Abbas F. Sadikot

Serotonin4 (5-HT4) Receptor Agonists Are Putative Antidepressants with a Rapid Onset of Action

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

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.

Fractionated stereotactic radiation therapy for intracranial tumors.

In stereotactic radio surgery, a single, large dose of radiation is delivered to a small, well‐defined, stereotactically localized intracranial lesion. In contrast to conventional radiation therapy, in radio surgery no attempt is made to spare normal cells within the target volume by fractionating the tumor dose. In 1987, the authors began a program of fractionated stereotactic radiation therapy for selected tumors involving sensitive brain structures. Their objective was to improve the therapeutic index and study the feasibility of the fractionated technique. Fifteen patients were treated with a multifraction regimen typically consisting of six fractions of 700 cGy each, given on alternate days for 2 weeks (total tumor dose, 4200 cGy). All patients were treated with the dynamic stereotactic radio surgical technique. A head ring (“halo frame”) was used for immobilization and setup during radiation treatments. At a median follow‐up time of 27 months, the symptoms of the majority of the patients improved clinically; this improvement usually occurred within a few weeks after completion of the treatment. The radiologic response was much slower. Currently, only two patients have had complete radiologic disappearance of their lesions; the majority of the patients have only had a decrease in tumor size. The treatments were well tolerated by the patients and no acute complications were observed. One patient who had a vasogenic edema 11 months after treatment fully recovered after steroid therapy. Fractionated stereotactic radiation therapy is a feasible treatment technique and may prove to be useful for selected patients with intracranial tumors. Although the preliminary data are encouraging, this technique should still be considered experimental. A larger number of patients and a longer follow‐up time are necessary to determine whether the results of this technique are actually better than those of conventional radiation therapy. Cancer 68:2101–2108.

Morphine-Induced Changes in δ 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 δ opioid receptors (δORs) in the rat lumbar (L4-5) spinal cord. Under basal conditions, intrathecal injection of Fluo-DLT resulted in the labeling of numerous δOR-internalizing neurons throughout dorsal and ventral horns. The distribution and number of Fluo-DLT-labeled perikaryal profiles were consistent with that of δOR-expressing neurons, as revealed by in situ hybridization and immunohistochemistry, suggesting that a large proportion of these cells was responsive to intrathecally administered δOR 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 δOR mRNA or 125I-deltorphin-II binding levels, suggesting that they were attributable to higher densities of cell surface δOR 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 δOR 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 μOR-induced changes in the cell surface availability of δOR depend on the integrity of primary afferent inputs. Together, these results suggest that regulation of δOR responsiveness through μOR activation in this region is linked to somatosensory information processing.

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

Beta oscillations (15–30xa0Hz) 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.

Towards a validation of atlas warping techniques

Pre-operative magnetic resonance (MRI) and computed tomography (CT) image volumes are often used for planning and guidance during functional neurosurgical procedures. These operations can include the creation of lesions in the thalamus (thalamotomy) or the globus pallidus (pallidotomy), or the insertion of deep brain stimulation (DBS) electrodes in the subcortical nuclei. These subcortical targets are often difficult to localize in pre-operative imaging data due to the limited resolution and contrast available in standard MRI or CT techniques. To address this problem, digital atlases of subcortical nuclei are often used to accurately identify surgical targets since they can be warped to fit each patients unique anatomy. Targeting accuracy thus depends on the quality of the atlas-to-patient warp. In this paper, three atlas-to-patient warping techniques are compared. Two methods rely on an MRI template as an intermediary to estimate a nonlinear atlas-to-patient transformation. The third is novel, and uses a pseudo-MRI derived from an atlas of the basal ganglia and thalamus to estimate the nonlinear atlas-to-patient transformation directly. The methods are compared using (1) manual segmentations of subcortical nuclei and (2) functional data from intra-operative thalamic stimulation. The results demonstrate that the template-based atlas-to-patient warping technique is the best of the three for customizing the atlas onto patient data.

Proton magnetic resonance spectroscopic imaging can predict length of survival in patients with supratentorial gliomas.

OBJECTIVEWe compared the ability of proton magnetic resonance spectroscopic imaging (1H-MRSI) measures with that of standard clinicopathological measures to predict length of survival in patients with supratentorial gliomas. METHODSWe developed two sets of leave-one-out logistic regression models based on either 1) intratumoral 1H-MRSI features, including maximum values of a) choline and b) lactate-lipid, c) number of 1H-MRSI voxels with low N-acetyl group values, and d) number of 1H-MRSI voxels with high lactate-lipid values, all (a–d) of which were normalized to creatine in normal-appearing brain, or 2) standard clinicopathological features, including a) tumor histopathological grade, b) patient age, c) performance of surgical debulking, and d) tumor diagnosis (i.e., oligodendroglioma, astrocytoma). We assessed the accuracy of these two models in predicting patient survival for 6, 12, 24, and 48 months by performing receiver operating characteristic curve analysis. Cox proportional hazards analysis was performed to assess the extent to which patient survival could be explained by the above predictors. We then performed a series of leave-one-out linear multiple regression analyses to determine how well patient survival could be predicted in a continuous fashion. RESULTSThe results of using the models based on 1H-MRSI and clinicopathological features were equally good, accounting for 81 and 64% of the variability (r2) in patients’ actual survival durations. All features except number of 1H-MRSI voxels with lactate-lipid/creatine values of at least 1 were significant predictors of survival in the 1H-MRSI model. Two features (tumor grade and debulking) were found to be significant predictors in the clinicopathological model. Survival as a continuous variable was predicted accurately on the basis of the 1H-MRSI data (r = 0.77, P < 0.001; median prediction error, 1.7 mo). CONCLUSIONOur results suggest that appropriate analysis of 1H-MRSI data can predict survival in patients with supratentorial gliomas at least as accurately as data derived from more invasive clinicopathological features.

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.

Using a smart phone as a standalone platform for detection and monitoring of pathological tremors

Introduction: Smart phones are becoming ubiquitous and their computing capabilities are ever increasing. Consequently, more attention is geared toward their potential use in research and medical settings. For instance, their built-in hardware can provide quantitative data for different movements. Therefore, the goal of the current study was to evaluate the capabilities of a standalone smart phone platform to characterize tremor. Results: Algorithms for tremor recording and online analysis can be implemented within a smart phone. The smart phone provides reliable time- and frequency-domain tremor characteristics. The smart phone can also provide medically relevant tremor assessments. Discussion: Smart phones have the potential to provide researchers and clinicians with quantitative short- and long-term tremor assessments that are currently not easily available. Methods: A smart phone application for tremor quantification and online analysis was developed. Then, smart phone results were compared to those obtained simultaneously with a laboratory accelerometer. Finally, results from the smart phone were compared to clinical tremor assessments.

Further evidence for an antidepressant potential of the selective δ1 agonist SA 4503: electrophysiological, morphological and behavioural studies

In this study, we evaluated the ability of the selective sigma1 agonist SA 4503 to produce changes in brain function, similar to those elicited by classical antidepressants. We focused more specifically on the influence of SA 4503 on central serotonergic (5-HT) transmission, and on hippocampal cell proliferation. A 2-d continuous treatment with SA 4503 (1-40 mg/kg.d) increased 5-HT neuron firing rate in a dose-dependent, bell-shaped manner, with a culminating effect of +90% at 10 mg/kg.d. The same dose induced the appearance of a 5-HT1A receptor-mediated inhibitory tonus on hippocampal pyramidal neurons, as revealed by intravenous injections of the selective 5-HT1A antagonist WAY 100635. Moreover, continuous administration of SA 4503 (3 and 10 mg/kg.d, 3 d) dose-dependently enhanced the number of bromodeoxyuridine-positive cells in the subgranular zone of the hippocampus (+48% and +94%, respectively), thus indicating an increased cell proliferation. Finally, a single administration of SA 4503 (3 and 10 mg/kg i.p.) increased the time spent swimming in the forced swimming test. Together, these results provide both functional and behavioural evidence that this compound has an important antidepressant potential. Further, the fact that the functional changes occurred within a short time-frame (2-3 d) suggest that this antidepressant potential might have a rapid onset of action.