Ipsilateral Frontal Cortex Research Articles

Longitudinal changes of motor cortex function during motor recovery after stroke

ABSTRACT Background and purpose Functional magnetic resonance imaging (fMRI) combined with behavioral assessments was used in our study to investigate the dynamic process of motor cortical functional reorganization after infarction. Therefore, we could provide a theoretical basis and build a useful evaluation system for rehabilitation after stroke and various other cerebral injuries. Methods Acute stroke patients with a single lesion in the middle cerebral artery supply area and age- and sex-matched healthy volunteers were recruited. A longitudinal observational study involving 20 patients with stroke was conducted using repeated fMRI. Task-based fMRI data were acquired 3 times over a period of 3 months. The behavioral assessment included dynamometer and finger-tapping tests to evaluate the strength and dexterity of each upper arm. Results Behavioral results: The behavioral assessments demonstrated large improvements in session 2 and session 3. fMRI results: The healthy group showed activation in the contralateral primary sensory-motor cortex (S1M1) when executing tasks with either the left or right hand. Compared with the healthy subjects, the patients demonstrated greater activation in the ipsilateral frontal and parietal cortices and supplementary motor areas (SMAs). Across all sessions, more motor activation was observed in the left infarction group. Conclusions Our results show that motor cortical activation induced by moving the paretic hand changes over time. There were differences in motor functional recovery and motor cortex compensation between the dominant hemisphere and nondominant hemisphere after stroke.

Changes in sensory-related brain networks of patients with moyamoya disease with limb paresthesia: A resting-state fMRI-based functional connectivity analysis

This study’s aim was to investigate functional brain connectivity changes among patients with moyamoya disease (MMD) with limb paresthesia, using functional connectivity analysis based on resting-state functional magnetic resonance imaging (rs-fMRI). A total of 181 patients with MMD were enrolled, including 57 with left limb paresthesia (MLP group), 61 with right limb paresthesia (MRP group), and 63 without paresthesia (MWP group). Encephaloduroarteriosynangiosis (EDAS) was performed in 20 of the 57 patients with left limb paresthesia and 15 of the 61 patients with right limb paresthesia. Twenty-nine age- and sex-matched healthy controls (HC group) were recruited during the same period. All participants underwent rs-fMRI examination, and the patients treated with EDAS were re-examined 3–4 months after the surgery. After data preprocessing, we selected Brodmann area 3 on each side of the brain as the seed region to construct a functional connectivity network of the whole brain, and then we analyzed the differences in functional connectivity between the HC group, MWP group, MLP group, and MRP group. The functional connectivity of Brodmann area 3 (on either side) with the ipsilateral frontal (superior frontal gyrus, middle frontal gyrus, and inferior frontal gyrus) and parietal (supramarginal gyrus, angular gyrus, and superior parietal lobule) cortices was increased among patients with MMD. The functional connectivity enhancement in these brain regions was broader and greater in patients with contralateral limb paresthesia than in patients without paresthesia, and the regions with functional connectivity changes were roughly distributed symmetrically among the MLP group and the MRP group. There were no changes 3–4 months after EDAS in the increased functional connectivity between the frontal and parietal cortices and Brodmann area 3. Limb paresthesia in patients with MMD may be driven by abnormal functional connectivity in the frontal and parietal cortices. Functional changes in associated brain regions may be a target for evaluating the severity of MMD and its response to treatment.

The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H2S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia.

Ischemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H2S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H2S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, LuminexTM assays, Western blot and immunofluorescent double-staining to determine the absolute H2S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1β, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75NTR-sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia.

Aquaporin-4 Dysregulation in a Controlled Cortical Impact Injury Model of Posttraumatic Epilepsy

Posttraumatic epilepsy (PTE) is a long-term negative consequence of traumatic brain injury (TBI) in which recurrent spontaneous seizures occur after the initial head injury. PTE develops over an undefined period during which circuitry reorganization in the brain causes permanent hyperexcitability. The pathophysiology by which trauma leads to spontaneous seizures is unknown and clinically relevant models of PTE are key to understanding the molecular and cellular mechanisms underlying the development of PTE. In the present study, we used the controlled-cortical impact (CCI) injury model of TBI to induce PTE in mice and to characterize changes in aquaporin-4 (AQP4) expression. A moderate-severe TBI was induced in the right frontal cortex and video-electroencephalographic (vEEG) recordings were performed in the ipsilateral hippocampus to monitor for spontaneous seizures at 14, 30, 60, and 90 days post injury (dpi). The percentage of mice that developed PTE were 13%, 20%, 27%, and 14% at 14, 30, 60, and 90 dpi, respectively. We found a significant increase in AQP4 in the ipsilateral frontal cortex and hippocampus of mice that developed PTE compared to those that did not develop PTE. Interestingly, AQP4 was found to be mislocalized away from the perivascular endfeet and towards the neuropil in mice that developed PTE. Here, we report for the first time, AQP4 dysregulation in a model of PTE which may carry significant implications for epileptogenesis after TBI.

Improvement of Spatial Learning and Memory Impairments by Fetal Neural Tissue Transplantation in Experimental Rat Model of Alzheimer’s Disease

ABSTRACT Objective: It is known that the acetylcholinergic afferents of the neocortex from subcortical areas participate in learning and memory. Autopsy studies in cases of Alzheimer’s disease have shown that most of the neurons of nucleus basalis magnocellularis are atrophic or decreased in number. In this study, we searched for whether or not it was possible to improve the impaired learning and memory functions with fetal neural tissue transplantation in an experimental model of Alzheimer ‘s disease. Material & Methods: A total of thirty seven young adult male Wistar albino rats were served as experimental subjects.The nucleus basalis magnocellularis on the right side was destroyed by the injection of kainic acid stereotactically so as to make a model of Alzheimer’s disease. The grafts were obtained from 14-16 day old fetuses of the same genus.After the tissue with cholinergic neurons dissected from ventral forebrain and tissue with non-cholinergic neurons dissected from telencephalic vesicle, cell suspensions were prepared and injected stereotactically to the ipsilateral frontal cortex. Spatial learnig and memory functions were tested by Morris’ water maze tasks. Results: Spatial learning and memory functions in rats were impaired by unilateral lesions of nucleus basalis magnocellularis. The impairment observed during the early period partially improved by the time. It was observed that this amelioration was accelerated with both cholinergic and non-cholinergic fetal neural tissue implantation Conclusion: In our study, improvement of spatial learning and memory impairment with both cholinergic and non-cholinergicfetal neural tissue implantation can be explained by reestablishment of impaired connections via proliferation of limited number of surviving cholinergic neurons creating new synapses, as a result of upregulation of endogenous neural stem cells and activation of trophic mechanisms by implantation, rather than creation of functional synapses between the graft andthe recipient tissue.

F126. Focal seizures detected with intracranial electrodes after traumatic hemorrhage may appear as focal slowing on scalp EEG and be missed

Traumatic intracranial hemorrhage (TIH) predisposes patients to clinical and subclinical seizures, which may contribute to worsened neurological outcomes. However, experimental data suggests that scalp EEG may be insensitive for detecting some nonconvulsive seizures, especially those originating from a deeper focus. We report the simultaneous scalp and intracranial EEG findings of a 32-year-old man following evacuation of a traumatic left epidural and subdural hematoma. The patient was enrolled in an exploratory study to obtain intracranial electroencephalography (IEEG) in adults undergoing emergent post-traumatic hemicraniectomy for TIH. Following hemicraniectomy and opening of the dura mater, a 4-contact depth electrode was placed in the subdural space overlying the ipsilateral frontal cortex adjacent to the evacuated hematoma. Intraparenchymal placement was avoided to prevent insertional damage in a friable brain. The leads were tunneled through the skin adjacent to the incision, and secured externally with a silk suture, under a single layer of oxidized regenerated cellulose sheet. Positioning of the electrodes was confirmed using routine postoperative noncontrast head CT. Scalp and intracranial EEG were recorded for 94 h. Scalp EEG demonstrated severe diffuse slowing (1–4 Hz) with overlying fast activity (12–20 Hz), consistent with anesthetic effect, and a left hemispheric breech rhythm. Focal slowing persisted over the left hemisphere despite anesthetic wean. Throughout the recording, IEEG showed intermittent rhythmic or sharp waves consistent with lateralized periodic discharges (1–2 Hz). At times these evolved sufficiently in frequency, morphology and amplitude to meet criteria for nonconvulsive seizures, and could be triggered consistently with stimulation. On scalp EEG however, these periodic discharges and seizures were not detected, although rhythmic or semi-rhythmic focal slowing (1–2 Hz) was concurrently seen on occasion. In response to the IEEG findings and given the persistence of clinical encephalopathy despite weaning of anesthesia, antiseizure treatment was increased until the seizures identified on IEEG resolved. The patient’s level of consciousness subsequently improved, suggesting that the nonconvulsive seizures may have contributed to a worsened encephalopathy. Following the recording, a rhythmicity spectrogram trends panel was developed for the intracranial electrode and consistently demonstrated low-frequency bands during seizure activity that could be used for rapid seizure identification. Following TIH, clinically relevant focal seizure activity may be entirely missed on scalp EEG or have subtle intermittent nonspecific correlate such as focal slowing. More research is needed to determine the frequency of this phenomenon and determine whether treatment of such seizures improves patient outcomes.

Quantitative Visualization of Dynamic Tracer Transportation in the Extracellular Space of Deep Brain Regions Using Tracer-Based Magnetic Resonance Imaging.

BackgroundThis study assessed an innovative tracer-based magnetic resonance imaging (MRI) system to visualize the dynamic transportation of tracers in regions of deep brain extracellular space (ECS) and to measure transportation ability and ECS structure.Material/MethodsGadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) was the chosen tracer and was injected into the caudate nucleus and thalamus. Real-time dynamic transportation of Gd-DTPA in ECS was observed and the results were verified by laser scanning confocal microscopy. Using Transwell assay across the blood-brain barrier, a modified diffusion equation was further simplified. Effective diffusion coefficient D* and tortuosity λ were calculated. Immunohistochemical staining and Western blot analysis were used to investigate the extracellular matrix contributing to ECS structure.ResultsTracers injected into the caudate nucleus were transported to the ipsilateral frontal and temporal cortices away from the injection points, while both of them injected into the thalamus were only distributed on site. Although the caudate nucleus was closely adjacent to the thalamus, tracer transportation between partitions was not observed. In addition, D* and the λ showed statistically significant differences between partitions. ECS was shown to be a physiologically partitioned system, and its division is characterized by the unique distribution territory and transportation ability of substances located in it. Versican and Tenascin R are possible contributors to the tortuosity of ECS.ConclusionsTracer-based MRI will improve our understanding of the brain microenvironment, improve the techniques for local delivery of drugs, and highlight brain tissue engineering fields in the future.

Induction of calcitonin gene-related peptide expression in rats by cortical spreading depression.

The neuropeptide calcitonin gene-related peptide (CGRP) has now been established as a key player in migraine. However, the mechanisms underlying the reported elevation of CGRP in the serum and cerebrospinal fluid of some migraineurs are not known. A candidate mechanism is cortical spreading depression (CSD), which is associated with migraine with aura and traumatic brain injury. The aim of this study was to investigate whether CGRP gene expression may be induced by experimental CSD in the rat cerebral cortex. CSD was induced by topical application of KCl and monitored using electrophysiological methods. Quantitative PCR and ELISA were used to measure CGRP mRNA and peptide levels in discrete ipsilateral and contralateral cortical regions of the rat brain 24 hours following CSD events and compared with sham treatments. The data show that multiple, but not single, CSD events significantly increase CGRP mRNA levels at 24 hours post-CSD in the ipsilateral rat cerebral cortex. Increased CGRP was observed in the ipsilateral frontal, motor, somatosensory, and visual cortices, but not the cingulate cortex, or contralateral cortices. CSD also induced CGRP peptide expression in the ipsilateral, but not contralateral, cortex. Repeated CSD provides a mechanism for prolonged elevation of CGRP in the cerebral cortex, which may contribute to migraine and post-traumatic headache.

Whole-brain MRI phenotyping in dysplasia-related frontal lobe epilepsy.

To perform whole-brain morphometry in patients with frontal lobe epilepsy and evaluate the utility of group-level patterns for individualized diagnosis and prognosis. We compared MRI-based cortical thickness and folding complexity between 2 frontal lobe epilepsy cohorts with histologically verified focal cortical dysplasia (FCD) (13 type I; 28 type II) and 41 closely matched controls. Pattern learning algorithms evaluated the utility of group-level findings to predict histologic FCD subtype, the side of the seizure focus, and postsurgical seizure outcome in single individuals. Relative to controls, FCD type I displayed multilobar cortical thinning that was most marked in ipsilateral frontal cortices. Conversely, type II showed thickening in temporal and postcentral cortices. Cortical folding also diverged, with increased complexity in prefrontal cortices in type I and decreases in type II. Group-level findings successfully guided automated FCD subtype classification (type I: 100%; type II: 96%), seizure focus lateralization (type I: 92%; type II: 86%), and outcome prediction (type I: 92%; type II: 82%). FCD subtypes relate to diverse whole-brain structural phenotypes. While cortical thickening in type II may indicate delayed pruning, a thin cortex in type I likely results from combined effects of seizure excitotoxicity and the primary malformation. Group-level patterns have a high translational value in guiding individualized diagnostics.

Wakefulness delta waves increase after cortical plasticity induction

ObjectiveDelta waves (DW) are present both during sleep and in wakefulness. In the first case, DW are considered effectors of synaptic plasticity, while in wakefulness, when they appear in the case of brain lesions, their functional meaning is not unanimously recognized. To throw light on the latter, we aimed to investigate the impact on DW exerted by the cortical plasticity-inducing protocol of intermittent theta burst stimulation (iTBS). MethodsTwenty healthy subjects underwent iTBS (11 real iTBS and nine sham iTBS) on the left primary motor cortex with the aim of inducing long-term potentiation (LTP)-like phenomena. Five-minute resting open-eye 32-channel EEG, right opponens pollicis motor-evoked potentials (MEPs), and alertness behavioral scales were collected before and up to 30min after the iTBS. Power spectral density (PSD), interhemispheric coherence between homologous sensorimotor regions, and intrahemispheric coherence were calculated for the frequency bands ranging from delta to beta. ResultsReal iTBS induced a significant increase of both MEP amplitude and DW PSD lasting up to 30min after stimulation, while sham iTBS did not. The DW increase was evident over frontal areas ipsilateral and close to the stimulated cortex (electrode F3). Neither real nor sham iTBS induced significant modifications in the PSD of theta, alpha, and beta bands and in the interhemispheric coherence. Behavioral visuo-analogic scales score did not demonstrate changes in alertness after stimulations. No correlations were found between MEP amplitude and PSD changes in the delta band. ConclusionsOur data showed that LTP induction in the motor cortex during wakefulness, by means of iTBS, is accompanied by a large and enduring increase of DW over the ipsilateral frontal cortex. SignificanceThe present results are strongly in favor of a prominent role of DW in the neural plasticity processes taking place during the awake state.

Cortico-striatal-thalamic network functional connectivity in hemiparkinsonism

Cortico-striatal-thalamic network functional connectivity (FC) and its relationship with levodopa (L-dopa) were investigated in 69 patients with hemiparkinsonism (25 drug-naïve [n-PD] and 44 under stable/optimized dopaminergic treatment [t-PD]) and 27 controls. Relative to controls, n-PD patients showed an increased FC between the left and the right basal ganglia, and a decreased connectivity of the affected caudate nucleus and thalamus with the ipsilateral frontal and insular cortices. Compared with both controls and n-PD patients, t-PD patients showed a decreased FC among the striatal and thalamic regions, and an increased FC between the striatum and temporal cortex, and between the thalamus and several sensorimotor, parietal, temporal, and occipital regions. In both n-PD and t-PD, patients with more severe motor disability had an increased striatal and/or thalamic FC with temporal, parietal, occipital, and cerebellar regions. Cortico-striatal-thalamic functional abnormalities occur in patients with hemiparkinsonism, antecede the onset of the motor symptoms on the opposite body side and are modulated by L-dopa. In patients with hemiparkinsonism, L-dopa is likely to facilitate a compensation of functional abnormalities possibly through an increased thalamic FC.

Cortical and thalamic excitation mediate the multiphasic responses of striatal cholinergic interneurons to motivationally salient stimuli.

Cholinergic interneurons are key components of striatal microcircuits. In primates, tonically active neurons (putative cholinergic interneurons) exhibit multiphasic responses to motivationally salient stimuli that mirror those of midbrain dopamine neurons and together these two systems mediate reward-related learning in basal ganglia circuits. Here, we addressed the potential contribution of cortical and thalamic excitatory inputs to the characteristic multiphasic responses of cholinergic interneurons in vivo. We first recorded and labeled individual cholinergic interneurons in anesthetized rats. Electron microscopic analyses of these labeled neurons demonstrated that an individual interneuron could form synapses with cortical and, more commonly, thalamic afferents. Single-pulse electrical stimulation of ipsilateral frontal cortex led to robust short-latency (<20 ms) interneuron spiking, indicating monosynaptic connectivity, but firing probability progressively decreased during high-frequency pulse trains. In contrast, single-pulse thalamic stimulation led to weak short-latency spiking, but firing probability increased during pulse trains. After initial excitation from cortex or thalamus, interneurons displayed a "pause" in firing, followed by a "rebound" increase in firing rate. Across all stimulation protocols, the number of spikes in the initial excitation correlated positively with pause duration and negatively with rebound magnitude. The magnitude of the initial excitation, therefore, partly determined the profile of later components of multiphasic responses. Upon examining the responses of tonically active neurons in behaving primates, we found that these correlations held true for unit responses to a reward-predicting stimulus, but not to the reward alone, delivered outside of any task. We conclude that excitatory inputs determine, at least in part, the multiphasic responses of cholinergic interneurons under specific behavioral conditions.

Antioxidant Activities of Dracocephalum tanguticum Maxim Extract and Its Up-Regulation on the Expression of Neurotrophic Factors in a Rat Model of Permanent Focal Cerebral Ischemia

The aim of this study was to investigate the effect of a BuOH-soluble fraction from Dracocephalum tanguticum Maxim (DME), which contained 52% of total flavonoid, on the cerebral ischemia injury induced by permanent middle cerebral artery occlusion (pMCAO) in rats. RT-PCR and Western blot analysis showed that DME (30 mg/kg/day for seven days) by intragastric administration modulated the mRNA expression and protein synthesis of two neurotrophic factors: brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3). DME was effective in stimulating BDNF mRNA expression and protein synthesis in the ipsilateral frontal cortex (IFC) of both the sham-operated and pMCAO rats and this effect was also observed in the hippocampus of the pMCAO rats. DME significantly increased NT-3 mRNA expression and protein synthesis in the IFC and hippocampus of the pMCAO rats, although it had no effect on NT-3 expression in the sham-operated groups. Meanwhile, DME also decreased the malondialdehyde contents in the hippocampus of the sham-operated and pMCAO groups, and significantly attenuated the decrease of endogenous antioxidant (superoxide dismutase, glutathione peroxidase and catalase) activities in both the IFC and hippocampus of the rats after ischemia insult injury. Moreover, DME facilitated the neurobehavioral recovery after the cerebral ischemia. These findings suggested that DME has potential for treatment of ischemia-induced brain damage through stimulation of antioxidant activity and neurotrophic factor synthesis.

Nitric Oxide Synthase Inhibitor Improves De Novo and Long-Term l-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats

Inhibitors of neuronal and endothelial nitric oxide synthase decrease l-3,4-dihidroxifenilalanine (l-DOPA)-induced dyskinesias in rodents. The mechanism of nitric oxide inhibitor action is unknown. The aims of the present study were to investigate the decrease of l-DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA)-lesioned rats by nitric oxide inhibitors following either acute or chronic treatment. The primary findings of this study were that NG-nitro-l-Arginine, an inhibitor of endothelial and neuronal nitric oxide synthase, attenuated AIMs induced by chronic and acute l-DOPA. In contrast, rotational behavior was attenuated only after chronic l-DOPA. The 6-OHDA lesion and the l-DOPA treatment induced a bilateral increase (1.5 times) in the neuronal nitric oxide synthase (nNOS) protein and nNOS mRNA in the striatum and in the frontal cortex. There was a parallel increase, bilaterally, of the FosB/ΔFosB, primarily in the ipsilateral striatum. The exception was in the contralateral striatum and the ipsilateral frontal cortex, where chronic l-DOPA treatment induced an increase of approximately 10 times the nNOS mRNA. Our results provided further evidence of an anti-dyskinetic effect of NOS inhibitor. The effect appeared under l-DOPA acute and chronic treatment. The l-DOPA treatment also revealed an over-expression of the neuronal NOS in the frontal cortex and striatum. Our results corroborated findings that l-DOPA-induced rotation differs between acute and chronic treatment. The effect of the NOS inhibitor conceivably relied on the l-DOPA structural modifications in the Parkinsonian brain. Taken together, these data provided a rationale for further evaluation of NOS inhibitors in the treatment of l-DOPA-induced dyskinesia.

Comparison Between a Real Sequential Finger and Imagery Movements: An fMRI Study Revisited

Recently, much discussion has been centered on the brain networks of recall, memory, and execution. This study utilized functional magnetic resonance imaging to compare activation between a simple sequential finger movement (real task) and recalling the same task (imagery task) in 15 right-handed normal subjects. The results demonstrated a greater activation in the contralateral motor and somatosensory cortex during the real task, and a higher activation in the contralateral inferior frontal cortex, ipsilateral motor, somatosensory cortex, and midbrain during the imagery task. These real task-specific areas and imagery-specific areas, including the ipsilateral motor and somatosensory cortex, are consistent with recent studies. However, this is the first report to demonstrate that the imagery-specific regions involve the ipsilateral inferior frontal cortex and midbrain. Directly comparing the activation between real and imagery tasks demonstrated the inferior frontal cortex and midbrain to therefore play important roles in cognitive feedback.

VEGF enhance cortical newborn neurons and their neurite development in adult rat brain after cerebral ischemia

To study the effect of VEGF overexpression on development of cortical newborn neurons in the brains after stroke, we injected human VEGF 165-expressive plasmids (phVEGF) into the lateral ventricle of rat brains with a transient middle cerebral artery occlusion (MCAO). An injection of phVEGF significantly promoted angiogenesis (BrdU +-von Willebrand's factor +) and reduced infarct volume in the rat brain after MCAO. Single labeling of 5′-bromodeoxyuridine (BrdU) and double staining of BrdU with lineage-specific neuronal markers were used to indicate the proliferated cells and maturation of newborn neurons in the brain section of rats at 2, 4, and 8 weeks after MCAO. The results showed that BrdU positive (BrdU +) cells existed in ipsilateral frontal cortex within 8 weeks after MCAO and reached the maximum at 2 weeks of reperfusion. The phVEGF treatment significantly increased BrdU + cells compared with the control plasmid (pEGFP) injection. Cortical neurogenesis was indicated by the presence of newborn immature (BrdU +-Tuj1 +), newborn mature (BrdU +-MAP-2 +), and newborn GABAergic (BrdU +-GAD67 +) neurons. All these neurons declined within 8 weeks after MCAO in the controls. Injection of phVEGF significantly increased BrdU +-Tuj1 + neurons at 2 weeks, and BrdU +-MAP-2 + neurons and BrdU +-GAD67 + neurons at 4 and 8 weeks, respectively after MCAO. Moreover, phVEGF treatment significantly increased neurite length and branch numbers of BrdU +-MAP-2 + newborn neurons compared with pEGFP treatment. These results demonstrate that VEGF enhances maturation of stroke-induced cortical neurogenesis and dendritic formation of newborn neurons in adult mammalian brains.

Experimental Petit Mal-Like Seizure Induced by Microinjection of Kainic Acid Into the Unilateral Mediodorsal Nucleus of the Thalamus

The mediodorsal nucleus (MD) of the thalamus has reciprocal projections with the frontal cortex and limbic system, and may be involved in absence seizures. Kainic acid was injected into the left MD of Wistar rats, and behavior and electroencephalography were monitored for 24 hours, then continued intermittently for 8 weeks. The rat brains were then examined histologically. Brain metabolic changes were also investigated by intravenous injection of 100 microCi/kg of [(14)C]2-deoxyglucose to measure local cerebral glucose metabolism. Bilateral synchronous spike and wave complexes appeared almost 2 hours after kainic acid injection, and the waveforms continued for about 5-7 hours in the bilateral MDs, ipsilateral sensorimotor cortex, and basolateral nucleus of the amygdala. The associated behavioral changes were mainly those of behavioral arrest and staring, associated with occasional limbic seizures. Clear metabolic increases were found in the ipsilateral frontal cortex, hippocampus, and amygdala. The present results suggest that the MD was involved in both the mechanism of spike and wave complexes in the bilateral frontal cortices, and in seizure propagation to the limbic system. Consequently, kainic acid-induced MD seizure is associated with significant cognitive impairment and may explain the mechanism of petit mal seizure.

Delayed synchronization of activity in cortex and subthalamic nucleus following cortical stimulation in the rat

Oscillations may play a role in the functional organization of cortico-basal ganglia-thalamocortical circuits, and it is important to understand their underlying mechanisms. The cortex often drives basal ganglia (BG) activity, and particularly, oscillatory activity in the subthalamic nucleus (STN). However, the STN may also indirectly influence cortex. The aim of this study was to characterize the delayed (>200 ms) responses of STN neurons to synchronized cortical inputs, focusing on their relationship with oscillatory cortical activity. We recorded the short-latency and delayed responses of STN units and frontal electrocorticogram (ECoG) to cortical stimulation in anaesthetized rats. Similar to previous studies, stimulation of ipsilateral frontal cortex, but not temporal cortex, evoked a short-latency triphasic response, followed by a sustained reduction or pause in firing, in rostral STN units. Caudal STN units did not show the short-latency triphasic response but often displayed a prolonged firing reduction. Oscillations in STN unit activity and ECoG were common after this sustained firing reduction, particularly between 200 and 600 ms after frontal cortical stimulation. These delayed oscillations were significantly coherent in a broad frequency band of 5-30 Hz. Coherence with ECoG at 5-15 Hz was observed throughout STN, though coherence at 15-30 Hz was largely restricted to rostral STN. Furthermore, oscillatory responses at 5-30 Hz in rostral STN predominantly led those in cortex (mean latency of 29 ms) after frontal cortical stimulation. These findings suggest that STN neurons responding to corticosubthalamic inputs may provide a delayed input to cortex, via BG output nuclei, and thence, thalamocortical pathways.

Gender and environmental enrichment impact dopamine transporter expression after experimental traumatic brain injury

Dopamine (DA) systems are implicated in cognitive deficits following traumatic brain injury (TBI). Rodent studies have demonstrated that both environmental enrichment (EE) and sex hormones can influence DA systems. The dopamine transporter (DAT) plays a crucial role in regulating DA transmission, and previous work shows that DAT is decreased after TBI in males. Therefore, the purpose of this study was to examine the effects of gender and EE on frontal cortex and striatal DAT expression after TBI. Sprague–Dawley male ( n = 24) and cycling female rats ( n = 24) were placed into EE or standard housing after controlled cortical impact (2.7 mm, 4.0 m/s) injury or sham surgery (eight groups, n = 6/group). Four weeks post-surgery, bilateral frontal cortex and striatal DAT expression was examined via Western blot. Results demonstrated that there was a significant effect of injury, EE, and region on DAT expression ( P < 0.05 all comparisons) on female groups. There were no significant DAT decreases in any region as a result of injury, however, EE did promote significant post-injury DAT decreases in the striatum and ipsilateral frontal cortex ( P < 0.05 all comparisons) compared to female shams housed in the standard environment. For males, there was a significant effect of injury, EE, and region for male groups ( P < 0.05 all comparisons). There were decreases in DAT expression in three regions studied for injured males housed in the standard environment compared to sham males in the standard environment ( P < 0.05 all comparisons), however, EE did not add significantly to post-injury DAT decreases in these regions. These results suggest that CCI causes larger relative decreases in DAT expression for males compared to females and that treatment with EE has larger effects on post-injury DAT expression for females than males. These findings may have some relevance to treatment paradigms using dopaminergic neurostimulants after TBI.

MicroPET detection of enhanced 18F-FDG utilization by PKA inhibitor in awake rat brain

To obtain PET imaging of glucose metabolism in the brains of conscious rats, a method of rat head fixation was developed. PET measurement with microPET was performed for 60 min after 18F-FDG injection. Significant enhancement of glucose utilization in the right striatum was observed with infusion of Rp-adenosine-3,5-cyclic phosphorothioate triethylamine (Rp-cAMPS). FDG uptake increments were also seen in the ipsilateral frontal cortex and thalamus. As initial FDG uptake in the brain was not significantly altered by Rp-cAMPS, increased glucose metabolism might be due to an increase in the phosphorylation rate by hexokinase rather than the delivery process from plasma to the brain. In contrast to awake rats, the effect of Rp-cAMPS was abolished by anesthesia using chloral hydrate, indicating that neuronal activity has an important role in short term regulation of hexokinase activity through the cAMP/PKA system in the brain. These results strongly demonstrated the value of measuring glucose utilization in the brains of conscious rats.