Homa Sadeghian

Neuronal death by repetitive cortical spreading depression in juvenile rat brain

Spreading depression (SD) is an intrinsic bioelectrical property of the human central nervous system, which plays a key role in neurological disorders. In the present study, we investigated whether experimentally induced repetitive SD caused neuronal death in cortical and subcortical regions of the juvenile rat brain. The animals were anesthetized and the electrodes as well as a cannula were implanted over the brain. Repetitive cortical SD events were induced by KCl injection. The brains were removed after 4 weeks. Repetitive SD enhanced the production of dark neurons, reduced the mean volume of normal neurons, increased the number of apoptotic neurons, and enhanced expression of the NR(2B) subunit of NMDA receptors as well as the GluR1 subunit of AMPA receptors in various regions of the juvenile rat brain. In addition, induction of repetitive SD enhanced long-term potentiation in CA1 hippocampal area. We observed a correlation between cell injury/neuronal death induced by repetitive SD and changes in glutamate receptor expression. The data indicate that repetitive cortical SD in juvenile rats causes neuronal damage in both cortical and subcortical areas of the brain. This may play an important role in the pathophysiology of SD-related neurological disorders, especially in children.

Vagus nerve stimulation inhibits cortical spreading depression.

Abstract Vagus nerve stimulation has recently been reported to improve symptoms of migraine. Cortical spreading depression is the electrophysiological event underlying migraine aura and is a trigger for headache. We tested whether vagus nerve stimulation inhibits cortical spreading depression to explain its antimigraine effect. Unilateral vagus nerve stimulation was delivered either noninvasively through the skin or directly by electrodes placed around the nerve. Systemic physiology was monitored throughout the study. Both noninvasive transcutaneous and invasive direct vagus nerve stimulations significantly suppressed spreading depression susceptibility in the occipital cortex in rats. The electrical stimulation threshold to evoke a spreading depression was elevated by more than 2-fold, the frequency of spreading depressions during continuous topical 1 M KCl was reduced by ∼40%, and propagation speed of spreading depression was reduced by ∼15%. This effect developed within 30 minutes after vagus nerve stimulation and persisted for more than 3 hours. Noninvasive transcutaneous vagus nerve stimulation was as efficacious as direct invasive vagus nerve stimulation, and the efficacy did not differ between the ipsilateral and contralateral hemispheres. Our findings provide a potential mechanism by which vagus nerve stimulation may be efficacious in migraine and suggest that susceptibility to spreading depression is a suitable platform to optimize its efficacy.

The Underlying Factor Structure of National Institutes of Health Stroke Scale: An Exploratory Factor Analysis

ABSTRACT The underlying structure of National Institutes of Health Stroke Scale (NIHSS) as the most widely used scale in clinical trials has been the focus of little attention. The aim of the current study was to elucidate the clustering pattern of NIHSS items in ischemic stroke patients. A series of 152 consecutive patients with first-ever ischemic strokes admitted to a university affiliated hospital were enrolled. NIHSS score was estimated on admission and correlation coefficients between its items were calculated. Further, exploratory factor analysis was used to study the clustering pattern of NIHSS items. Extinction neglect, visual field, and facial palsy were weakly associated with other NIHSS items. Factor analysis led to a four-factor structure. Factors 1 and 3 were determined by left brain function as items of right arm and leg motor, language and dysarthria loaded on both of them. By contrast, factor 2 reflected right brain involvement. Since visual field and ataxia loaded on factor 4, this factor was primarily associated with posterior strokes. Our study shows that a four-factor structure model is plausible for NIHSS. Further, for the first time, a single distinct factor is identified for posterior strokes.

Decreased microvascular cerebral blood flow assessed by diffuse correlation spectroscopy after repetitive concussions in mice.

Repetitive concussions are associated with long-term cognitive dysfunction that can be attenuated by increasing the time intervals between concussions; however, biomarkers of the safest rest interval between injuries remain undefined. We hypothesize that deranged cerebral blood flow (CBF) is a candidate biomarker for vulnerability to repetitive concussions. Using a mouse model of human concussion, we examined the effect of single and repetitive concussions on cognition and on an index of CBF (CBFi) measured with diffuse correlation spectroscopy. After a single mild concussion, CBFi was reduced by 35±4% at 4 hours (P < 0.01 versus baseline) and returned to preinjury levels by 24 hours. After five concussions spaced 1 day apart, CBFi was also reduced from preinjury levels 4 hours after each concussion but had returned to preinjury levels by 72 hours after the final concussion. Interestingly, in this repetitive concussion model, lower CBFi values measured both preinjury and 4 hours after the third concussion were associated with worse performance on the Morris water maze assessed 72 hours after the final concussion. We conclude that low CBFi measured either before or early on in the evolution of injury caused by repetitive concussions could be a useful predictor of cognitive outcome.

A simple risk score for early ischemic stroke mortality derived from National Institutes of Health Stroke Scale: a discriminant analysis.

OBJECTIVES The aim of the current study was to design a new simpler form of National Institutes of Health Stroke Scale (NIHSS) for use in emergency settings, and compare its predictive ability with original NIHSS score for mortality. METHODS A total of 152 consecutive patients with first ever ischemic stroke admitted to a university affiliated hospital were recruited. NIHSS score on admission was estimated and the predictive ability of NIHSS items for mortality at 28 days was evaluated by logistic regression. Stepwise discriminant analysis was performed on NIHSS items to obtain a discriminant function with the best discriminative ability for mortality. Further, receiver operating characteristics (ROC) curves were depicted to compare the new determined discriminant function with the original NIHSS score. RESULTS Cumulative rate of mortality was 11.8% for 28-day follow-up period. Among NIHSS items, scores of visual field, limb ataxia and extinction neglect were not associated with mortality (P>0.05). On the contrary, level of consciousness-commands, language and gaze were determined as independent indicators of mortality (P<0.05), and their coefficients on discriminant function were equal to 0.65, 0.44 and 0.30, respectively. In addition, area under the ROC curve of the calculated discriminant function was not statistically different from NIHSS score (P>0.05). CONCLUSIONS The suggested discriminant function, comprising NIHSS items of level of consciousness-commands, language and gaze, can predict 28-day mortality after ischemic stroke in a similar way to the original NIHSS score and can provide a baseline for stroke severity in emergency settings.

Assessment of pedicle screw placement accuracy in thoracolumbosacral spine using freehand technique aided by lateral fluoroscopy: results of postoperative computed tomography in 114 patients.

BACKGROUND CONTEXT Pedicle screw fixation is currently widely used in spine surgery for various pathologies. Increasing screw placement accuracy would improve the outcomes. PURPOSE To determine the accuracy rate of screw placement in a group of patients who underwent pedicle screw fixation with conventional techniques. STUDY DESIGN A case series. PATIENT SAMPLE It includes patients undergoing posterior spinal fixation with pedicle screw insertion. Outcome measures include the accuracy of screw placement in pedicles defined by postoperative computed tomography (CT). METHODS After surgery, an axial thin-cut CT scan was performed in all patients. Screw position was classified as correct when the screw was completely surrounded by the pedicle cortex and incorrect when any part of the screw was outside the pedicle boundaries. RESULTS Seven hundred seventy screws were inserted at vertebral levels T7-S1 of 114 patients between March 2012 and December 2012. There were three wound infections and one death. Eighteen screws were diagnosed as having an incorrect position (2.3%). The highest accuracy was observed in levels L4 and L5 (0.8% inaccuracy rate for each), whereas the highest inaccuracy rate was observed in T9. The mean inaccuracy rate was 10.5% for levels T7-T9, 3.5% for levels T10-L2, and 0.9% for levels L3-S1. The differences were statistically significant. Only one screw (5%) needed revision. CONCLUSIONS The results of our study show that conventional methods for pedicle screw placement remain safe and accurate, with best results obtained in the lumbosacral spine, followed by the thoracolumbar junction. Nonetheless, results are less accurate in the midthoracic spine.

Altered inhibition in the hippocampal neural networks after spreading depression

Prolonged neuronal depression after spreading depression (SD) is followed by a late cellular and synaptic hyperexcitability. Intra- and extracellular recordings of bioelectrical activities were performed in the rodent hippocampus to investigate the role of γ-aminobutyric acid (GABA)-mediated inhibition in the late hyperexcitable state of SD. The effect of KCl-induced negative DC potential shifts was investigated on extracellularly recorded paired-pulse depression (PPD) and bicuculline-induced afterdischarges as well as intracellularly recorded inhibitory post synaptic potentials (IPSPs) in the hippocampal CA1 area. The results revealed that SD decreased the degree of PPD, enhanced the number and duration of bicuculline-induced afterdischarges, and reduced the amplitude and duration of IPSPs. Application of low concentrations of bicuculline before the induction of SD enhanced the inhibitory effect of SD on IPSPs. Data indicate the contribution of GABA-mediated inhibition to SD-induced delayed hyperexcitability. Modulation of GABA function in the late hyperexcitability phase of SD may play a role in therapeutic management of SD-related neurological disorders.

Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice

Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood-brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke.

Outcome of Microscopic Transsphenoidal Surgery in Cushing Disease: A Case Series of 96 Patients.

OBJECTIVE To analyze the results of transsphenoidal surgery in patients with Cushing disease and outcome. METHOD Retrospective analysis of the records of 96 patients with Cushing disease from 1997 to 2012. RESULTS There were 73 females and 23 males, with a mean follow-up of 44 months (range, 3-13 years). The sex ratio was significantly different in children and teenagers versus adults. Magnetic resonance imaging showed microadenoma, macroadenoma, and no adenoma in 66, 18, and 12 patients, respectively. There was no surgical mortality. Early remission (normal 24-hour urinary free cortisol and basal serum cortisol <5 μg/dL) was achieved in 94.8%. Regression analysis showed that only tumor size, cavernous sinus extension, and tumor consistency influenced remission. Recurrence was seen in 21.9%. Regression analysis showed that age, preoperative basal cortisol levels, and follow-up duration influenced recurrence. Correlation analysis showed that there was a significant negative correlation between patient age and the follow-up period. After detection of recurrence, 17 patients underwent repeat transsphenoidal surgery that resulted in remission in 12 patients (70.6%). The other 5 patients were referred for gamma knife radiosurgery or bilateral adrenalectomy. CONCLUSIONS Transsphenoidal surgery is a safe and highly efficient procedure in the treatment of Cushing disease. Macroadenomas, cavernous sinus invasion, and harder tumor consistencies, however, are associated with lower remission rates (higher disease persistence) and younger age, higher preoperative cortisol levels, and longer follow-up periods are associated with higher recurrence.

Clinical and Magnetic Resonance Imaging Factors Which May Predict the Need for Surgery in Lumbar Disc Herniation

Study Design Case-control. Purpose Evaluate clinical and imaging factors which may predict the risk of failure of medical therapy in patients with lumbar disc herniation (LDH). Overview of Literature LDH is a common cause of low back pain and radicular leg pain, with a generally favorable natural course. At present, however, it is not possible to identify patients who may be candidates for surgery in an early stage of their disease by means of clinical signs or diagnostic imaging criteria. Methods We designed a study investigating patients with untreated low back pain to assess the predictive value of demographic, clinical or imaging findings in identifying patients who finally would meet the classic current criteria for surgery. Results Among 134 patients, 80.6% were successfully treated with conservative therapy and 19.4% finally underwent surgery. Sex, occupation, involved root level, presence of Modic changes, osteophytes or annular tears were not significantly different between the 2 groups, while cerebrospinal fluid block, Pfirrmanns grade, location of herniation with regard to the midline, and type of herniation were significantly different. Anteroposterior fragment size was significantly higher and intervertebral foramen height and thecal sac diameters were significantly lower in the surgical group. Conclusions Although it is strongly recommended to practice conservative management at first for patients with LDH symptoms, the results of this study shows that higher Pfirrmanns grade, more laterally located discs, extrusion and protrusion herniation types, and larger fragments could predict the risk of conservative treatment failure. This way, unnecessarily prolonged conservative management (beyond 4-8 weeks) may be precluded.