The neurobiology of focus and distraction: The case for incorporating mindfulness into leadership.

Increasingly health leaders are experiencing greater demands and pressures, which require the need for better focus while limiting unwarranted distractions. This article offers a neurobiological explanation of how the brain focuses and becomes distracted, in order to help health leaders gain insight into their own effectiveness. Two main neural circuits are contrasted: the mind-wandering default mode circuit and the attentional central executive system. These two systems act in an antagonistic pairing, where the degree of toggling between systems is associated with the degree a person can sustain focus and filter out unwarranted distractions. Excessive multitasking appears to compromise the neural switch of these two systems, thereby diminishing our focus and concentration. In contrast, mindfulness practice is shown to have the opposite effect by enhancing the neural switch, thereby enhancing leadership focus that can lead to greater flexibility, foresight, regulation, and creativity. To conclude, leaders who are excessively distracted, such as with multitasking, may be compromising cognitive brain functioning, while engaging in mindfulness may replenish the brain and thereby enhance leaders' ability to sustain focus and tap into higher cognitive functioning.

Calpain activation is involved in early caspase-independent neurodegeneration in the hippocampus following status epilepticus.

Evidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (10 mg/kg) intraperitoneally and killed 24 h later, after development of grade 5 seizures. We observed a strong Fluoro-Jade labeling in the CA1 and CA3 areas of the hippocampus in the rats that received kainic acid, when compared with saline-treated rats. Immunohistochemistry and western blot analysis for the calpain-derived breakdown products of spectrin showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.

Endothelial proliferation and increased blood-brain barrier permeability in the basal ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia.

3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia is associated with molecular and synaptic plasticity in the basal ganglia, but the occurrence of structural remodeling through cell genesis has not been explored. In this study, rats with 6-hydroxydopamine lesions received injections of the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) concomitantly with L-DOPA for 2 weeks. A large number of BrdU-positive cells were found in the striatum and its output structures (globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata) in L-DOPA-treated rats that had developed dyskinesia. The vast majority (60-80%) of the newborn cells stained positively for endothelial markers. This endothelial proliferation was associated with an upregulation of immature endothelial markers (nestin) and a downregulation of endothelial barrier antigen on blood vessel walls. In addition, dyskinetic rats exhibited a significant increase in total blood vessel length and a visible extravasation of serum albumin in the two structures in which endothelial proliferation was most pronounced (substantia nigra pars reticulata and entopeduncular nucleus). The present study provides the first evidence of angiogenesis and blood-brain barrier dysfunction in an experimental model of L-DOPA-induced dyskinesia. These microvascular changes are likely to affect the kinetics of L-DOPA entry into the brain, favoring the occurrence of motor complications.

Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning.

Hippocampus-mediated learning enhances neurogenesis in the adult dentate gyrus (DG), and this process has been suggested to be involved in memory formation. The hippocampus receives abundant cholinergic innervation and acetylcholine (ACh) plays an important role in learning and Alzheimer's disease (AD) pathophysiology. Here, we show that a selective neurotoxic lesion of forebrain cholinergic input with 192 IgG-saporin reduces DG neurogenesis with a concurrent impairment in spatial memory. Conversely, systemic administration of the cholinergic agonist physostigmine increases DG neurogenesis. We find that changes of forebrain ACh levels primarily influence the proliferation and/or the short-term survival rather than the long-term survival or differentiation of the new neurons. We further demonstrate that these newly born cells express the muscarinic receptor subtypes M1 and M4. Our data provide evidence that forebrain ACh promotes neurogenesis, and suggest that the impaired cholinergic function in AD may in part contribute to deficits in learning and memory through reductions in the formation of new hippocampal neurons.

Proteolysis of NR2B by calpain in the hippocampus of epileptic rats.

Overactivation of N-methyl-D-aspartate receptors is known to mediate excitotoxicity due to excessive entry of calcium, leading to the activation of several calcium-dependent enzymes. Calpains are calcium-activated proteases that appear to play a role in excitotoxic neuronal death. Several cellular proteins are substrates for these proteases, particularly the N-methyl-D-aspartate receptor. Recently, cleavage of NR2B subunits has been implicated in excitotoxic neurodegeneration in ischemia. In this work, we investigated the proteolysis by calpains of NR2B subunits of the N-methyl-D-aspartate receptor in the hippocampus of epileptic rats. Our results show that cleaved forms of NR2B subunits are formed after status epilepticus, in the same areas of the hippocampus where calpain activation was detected by immunohistochemical staining of calpain-specific spectrin breakdown products.

Behavioral characterization of a unilateral 6-OHDA-lesion model of Parkinson's disease in mice.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Several toxin-induced animals models simulate the motor deficits occurring in PD. Among them, the unilateral 6-hydroxydopamine (6-OHDA) model is frequently used in rats and has the advantage of presenting side-biased motor impairments. However, the behavioral consequences of a unilateral 6-OHDA-lesion have, so far, not been described in detail in mice. The aim of this study was to characterize mice with unilateral 6-OHDA-lesions placed in the median forebrain bundle using several motor behavioral tests in order to identify the most suitable predictor of nigral cell loss. Mice underwent various drug-induced (amphetamine- and apomorphine-induced rotation) and spontaneous motor tests (cylinder, rotarod, elevated body swing, and stride length test). The amphetamine-induced rotation test, the cylinder and the rotarod test were most sensitive and reliable in detecting loss of tyrosine hydroxylase-immunoreactive cells in the substantia nigra. This study demonstrates that substantial and stable unilateral 6-OHDA-induced lesions can be established in mice, and that these lesions can be functionally assessed using several different side-bias-based behavioral tests. This mouse model offers the opportunity to use transgenic mouse strains and study the interactions between genes of interest and toxins in relation to Parkinson's disease etiology in the future.

Electroconvulsive seizures induce endothelial cell proliferation in adult rat hippocampus.

BACKGROUND: Electroconvulsive seizures, an animal model for electroconvulsive treatment, induce a strong increase in neurogenesis in the dentate gyrus of adult rats. Hippocampal neurogenesis has previously been described as occurring in an angiogenic niche. This study examines the effect of electroconvulsive seizures on proliferation of vascular cells in rat hippocampus. METHODS: Rats were injected with bromodeoxyuridine to label proliferating cells in the dentate gyrus after single/multiple electroconvulsive seizures in a dose-response study and at various time points after single electroconvulsive seizures in a time-course study. RESULTS: A dose-response effect on the number of bromodeoxyuridine-labeled endothelial cells located in the granule cell layer, hilus, and molecular layer was noted, as was the case with the number of neural precursors in the subgranular zone. The time-course study revealed that endothelial cell and neural precursor proliferation occurred in concert in response to a single electroconvulsive seizure. CONCLUSIONS: Our data suggest that in response to electroconvulsive seizures, endothelial cell and neural proliferation is coregulated. The increase in endothelial cell proliferation may act to support the increased neural proliferation and neuronal activity or vice versa, possibly leading to structural changes within the hippocampus of importance for the antidepressant effect of electroconvulsive seizures.

Neuronal apoptosis after brief and prolonged seizures.

Evidence has accumulated that apoptotic cell death contributes to brain damage following experimental seizures. A substantial number of degenerating neurons within limbic regions display morphological features of apoptosis following prolonged seizures evoked by systemic or local injections of kainic acid, systemic injections of pilocarpine and sustained stimulation of the perforant path. Although longer periods of seizures consistently result in brain damage, it has previously not been clear whether brief single or intermittent seizures lead to cell death. However, recent results indicate that also single seizures lead to apoptotic neuronal death. A brief, non-convulsive seizure evoked by kindling stimulation was found to produce apoptotic neurons bilaterally in the rat dentate gyrus. The mechanism triggering and mediating apoptotic degeneration is at present being studied. Alterations in the expression and activity of cell-death regulatory proteins such as members of the Bcl-2 family and the cysteinyl aspartate-specific proteinase (caspase) family occur in regions vulnerable to cell degeneration, suggesting an involvement of these factors in mediating apoptosis following seizures. Findings of decreased apoptotic cell death following administration of caspase inhibitors prior to and following experimentally induced status epilepticus, further suggest a role for caspases in seizure-evoked neuronal degeneration. Intermediate forms of cell death with both necrotic and apoptotic features have been found after seizures and investigation into the detailed mechanisms of the different forms of cell degeneration is needed before attempts to specific prevention can be made.

Measurement of cortical and hippocampal epileptiform activity in freely moving rats by means of implantable radiotelemetry.

Implanted radiotelemetry has been used for the measurement of cortical electroencephalogram (EEG), locomotor activity, body temperature and cardiovascular parameters. This technique allows high quality data acquisition from freely moving animals with no complications of externalised apparatus. This paper focuses on the methodology for short and long-term monitoring of epileptiform activity by simultaneous cortical EEG, hippocampal (HC) EEG and electromyogram (EMG) in rats. The circadian rhythm of temperature (CRT) was monitored after surgery to estimate the need for post surgical recovery of animals. Different placements of EMG electrodes were assessed in order to minimise artefacts and increase sensitivity. The occurrence of epileptiform ictal and interictal activity following an acute injection of either 40 mg/kg pentylenetetrazole (PTZ) or 13.8 mg/kg kainic acid (KA) was investigated. The occurrence of spontaneous seizures was also monitored 5-8 weeks after administration of KA. The present study demonstrated a sensitive method for monitoring cortical EEG, hippocampal EEG and EMG short and long-term by implantable radiotelemetry in freely moving rats.

Harnessing endogenous stem cells to treat neurodegenerative disorders of the basal ganglia.

New neurons are continuously generated in selective regions of the normal adult mammalian brain. Recent evidence suggests that neural stem or progenitor cells located in the subventricular zone lining of the lateral ventricles can be induced to proliferate and migrate to the adjacent striatum following brain insults or growth factor treatment. This ability to incorporate new cells into the striatum gives the potential of repairing and restoring basal ganglia functions in Parkinson's and Huntington's diseases. The future challenges lay in directing these new cells to adopt the appropriate neuronal phenotypes and to re-establish proper connections and functional circuitry.

Spontaneous epileptic rats show changes in sleep architecture and hypothalamic pathology.

PURPOSE: The goal of the present study was to investigate the relationship between sleep, hypothalamic pathology, and seizures in spontaneous epileptic rats. METHODS: Rats were implanted with radiotelemetry transmitters for measuring electrocorticogram (ECoG) and stimulation electrodes in the hippocampus. Epileptogenesis was triggered by 2 h of electical stimulation-induced self-sustained status epilepticus (SSSE). After SSSE, ECoGs were monitored over a 15-week period for the occurrence of interictal high-amplitude low-frequency (HALF) acitvity and spontaneous reoccurring seizures (SRSs). RESULTS: Spontaneous epileptic rats showed clinical features of temporal lobe epilepsy (TLE), such as spontaneous seizures, interictal activity and neuronal cell loss in the dorsomedial hypothalamus, a region important for normal sleep regulation. Interestingly, epileptic rats showed disturbances in sleep architecture, with a high percentage of the seizures occurring during sleep. CONCLUSIONS: Therefore we conclude that a close association exists between epileptiform activity and alterations in sleep architecture that may be related to hypothalamic pathology.

Reduced hippocampal neurogenesis in R6/2 transgenic Huntington's disease mice.

We investigated whether cell proliferation and neurogenesis are altered in R6/2 transgenic Huntington's disease mice. Using bromodeoxyuridine (BrdU), we found a progressive decrease in the number of proliferating cells in the dentate gyrus of R6/2 mice. This reduction was detected in pre-symptomatic mice, and by 11.5 weeks, R6/2 mice had 66% fewer newly born cells in the hippocampus. The results were confirmed by immunohistochemistry for the cell cycle markers Ki-67 and proliferating cell nuclear antigen (PCNA). We did not observe changes in cell proliferation in the R6/2 subventricular zone, indicating that the decrease in cell proliferation is specific for the hippocampus. This decrease corresponded to a reduction in actual hippocampal neurogenesis as assessed by double immunostaining for BrdU and the neuronal marker neuronal nuclei (NeuN) and by immunohistochemistry for the neuroblast marker doublecortin. Reduced hippocampal neurogenesis may be a novel neuropathological feature in R6/2 mice that could be assessed when evaluating potential therapies.

No evidence for new dopaminergic neurons in the adult mammalian substantia nigra.

A recent report by Zhao et al. [Zhao, M., Momma, S., Delfani, K., Carlen, M., Cassidy, R. M., Johansson, C. B., Brismar, H., Shupliakov, O., Frisen, J. & Janson, A. M. (2003) Proc. Natl. Acad. Sci. USA 100, 7925-7930] suggests that dopaminergic neurons, the cell type lost in Parkinson's disease, are continuously generated in the adult substantia nigra pars compacta. Using similar methodological procedures to label dividing cells, we found no evidence of new dopaminergic neurons in the substantia nigra, either in normal or 6-hydroxydopamine-lesioned hemi-Parkinsonian rodents, or even after growth factor treatment. Furthermore, we found no evidence of neural stem cells emanating from the cerebroventricular system and migrating to the substantia nigra. We conclude that it is unlikely that dopaminergic neurons are generated in the adult mammalian substantia nigra.

Status epilepticus severity influences the long-term outcome of neurogenesis in the adult dentate gyrus.

Status epilepticus (SE) is characterized by continual seizure activity that can vary widely in the intensity of convulsions. We induced seizures by applying continuous electrical stimulation to the hippocampus in adult rats to explore the effects of three different SE states on neurogenesis and neuronal death in the hippocampus. Rats exhibiting the most severe SE state (fully convulsive) demonstrated profound increases in cell proliferation in the dentate gyrus (DG) at 1 week post-insult, but the majority of the new neurons had died at 4 weeks. In contrast, rats exhibiting less severe SE states (ambulatory or masticatory, partial convulsive) had the same degree of cell proliferation at 1 week, but most new neurons survived at 4 weeks. As compared to partially convulsive SE rats, fully convulsive SE rats had significantly greater DG pathology. Our data indicate that SE of varying severity triggers similar short-term proliferation of neural progenitors, but that the long-term outcome of neurogenesis is influenced by the degree of insult-induced degeneration in the DG tissue environment.

Caspase-mediated death of newly formed neurons in the adult rat dentate gyrus following status epilepticus.

A large proportion of cells that proliferate in the adult dentate gyrus under normal conditions or in response to brain insults exhibit only short-term survival. Here, we sought to determine which cell death pathways are involved in the degeneration of newly formed neurons in the rat dentate gyrus following 2 h of electrically induced status epilepticus. We investigated the role of three families of cysteine proteases, caspases, calpains, and cathepsins, which can all participate in apoptotic cell death. Status epilepticus increased the number of bromodeoxyuridine (BrdU)-positive proliferated cells in the subgranular zone of the dentate gyrus. At the time of maximum cell proliferation, immunohistochemical analyses revealed protein expression of active caspase-cleaved poly (ADP-ribose) polymerase (PARP) in approximately 66% of the BrdU-positive cells, while none of them expressed cathepsin B or the 150-kDa calpain-produced fodrin breakdown product. To evaluate the importance of cysteine proteases in regulating survival of the newly formed neurons, we administered intracerebroventricular infusions of a caspase inhibitor cocktail (zVAD-fmk, zDEVD-fmk and zLEHD-fmk) over a 2-week period, sufficient to allow for neuronal differentiation, starting 1 week after the epileptic insult. Increased numbers of cells double-labelled with BrdU and neuron-specific nuclear protein (NeuN) marker were detected in the subgranular zone and granule cell layer of the caspase inhibitor-treated rats. Our data indicate that caspase-mediated cell death pathways are active in progenitor cell progeny generated by status epilepticus and compromise survival during neuronal differentiation.

Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment.

Major depression is often associated with elevated glucocorticoid levels. High levels of glucocorticoids reduce neurogenesis in the adult rat hippocampus. Electroconvulsive seizures (ECS) can enhance neurogenesis, and we investigated the effects of ECS in rats where glucocorticoid levels were elevated in order to mimic conditions seen in depression. Rats given injections of corticosterone or vehicle for 21 days were at the end of this period treated with either a single or five daily ECSs. Proliferating cells were labelled with bromodeoxyuridine (BrdU). After 3 weeks, BrdU-positive cells in the dentate gyrus were quantified and analyzed for co-labelling with the neuronal marker neuron-specific nuclear protein (NeuN). In corticosterone-treated rats, neurogenesis was decreased by 75%. This was counteracted by a single ECS. Multiple ECS further increased neurogenesis and no significant differences in BrdU/NeuN positive cells were detected between corticosterone- and vehicle-treated rats given five ECS. Approximately 80% of the cells within the granule cell layer and 10% of the hilar cells were double-labelled with BrdU and NeuN. We therefore conclude that electroconvulsive seizures can increase hippocampal neurogenesis even in the presence of elevated levels of glucocorticoids. This further supports the hypothesis that induction of neurogenesis is an important event in the action of antidepressant treatment.

Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke.

To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.