specific frequency bands (0-3.5, 3.5-7.5, 7.5-12.5, 12.5-16.5, 16.5-30 and 30-45), power regained normal values at frequencies below 7.5 Hz. Power within higher frequency bands was systematically lower, indicating that the surgical procedure had an impact on high-frequency components of tremor. CONCLUSIONS: Results from the present study showed that VL thalamotomy reduced tremor amplitude by selectively targeting centrally driven components of PD tremor. The high-frequency component of physiological tremor failed to emerge after amplitude normalization. SIGNIFICANCE: The thalamus should then be considered as an important component of the generation and/or propagation of high-frequency components of physiological tremor.

Adult↗

PubMed2005

Anatomical and electrophysiological validation of an atlas for neurosurgical planning.

Digital brain atlases can be used in conjunction with magnetic resonance imaging (MRI) and computed tomography (CT) for planning and guidance during neurosurgery. Digital atlases are advantageous, since they can be warped nonlinearly to fit each patient's unique anatomy. Two atlas-to-patient warping techniques are compared in this paper. The first technique uses an MRI template as an intermediary to estimate a nonlinear atlas-to-patient transformation. The second, is novel, and uses a pseudo-MRI volume, derived from the voxel-label-atlas, to estimate the atlas-to-patient transformation directly. Manual segmentations and functional data are used to validate the two methods.

Brain↗

PubMed2004

Morphine-induced changes in delta opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord.

An in vivo fluorescent deltorphin (Fluo-DLT) internalization assay was used to assess the distribution and regulation of pharmacologically available delta opioid receptors (deltaORs) in the rat lumbar (L4-5) spinal cord. Under basal conditions, intrathecal injection of Fluo-DLT resulted in the labeling of numerous deltaOR-internalizing neurons throughout dorsal and ventral horns. The distribution and number of Fluo-DLT-labeled perikaryal profiles were consistent with that of deltaOR-expressing neurons, as revealed by in situ hybridization and immunohistochemistry, suggesting that a large proportion of these cells was responsive to intrathecally administered deltaOR agonists. Pretreatment of rats with morphine for 48 hr resulted in a selective increase in Fluo-DLT-labeled perikaryal profiles within the dorsal horn. These changes were not accompanied by corresponding augmentations in either deltaOR mRNA or (125)I-deltorphin-II binding levels, suggesting that they were attributable to higher densities of cell surface deltaOR available for internalization rather than to enhanced production of the receptor. Unilateral dorsal rhizotomy also resulted in increased Fluo-DLT internalization in the ipsilateral dorsal horn when compared with the side contralateral to the deafferentation or to non-deafferented controls, suggesting that deltaOR trafficking in dorsal horn neurons may be regulated by afferent inputs. Furthermore, morphine treatment no longer increased Fluo-DLT internalization on either side of the spinal cord after unilateral dorsal rhizotomy, indicating that microOR-induced changes in the cell surface availability of deltaOR depend on the integrity of primary afferent inputs. Together, these results suggest that regulation of deltaOR responsiveness through microOR activation in this region is linked to somatosensory information processing.

Animals↗

PubMed2004

Neurogenesis and stereological morphometry of calretinin-immunoreactive GABAergic interneurons of the neostriatum.

We determined the neurogenesis characteristics of a distinct subclass of rat striatum gamma-aminobutyric acidergic (GABAergic) interneurons expressing the calcium-binding protein calretinin (CR). Timed-pregnant rats were given an intraperitoneal injection of 5-bromo-2'-deoxyuridine (BrdU), a marker of cell proliferation, on designated days between embryonic day 12 (E12) and E21. CR-immunoreactive (-IR) neurons and BrdU-positive nuclei were labeled in the adult neostriatum by double immunohistochemistry, and the proportion of double-labeled cells was quantified. CR-IR interneurons of the neostriatum show maximum birth rates (>10% double labeling) between E14 and E17, with a peak at E15. CR-IR interneurons occupying the lateral half of the neostriatum become postmitotic prior to medial neurons. In the precomissural neostriatum, the earliest-born neurons occupy the lateral quadrants and the latest-born neurons occupy the dorsomedial sector. No significant rostrocaudal neurogenesis gradient is observed. CR-IR neurons make up 0.5% of the striatal population and are localized in both the patch and the matrix compartments. CR-IR neurons of the patch compartment are born early (E13-15), with later-born neurons (E16-18) populating mainly the matrix compartment. CR-IR cells of the neostriatum are a distinct subclass of interneurons that are born at an intermediate time during striatal development and share common neurogenesis characteristics with other interneurons and projection neurons produced in the ventral telencephalon.

Age Factors↗

PubMed2004

Transcranial magnetic stimulation of the human motor cortex influences the neuronal activity of subthalamic nucleus.

The critical role of the subthalamic nucleus (STN) in the control of movement and parkinsonian symptoms is well established. Research in animals suggests that the cerebral cortex plays an important role in regulating the activity of the STN but this control is not known in humans. The most extensive cortical innervation of the STN originates from motor areas. Here, we used transcranial magnetic stimulation (TMS) during intraoperative single-unit recordings from STN, in six patients with Parkinson's disease (PD) undergoing implantation of deep brain stimulators, to determine whether TMS of the motor cortex (MC) modulates the activity of STN and to investigate in vivo the functional organization of the corticosubthalamic circuit in the human brain. Single-pulse TMS of the MC induced an excitation in 74.9% of neurons investigated. This activation was followed by a long-lasting inhibition of the STN neuronal activity that did not correlate with PD severity. Responsive neurons to TMS of the hand area of motor cortex were located mainly in the lateral and dorsal region of the subthalamus while unresponsive cells had a prevalently medial distribution. This is the first report of TMS-induced modulation of STN neuronal activity in humans. These findings open up new avenues for in vivo studies of corticosubthalamic interactions in human brain and PD.

Action Potentials↗

PubMed2003

The detection of tremor during slow alternating movements performed by patients with early Parkinson's disease.

The present study demonstrates that tremor can be detected during slow alternating movements (SAM) performed by patients with early Parkinson's disease (PD) and that its relative amplitude is strongly correlated with patients' rest and postural hand tremor amplitudes (Rho=0.80 and 0.61, respectively, P<0.05). However, the tremor detected during SAM did not influence the accuracy of patients because of its relatively low amplitude. These results imply that the presence of tremor during movement is not restricted to advanced PD, but can also be detected in patients with early PD having relatively low amplitude tremor. Evidence that the tremor detected at rest, during posture and during voluntary movement share similar or overlapping neural substrates is also presented.

Age of Onset↗

PubMed2003

Subthalamic deep brain stimulation does not induce striatal dopamine release in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN) is an increasingly prevalent treatment for advanced Parkinson's disease (PD). Its main mechanism of action is thought to be a reduction in the inhibitory outflow from basal ganglia to cerebral cortex. However, recent animal experiments have led to the suggestion that high frequency stimulation of the STN also acts by promoting dopamine release. We tested this hypothesis by performing [11C]raclopride PET on and off stimulation in six patients with PD and implanted STN stimulators. There was no difference in tracer binding in the striatum between the two testing conditions. We conclude that high frequency stimulation of the STN does not act by increasing dopamine release.

Aged↗

PubMed2003

Cerebral blood flow changes induced by subthalamic stimulation in Parkinson's disease.

The authors used PET to show that the abnormal pattern of cerebral blood flow (CBF) activation described in PD is normalized by electrical stimulation of subthalamic nucleus. Improvement in bradykinesia correlated with increase in CBF due to stimulation in the supplementary motor area and anterior cingulate cortex. Compared to unilateral stimulation, bilateral stimulation induced a greater extent of activation in bilateral cortical areas and additional bilateral activation of globus pallidus.

Brain↗

PubMed2003

Glutamate promotes proliferation of striatal neuronal progenitors by an NMDA receptor-mediated mechanism.

Increasing evidence suggests that classical neurotransmitters play important roles in the development of the mammalian CNS. We used in vivo and in vitro models to identify a novel role for glutamate in striatal neurogenesis mediated by NMDA receptors. In utero exposure to NMDA receptor antagonists during striatal neurogenesis caused a dramatic reduction in the total number of adult striatal neurons. In contrast, embryos exposed to NMDA receptor antagonists immediately after the main period of neurogenesis showed no significant change in neuronal number in the adult striatum. In addition, examination of embryos shortly after NMDA receptor blockade revealed reduced proliferation in the lateral ganglionic eminence (LGE). In culture, dividing neuronal progenitors derived from the embryonic LGE showed marked reduction in 5'-bromodeoxyuridine (BrdU) uptake when exposed to NMDA receptor antagonists, indicating reduced DNA synthesis. Low concentrations of NMDA significantly increased proliferation, whereas high concentrations were toxic. AMPA-KA receptor antagonists had no significant effect on striatal neuroblast proliferation either in vivo or in vitro. These results support the hypothesis that glutamate plays a novel role during early development of the ventral telencephalon, promoting proliferation of striatal neuronal progenitors by an NMDA receptor-dependent mechanism. In contrast, previous findings suggest that proliferation of cortical progenitors derived from the dorsal telencephalon is regulated by activation of AMPA-KA but not NMDA receptors. Heterogeneous responses to glutamate in different germinal zones of the telencephalon may be an important mechanism contributing to generating neuronal diversity in the forebrain.

Animals↗

PubMed2003

Three-dimensional database of subcortical electrophysiology for image-guided stereotactic functional neurosurgery.

We present a method of constructing a database of intraoperatively observed human subcortical electrophysiology. In this approach, patient electrophysiological data are standardized using a multiparameter coding system, annotated to their respective magnetic resonance images (MRIs), and nonlinearly registered to a high-resolution MRI reference brain. Once registered, we are able to demonstrate clustering of like interpatient physiologic responses within the thalamus, globus pallidus, subthalamic nucleus, and adjacent structures. These data may in turn be registered to a three-dimensional patient MRI within our image-guided visualization program enabling prior to surgery the delineation of surgical targets, anatomy with high probability of containing specific cell types, and functional borders. The functional data were obtained from 88 patients (106 procedures) via microelectrode recording and electrical stimulation performed during stereotactic neurosurgery at the London Health Sciences Centre. Advantages of this method include the use of nonlinear registration to accommodate for interpatient anatomical variability and the avoidance of digitized versions of printed atlases of anatomy as a common database coordinate system. The resulting database is expandable, easily searched using a graphical user interface, and provides a visual representation of functional organization within the deep brain.

Brain↗

PubMed2003

Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons.

Mesencephalic dopaminergic (MesDA) neurons play crucial roles in motor and behavioral processes; their loss in Parkinson's disease (PD) results in striatal dopamine (DA) deficiency and hypokinetic movement disorder. The Pitx3 homeobox gene is expressed in the MesDA system. We now show that only a subset of MesDA neurons express Pitx3 and that in Pitx3-deficient aphakia mice, this subset is progressively lost by apoptosis during fetal (substantia nigra, SN) and postnatal (ventral tegmental area) development, resulting in very low striatal DA and akinesia. Similar to human PD, dorsal SN neurons (which are Pitx3 negative) are spared in mutant mice. Thus, Pitx3 defines a pathway for survival of neurons that are implicated in PD and that are required for spontaneous locomotor activity.

Animals↗

PubMed2002

p73 is required for survival and maintenance of CNS neurons.

Here, we show that the p53 family member, p73, is necessary for survival and long-term maintenance of CNS neurons, including postnatal cortical neurons. In p73-/- animals, cortical neuron number is normal at birth but decreases significantly by postnatal day 14 (P14)-P16 because of enhanced apoptosis. This decrease continues into adulthood, when p73-/- animals have approximately one-half as many cortical cells as their wild-type littermates. Cortical neurons express the DeltaNp73alpha protein, and overexpression of DeltaNp73 isoforms rescues cortical neurons from diverse apoptotic stimuli. Thus, DeltaNp73 isoforms are survival proteins in cortical neurons, and their deletion causes a gradual loss of cortical neurons in the weeks and months after birth. This decrease in CNS neuron number in p73-/- animals is not limited to the cortex; facial motor neuron number is decreased, and postnatal development of the olfactory bulb is greatly perturbed. These findings, together with our previous work showing that DeltaNp73 is essential for survival of peripheral sympathetic neurons (Pozniak et al., 2000), indicate that p73 isoforms are essential survival proteins in CNS as well as PNS neurons, and that they likely play a role not only during developmental cell death but also in the long-term maintenance of at least some adult neurons.

Animals↗