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Unitary pallido-nigral synaptic currents were measured using optogenetic stimulation, which activated up to three unitary synaptic inputs to each substantia nigra pars reticulata (SNr) cell. Episodic barrages of synaptic conductances were generated based on in vivo firing patterns of globus pallidus pars externa (GPe) cells and applied to SNr cells using conductance clamp. Barrage inputs were compared to continuous step conductances with the same mean. Barrage inputs and steps both slowed SNr neuron firing and produced disinhibition responses seen in peristimulus histograms. Barrages were less effective than steps at producing inhibition and disinhibition responses. Barrages, but not steps, produced irregular firing during the inhibitory response. Phase models of SNr neurons were constructed from their phase-resetting curves. The phase models reproduced the inhibition and disinhibition responses to the same inputs applied to the neurons. The disinhibition response did not require rebound currents but arose from reset of the cells’ oscillation. The differences in firing rate and irregularity in response to barrage and step inhibition resulted from the high sensitivity of SNr neurons to inhibition at late phases in their intrinsic oscillation. During step inhibition, cells continued rhythmic firing at a reduced rate. During barrages, brief bouts of intense inhibition stalled the cells’ phase evolution late in their cycle, close to firing, and even very brief respites from inhibition rapidly released single action potentials. The SNr cell firing pattern reflected the fine structure of the synaptic barrage from GPe, as well as its onset and offset. NEW & NOTEWORTHY The pallido-nigral pathway connects the striatum to spontaneously active basal ganglia output neurons in the substantia nigra. Each substantia nigra neuron receives powerful inhibitory synaptic connections from a small group of globus pallidus cells and may fire during pauses in pallidal activity. Despite lacking any hyperpolarization-activated rebound currents, they fire quickly to even brief pauses in the pallido-nigral inhibition. The mechanism of their rapid disinhibitory response is explained by features of their phase-resetting curves.

Background The Y-Balance Test (YBT) assesses dynamic stability and neuromuscular control of the lower extremity. Several authors have analyzed kinematic predictors of YBT performance with conflicting results, but the influence of kinetic factors is not well understood. Purpose To examine kinematic predictors of YBT performance and determine the joint kinetics which predict YBT performance. Study Design Cross-sectional study. Methods Thirty-one physically active individuals performed YBT trials on a force plate while whole body kinematics were recorded using a motion capture system. Sagittal, frontal, and transverse plane joint kinematics and joint moments were calculated at maximum reach in each YBT reach direction. Variables correlated with reach distances at the p < 0.2 level were entered into a stepwise linear regression. Results In the anterior direction, knee flexion and torso rotation (R2=0.458, pR2=0.461, pppR2=0.696, pR2=0.433, p=0.001) were the best kinematic and kinetic predictors of reach distance. Conclusion The ability to generate large hip and knee joint moments in the sagittal and frontal plane are critical for YBT performance. Level of Evidence 3.

Striatal interneurons and spiny projection (SP) neurons are differentially tuned to spectral components of their input. Previous studies showed that spike responses of somatostatin/NPY-expressing low threshold spike (LTS) interneurons have broad frequency tuning, setting these cells apart from other striatal GABAergic interneurons and SP neurons. We investigated the mechanism of LTS interneuron spiking resonance and its relationship to non-spiking membrane impedance resonance, finding that abolition of impedance resonance did not alter spiking resonance. Because LTS interneurons are pacemakers whose rhythmic firing is perturbed by synaptic input, we tested the hypothesis that their spiking resonance arises from their phase resetting properties. Phase resetting curves (PRCs) were measured in LTS interneurons and SP neurons and used to make phase-oscillator models of both cell types. The models reproduced the broad tuning of LTS interneurons, and the differences from SP neurons. The spectral components of the PRC predicted each cell’s sensitivity to corresponding input frequencies. LTS interneuron PRCs contain larger high-frequency components than SP neuron PRCs, providing enhanced responses to input frequencies above the cells’ average firing rates. Thus, LTS cells can be entrained by input oscillations to which SP neurons are less responsive. These findings suggest that feedforward inhibition by LTS interneurons may regulate SP neurons’ entrainment by oscillatory afferents.

Background The phase resetting curve (PRC) is a primary measure of a rhythmically firing neuron's responses to synaptic input, quantifying the change in phase of the firing oscillation as a function of the input phase. PRCs provide information about whether neurons will synchronize due to synaptic coupling or shared input. However, PRC estimation has been limited to in vitro preparations where stable intracellular recordings can be obtained and background activity is minimal, and new methods are required for in vivo applications. New method We estimated PRCs using dense optogenetic stimuli and extracellular spike recording. Autonomously firing neurons in substantia nigra pars reticulata (SNr) of Thy1-channelrhodopsin 2 (ChR2) transgenic mice were stimulated with random barrages of light pulses, and PRCs were determined using multiple linear regression. Results The PRCs obtained were type-I, showing only phase advances in response to depolarizing input, and generally sloped upward from early to late phases. Secondary PRCs, indicating the effect on the subsequent ISI, showed phase delays primarily for stimuli arriving at late phases. Phase models constructed from the optogenetic PRCs accounted for a large fraction of the variance in ISI length and provided a good approximation of the spike-triggered average stimulus. Comparison with existing methods Compared to methods based on intracellular current injection, the new method sacrifices some temporal resolution. However, it should be much more widely applicable in vivo , because only extracellular recording and optogenetic stimulation are required. Conclusions These results demonstrate PRC estimation using methods suitable for in vivo applications.

Anatomical studies have shown that the majority of callosal axons are glutamatergic. However, a small proportion of callosal axons are also immunoreactive for glutamic acid decarboxylase, an enzyme required for gamma-aminobutyric acid (GABA) synthesis and a specific marker for GABAergic neurons. Here, we test the hypothesis that corticocortical parvalbumin-expressing (CC-Parv) neurons connect the two hemispheres of multiple cortical areas, project through the corpus callosum, and are a functional part of the local cortical circuit. Our investigation of this hypothesis takes advantage of viral tracing and optogenetics to determine the anatomical and electrophysiological properties of CC-Parv neurons of the mouse auditory, visual, and motor cortices. We found a direct inhibitory pathway made up of parvalbumin-expressing (Parv) neurons which connects corresponding cortical areas (CC-Parv neurons → contralateral cortex). Like other Parv cortical neurons, these neurons provide local inhibition onto nearby pyramidal neurons and receive thalamocortical input. These results demonstrate a previously unknown long-range inhibitory circuit arising from a genetically defined type of GABAergic neuron that is engaged in interhemispheric communication.

It is often necessary to dissect the subcutaneous tissues to confirm or exclude the presence of cutaneous bruising. We undertook a literature search that demonstrated that there is currently no standardized technique for subcutaneous dissection, and the specific incisions and dissections used probably vary between individual pathologists. It is our experience that dissections wider than the area of cutaneous bruising visible externally often reveal bruises not identified on external inspection. We propose a standardized technique for subcutaneous dissection of the upper limb that allows direct inspection of the subcutaneous tissues of the forearm and dorsum of the hand. We have evaluated this technique by comparing the number of bruises detected on external inspection with the number of bruises verified by subcutaneous dissection. Our study has shown a significant increase in the detection of bruises on subcutaneous dissection when compared with external inspection alone. One hundred sixteen forensic autopsies in which the technique was performed were included in our series. We recorded bruises seen on external examination alone and compared the number with additional bruises that were discovered on dissecting the upper limbs. In 49 cases (42%), the technique uncovered additional bruises that were missed on external examination alone.

Although the relative expansion of the frontal cortex in primate evolution is generally accepted, the nature of the human uniqueness, if any, and between-species anatomo-functional comparisons of the frontal areas remain controversial. To provide a novel interpretation of the evolution of primate brains, sulcal morphological variability of the medial frontal cortex was assessed in old-world monkeys (macaque, baboon) and Hominoidea (chimpanzee, human). We discovered that both Hominoidea do possess a paracingulate sulcus, which was previously thought to be uniquely human and linked to higher cognitive functions like mentalizing. Also, we revealed systematic sulcal morphological organisations of the medial frontal cortex that can be traced from multiple old-world monkey to Hominoidea species, demonstrating an evolutionary conserved organizational principle. Our data provide a new framework to compare sulcal morphology, cytoarchitectonic areal distribution, connectivity, and function across the primate order, leading to clear predictions on how other primate brains might be anatomo-functionally organized.

The sulcal morphology of the human medial frontal cortex has received marked interest because of (1) its remarkable link with the functional organization of this region, and (2) observations that deviations from ‘normal’ sulcal morphological variability correlate with the prevalence of some psychiatric disorders, cognitive abilities, or personality traits. Unfortunately, background studies on environmental or genetic factors influencing the ontogenesis of the sulcal organization in this region are critically lacking. We analysed the sulcal morphological organization in this region in twins and non-twin siblings, as well as in control subjects for a total of 599 subjects from the Human Connectome Project. The data first confirm significant biases in the presence of paracingulate sulci in left vs right hemispheres in the whole population (twin: p −9; non-twin: p −6) demonstrating a clear general laterality in human subjects. Second, measures of similarity between siblings and estimations of heritability suggest significant environmental factors, in particular in-womb environment, and weak additive genetic factors influencing the presence of a paracingulate sulcus. Finally, we found that relationships between sulcal organization and performance in cognitive, motor, and affective tests depend on the twin status (Twins versus Non-twins). These results provide important new insights to the issue of the significance of sulcal organization in the human medial frontal cortex.

Neurons respond to synaptic inputs in cell-type-specific ways. Each neuron type may thus respond uniquely to shared patterns of synaptic input. We applied statistically identical barrages of artificial synaptic inputs to four striatal cell types to assess differences in their responses to a realistic input pattern. Each interneuron type fired in phase with a specific input-frequency component. The fast-spiking interneuron fired in relation to the gamma-band (and higher) frequencies, the low-threshold spike interneuron to the beta-band frequencies, and the cholinergic neurons to the delta-band frequencies. Low-threshold spiking and cholinergic interneurons showed input impedance resonances at frequencies matching their spiking resonances. Fast-spiking interneurons showed resonance of input impedance but at lower than gamma frequencies. The spiny projection neuron's frequency preference did not have a fixed frequency but instead tracked its own firing rate. Spiny cells showed no input impedance resonance. Striatal interneurons are each tuned to a specific frequency band corresponding to the major frequency components of local field potentials. Their influence in the circuit may fluctuate along with the contribution of that frequency band to the input. In contrast, spiny neurons may tune to any of the frequency bands by a change in firing rate.

The role of the phase response curve (PRC) shape on the synchrony of synaptically coupled oscillating neurons is examined. If the PRC is independent of the phase, because of the synaptic form of the coupling, synchrony is found to be stable for both excitatory and inhibitory coupling at all rates, whereas the antisynchrony becomes stable at low rates. A faster synaptic rise helps extend the stability of antisynchrony to higher rates. If the PRC is not constant but has a profile like that of a leaky integrate-and-fire model, then, in contrast to the earlier reports that did not include the voltage effects, mutual excitation could lead to stable synchrony provided the synaptic reversal potential is below the voltage level the neuron would have reached in the absence of the interaction and threshold reset. This level is controlled by the applied current and the leakage parameters. Such synchrony is contingent on significant phase response (that would result, for example, by a sharp PRC jump) occurring during the synaptic rising phase. The rising phase, however, does not contribute significantly if it occurs before the voltage spike reaches its peak. Then a stable near-synchronous state can still exist between type 1 PRC neurons if the PRC shows a left skewness in its shape. These results are examined comprehensively using perfect integrate-and-fire, leaky integrate-and-fire, and skewed PRC shapes under the assumption of the weakly coupled oscillator theory applied to synaptically coupled neuron models.

Histological and morphological studies indicate that approximately 5% of striatal neurons are cholinergic or γ-aminobutyric acidergic (GABAergic) interneurons (gINs). However, the number of striatal neurons expressing known interneuron markers is too small to account for the entire interneuron population. We therefore studied the serotonin (5HT) receptor 3a-enhanced green fluorescent protein (5HT3a(EGFP)) mouse, in which we found that a large number of striatal gINs are labeled. Roughly 20% of 5HT3a(EGFP)-positive cells co-express parvalbumin and exhibit fast-spiking (FS) electrophysiological properties. However, the majority of labeled neurons do not overlap with known molecular interneuron markers. Intrinsic electrical properties reveal at least 2 distinct novel subtypes: a late-spiking (LS) neuropeptide-Y (NPY)-negative neurogliaform (NGF) interneuron, and a large heterogeneous population with several features resembling low-threshold-spiking (LTS) interneurons that do not express somatostatin, NPY, or neuronal nitric oxide synthase. Although the 5HT3a(EGFP) NGF and LTS-like interneurons have electrophysiological properties similar to previously described populations, they are pharmacologically distinct. In direct contrast to previously described NPY(+) LTS and NGF cells, LTS-like 5HT3a(EGFP) cells show robust responses to nicotine administration, while the 5HT3a(EGFP) NGF cell type shows little or no response. By constructing a molecular map of the overlap between these novel populations and existing interneuron populations, we are able to reconcile the morphological and molecular estimates of striatal interneuron numbers.

The cytoarchitecturally-homogeneous appearance of the globus pallidus, subthalamic nucleus and substantia nigra has long been said to imply a high degree of afferent convergence and sharing of inputs by nearby neurons. Moreover, axon collaterals of neurons in the external segment of the globus pallidus and the substantia nigra pars reticulata arborize locally and make inhibitory synapses on other cells of the same type. These features suggest that the connectivity of the basal ganglia may impose spike-time correlations among the cells, and it has been puzzling that experimental studies have failed to demonstrate such correlations. One possible solution arises from studies of firing patterns in basal ganglia cells, which reveal that they are nearly all pacemaker cells. Their high rate of firing does not depend on synaptic excitation, but they fire irregularly because a dense barrage of synaptic inputs normally perturbs the timing of their autonomous activity. Theoretical and computational studies show that the responses of repetitively-firing neurons to shared input or mutual synaptic coupling often defy classical intuitions about temporal synaptic integration. The patterns of spike-timing among such neurons depend on the ionic mechanism of pacemaking, the level of background uncorrelated cellular and synaptic noise, and the firing rates of the neurons, as well as the properties of their synaptic connections. Application of these concepts to the basal ganglia circuitry suggests that the connectivity and physiology of these nuclei may be configured to prevent the establishment of permanent spike-timing relationships between neurons. The development of highly synchronous oscillatory patterns of activity in Parkinson's disease may result from the loss of pacemaking by some basal ganglia neurons, and accompanying breakdown of the mechanisms responsible for active decorrelation.

The relationship between anterograde and retrograde amnesia remains unclear. Previous data from both clinical neuropsychology and monkey lesion studies suggest that damage to discrete subcortical structures leads to a relatively greater degree of anterograde than retrograde amnesia, whereas damage to discrete regions of cortex leads to the opposite pattern of impairments. Nevertheless, damage to the medial diencephalon in humans is associated with both retrograde and anterograde amnesia. In the present study, we sought to reconcile this by assessing retention as well as subsequent relearning and new postoperative learning. Rhesus monkeys learned 300 unique scene discriminations preoperatively, and retention was assessed in a preoperative and postoperative one-trial retrieval test. Combined bilateral subcortical lesions to the magnocellular mediodorsal thalamus and fornix impaired postoperative retention of the preoperatively acquired information. In addition, subsequent relearning and new postoperative learning were also impaired. This contrasts with the effects of a discrete lesion to just one of these structures, after which retention is intact in both cases. Discrete bilateral ablations to the entorhinal cortex impaired retention but had no effect on new learning. Combined with previous work from our laboratory, these results support the hypothesis that subcortical damage has a relatively greater effect on new learning, and cortical damage has a relatively greater effect on retention. Furthermore, the results demonstrate that retrograde amnesia occurs as a result of subcortical damage only if it is widespread, leading to an extensive disruption of cortical functioning. Damage of this nature may account for dense amnesia. Copyright © 2008 Society for Neuroscience.

Striatal low-threshold spiking (LTS) interneurons spontaneously transition to a depolarized, oscillating state similar to that seen after sodium channels are blocked. In the depolarized state, whether spontaneous or induced by sodium channel blockade, the neurons express a 3- to 7-Hz oscillation and membrane impedance resonance in the same frequency range. The membrane potential oscillation and membrane resonance are expressed in the same voltage range (greater than −40 mV). We identified and recorded from LTS interneurons in striatal slices from a mouse that expressed green fluorescent protein under the control of the neuropeptide Y promoter. The membrane potential oscillation depended on voltage-gated calcium channels. Antagonism of L-type calcium currents (CaV1) reduced the amplitude of the oscillation, whereas blockade of N-type calcium currents (CaV2.2) reduced the frequency. Both calcium sources activate a calcium-activated chloride current (CaCC), the blockade of which abolished the oscillation. The blocking of any of these three channels abolished the membrane resonance. Immunohistochemical staining indicated anoctamin 2 (ANO2), and not ANO1, as the CaCC source. Biophysical modeling showed that CaV1, CaV2.2, and ANO2 are sufficient to generate a membrane potential oscillation and membrane resonance, similar to that in LTS interneurons. LTS interneurons exhibit a membrane potential oscillation and membrane resonance that are both generated by CaV1 and CaV2.2 activating ANO2. They can spontaneously enter a state in which the membrane potential oscillation dominates the physiological properties of the neuron.

Anatomical and physiological studies have led to the assumption that the dorsal striatum receives exclusively excitatory afferents from the cortex. Here we test the hypothesis that the dorsal striatum receives also GABAergic projections from the cortex. We addressed this fundamental question by taking advantage of optogenetics and directly examining the functional effects of cortical GABAergic inputs to spiny projection neurons (SPNs) of the mouse auditory and motor cortex. We found that the cortex, via corticostriatal somatostatin neurons (CS-SOM), has a direct inhibitory influence on the output of the striatum SPNs. Our results describe a corticostriatal long-range inhibitory circuit (CS-SOM inhibitory projections → striatal SPNs) underlying the control of spike timing/generation in SPNs and attributes a specific function to a genetically defined type of cortical interneuron in corticostriatal communication. DOI: http://dx.doi.org/10.7554/eLife.15890.001, eLife digest The striatum is located beneath the cerebral cortex, where it contributes to processes including learning and movement. The Spanish anatomist Ramon y Cajal, working in the early 20th century, was the first to observe individual neurons extending from the cortex to the striatum. Cajal published drawings of these neurons in his now celebrated anatomical papers, but knew little about their properties. In the 1980s, advances in techniques for labeling individual cells made it possible to study these neurons in detail. The results suggested that the pathways are exclusively excitatory: that is, the cortical neurons always increase the activity of their partners in the striatum. However, this result made it difficult to explain why electrically stimulating the cortex can sometimes reduce or inhibit the activity of the striatum. To reconcile these facts, most people assumed that inhibition must occur when excitatory cortical neurons activate networks of inhibitory cells within the striatum itself. Rock et al. now challenge this view by providing anatomical and physiological evidence for the existence of long-range inhibitory pathways from the cortex to the striatum in the mouse brain. These inhibitory neurons project from the auditory and motor regions of the cortex, and contain a substance called somatostatin. These neurons form connections with a specific type of striatal neuron called medium spiny neurons, which in turn project to other brain regions outside the striatum. The inhibitory cortical neurons can alter the activity of the medium spiny neurons, and can therefore directly control the output of the striatum. The discovery that the striatum receives both excitatory and inhibitory inputs from cortex suggests that the timing and relative strength of these inputs can affect the activity of the striatum. Future experiments should examine whether this is a general mechanism by which sensory stimuli can influence the processes controlled by the striatum, such as movement. DOI: http://dx.doi.org/10.7554/eLife.15890.002

Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was −64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate.

Summary The basal ganglia are involved in sensorimotor functions and action selection, both of which require the integration of sensory information. In order to determine how such sensory inputs are integrated, we obtained whole-cell recordings in mouse dorsal striatum during presentation of tactile and visual stimuli. All recorded neurons responded to bilateral whisker stimulation, and a subpopulation also responded to visual stimulation. Neurons responding to both visual and tactile stimuli were located in dorsomedial striatum, whereas those responding only to whisker deflections were located dorsolaterally. Responses were mediated by overlapping excitation and inhibition, with excitation onset preceding that of inhibition by several milliseconds. Responses differed according to the type of neuron, with direct pathway MSNs having larger responses and longer latencies between ipsilateral and contralateral responses than indirect pathway MSNs. Our results suggest that striatum acts as a sensory “hub” with specialized functional roles for the different neuron types., Highlights • Sensory integration in mouse striatum was studied using whole-cell in vivo recordings • Neurons in dorsomedial striatum integrate tactile and visual sensory inputs • Sensory responses are mediated by overlapping excitation and inhibition • Bilateral sensory input is integrated differently by direct and indirect pathway MSNs, In the paper by Reig and Silberberg, the authors describe integration of multisensory inputs by neurons in the striatum, the main input structure of the basal ganglia. Multisensory responding neurons included both types of projection neurons and interneurons.

Neurons of the subthalamic nucleus (STN) are very sensitive to applied currents, firing at 10–20/s during spontaneous activity, but increasing to peak firing rates of 200/s with applied currents + current. This current was independent of calcium or sodium entry and could be induced with long-duration voltage steps after blockade of action potentials. In addition to the adaptation current, driven firing produced slow inactivation of the persistent Na+ current, which also contributed to the reduced excitability of STN cells during and after driven firing.

Differences in the biological and ecological strategies of two tropical flatfishes, Etropus crossotus (fringed flounder) and Citharichthys spilopterus (bay whiff) are discussed. The comparative analysis was based on the seasonal distribution of relative abundance of the two species and flatfish movements utilizing estuarine plume influenced areas as part of their life cycles. Growth parameters of the von Bertalanffy equation and recruitment were estimated (FISAT software) to compare life cycle patterns. The recruitment patterns illustrate the key difference between “estuarine-dependent” and “estuarine-related” nekton strategies. Both species have a short life cycle with a continuous recruitment activity. E. crossotus is an estuarine-related species, with two recruitment pulses (winter frontal season), in the estuarine plume on the shelf. C. spilopterus is an estuarine-dependent species, with a main recruitment pulse during the rainy season in the estuarine plume, and a residual secondary pulse inside the adjacent estuarine system (Terminos Lagoon). The results show that the ecological success of these tropical coastal marine flatfish, with similar biological patterns, is based upon the sequential use (in time and space) of estuarine plume influenced habitats, suggesting that fish migration to shallow waters is related to food availability changes as a strategy towards optimum recruitment.

We examined otolith chemistry of age-0 red snapper Lutjanus campechanus in U.S. waters of the northern Gulf of Mexico (GOM) to determine if otolith elemental signatures could be employed as natural tags to estimate postsettlement population connectivity. Fish (n = 755) belonging to five successive year-classes (1996-2000) were sampled from three GOM regions. Solution-based analysis of otolith chemistry was accomplished with sector field-inductively coupled plasma-mass spectrometry (Ba, Mg, Mn, and Sr) and inductively coupled plasma-optical emissions spectrometry (Ca). Several regional trends observed for individual elements were consistent among year-classes, yet elemental signatures were significantly different among years as well as among regions (multivariate analysis of variance [MANOVA]; p < 0.001). Jackknifed classification accuracies from linear discriminant function analysis approached 80% (mean = 78.4%) in all years except 1998 (62.4%). Overall, these results indicate otolith elemental s...

Cholinergic interneurons make up a tiny fraction of cells in the striatum, but yet are critical modulators of neuronal excitability, synaptic transmission, and synaptic plasticity within the striatal circuitry, primarily through activation of muscarinic receptors. Cholinergic interneurons are tonically active in primates and rodents, and display various rhythmic and irregular firing patterns that are generated autonomously. A pause in their ongoing activity represents the motivational value of external stimuli. Cholinergic interneurons receive extrinsic input from various brain regions, notably glutamatergic input from cortex and thalamus, dopaminergic input from the substantia nigra pars compacta, and GABAergic input primarily of striatal origin. Here, we briefly review what is known about the biophysics of these neurons and of their neuromodulatory role. In addition, we review recent findings that underscore the fast nicotinic action of cholinergic interneurons on striatal circuitry, especially when these neurons are activated synchronously.

Summary Purpose: To determine whether hippocampal sclerosis might form an anatomical substrate for pathological high-frequency oscillations in patients with temporal lobe epilepsy (TLE). Methods: Intracerebral wide bandwidth electroencephalogram was recorded in patients with medically intractable complex partial seizures. A computer-automated program detected interictal normal ripples (80–150 Hz) and pathologic fast ripples (FR, 151–500 Hz) from microelectrodes within hippocampus, entorhinal, and subicular cortices. Hippocampal MRI volumetric analysis and cell density measurements were correlated with rates of FR and ripple discharge. Results: In all 13 patients, higher rates of FR (p = 0.03) and ratios of FR to ripple discharges (p = 0.02) were observed in sites ipsilateral to seizure onset compared with rates within contralateral nonictal sites. Higher ratios of FR to ripple discharge were associated with smaller ipsilateral hippocampal volumes (p = 0.02) and lower fascia dentata (FD; p = 0.02) and Ammon's horn (p = 0.0005) neuron densities. While reduced FD and Ammon's horn neuron densities correlated with higher ratios of discharges, stepwise multiple regression analysis revealed that decreased neuron densities within CA1 and prosubiculum regions most strongly predicted ratios of FR to ripples (r2= 0.78, p = 0.008). Conclusions: In surgical patients with TLE, higher ratios of FR to ripple discharges are associated with histopathologic changes found in hippocampal sclerosis. These findings support the hypothesis that pathological alterations linked with hippocampal cell loss and synaptic reorganization promote FR and reduce ripple generation.

Disconnection of the frontal lobe from the inferotemporal cortex produces deficits in a number of cognitive tasks that require the application of memory-dependent rules to visual stimuli. The specific regions of frontal cortex that interact with the temporal lobe in performance of these tasks remain undefined. One capacity that is impaired by frontal–temporal disconnection is rapid learning of new object-in-place scene problems, in which visual discriminations between two small typographic characters are learned in the context of different visually complex scenes. In the present study, we examined whether neurotoxic lesions of ventrolateral prefrontal cortex in one hemisphere, combined with ablation of inferior temporal cortex in the contralateral hemisphere, would impair learning of new object-in-place scene problems. Male macaque monkeys learned 10 or 20 new object-in-place problems in each daily test session. Unilateral neurotoxic lesions of ventrolateral prefrontal cortex produced by multiple injections of a mixture of ibotenate and N-methyl-d-aspartate did not affect performance. However, when disconnection from inferotemporal cortex was completed by ablating this region contralateral to the neurotoxic prefrontal lesion, new learning was substantially impaired. Sham disconnection (injecting saline instead of neurotoxin contralateral to the inferotemporal lesion) did not affect performance. These findings support two conclusions: first, that the ventrolateral prefrontal cortex is a critical area within the frontal lobe for scene memory; and second, the effects of ablations of prefrontal cortex can be confidently attributed to the loss of cell bodies within the prefrontal cortex rather than to interruption of fibres of passage through the lesioned area.

The goal of this study was to characterize the electrophys- iological features of single neurons recorded deep within the medial tem- poral lobes in humans. Using three physiological criteria to distinguish principal cells and interneurons (firing rate, burst propensity, and action potential waveform) and a large data set of human single neurons (585) from thirteen patients, we show that single neurons in the human MTL separate into two distinct classes comparable to the pyramidal cell and interneuron classes described in animals. We also find that the four dif- ferent MTL brain regions that we examined (amygdala, hippocampus, entorhinal cortex, and posterior parahippocampal cortex) show unique action potential characteristics, which may in turn relate to the role that neurons from these regions play in behavior. A subset of cells were recorded while patients engaged in both slow-wave (SWS) and rapid-eye movement (REM) sleep and a comparison of the electrophysiological fea- tures during these different sleep stages showed that interneurons tended to burst more during SWS compared to REM, while only principal cells in the EC and hippocampus showed a greater propensity for bursting during SWS. Together, our results support the idea that human single neurons have electrophysiologically identifiable cell types, similar to those observed in other mammals, and provide insight into regional and func- tional differences in spike-wave characteristics relevant to considerations about neural populations in the human brain. V C 2006 Wiley-Liss, Inc.

SummaryStriatal cholinergic interneurons pause their ongoing firing in response to sensory stimuli that have acquired meaning as a signal for learned behavior. In slices, these cells exhibit both spontaneous activity patterns and spontaneous pauses very similar to those seen in vivo. The mechanisms responsible for ongoing firing and spontaneous pauses were studied in striatal slices using perforated patch recordings. All hyperpolarizations, whether spontaneous or generated by current injection, were amplified and shaped by two hyperpolarization-activated currents. Hyperpolarization onsets were regeneratively amplified by a potassium current (KIR) whose activation promoted further hyperpolarization. The termination of hyperpolarizations was controlled by a time-dependent nonspecific cation current (HCN). The duration and even the sizes of spontaneous and driven hyperpolarizations and pauses in spontaneous activity in cholinergic interneurons are largely autonomous properties of the neuron, rather than reflections of characteristics of the input eliciting the response.

The present study was performed (1) to explore the mechanism of skeletal healing following distraction osteogenesis of the mandible and to evaluate whether the same process is involved following acute mandibular resection and rigid external fixation, and (2) to examine the role of the periosteum in skeletal healing in both models. The study was performed using 16 mongrel dogs divided into two equal groups. In the first group, distraction of 20 mm was performed at a rate of 1 mm/day. In the second group, bone resection of 20 mm was performed, followed by rigid external fixation. The buccal periosteum was stripped in four dogs from each group, and the periosteum was left intact in the remaining four dogs. Dogs were euthanized after a survival period of either 2 or 3 months, and the new bone regenerate was evaluated. Analysis consisted of three-dimensional computed tomography scanning, histometric analysis, and immunostaining. Analysis of bone mineral content in the residual gap was conducted. Bone mineral content was increased in 3- versus 2-month survival for all groups (p < 0.05). The distracted groups had greater bone mineral content than their acutely resected counterparts, with the difference achieving statistical significance by 3-month survival (p < 0.05). Although periosteal preservation resulted in increased bone mineral content over time for all groups (p = 0.044), periosteal preservation had no significant effect on bone mineral content in the distracted groups. After periosteal stripping, however, bone mineral content was significantly increased in dogs that underwent distraction rather than acute resection and rigid external fixation (p = 0.022). Regarding histometric analysis, analysis of fibrous tissue content in the bone regenerate demonstrated that by 3 months the distracted groups had significantly less fibrous tissue in the new bone regenerate than did the acutely resected groups (p < 0.001). Regarding immunostaining, diffuse localization of transforming growth factor-beta1 was observed in all groups at 2 months, returning to nearly baseline levels by 3 months. These data demonstrate that significant bone formation in a segmental gap can be achieved after acute mandibular resection and rigid external fixation if the periosteum is preserved. However, after periosteal injury or stripping, significant bone formation can only be achieved by distraction osteogenesis. In both processes, bone formation is preceded by up-regulation of transforming growth factor-beta1.

The normal processes of learning and memory as well as the pathological progress of various neurological diseases may result in changes in gene expression in small, local populations of neurons in any given brain area, leading to the occurrence of specific patterns of electrical activity without easily detectable changes in the morphology of this brain area. One way of identifying these changes might be the comparison of gene expression of areas which generate and areas which do not generate specific patterns of electrical activity. A method for microbiopsy of limited (0.5-1.0 mm3) tissue samples from electrophysiologically identified areas of neurons generating epileptiform activity in the rat brain is described. Here we demonstrate that total RNA isolated from individual microbiopsy samples might be successfully used for microarray based gene expression analysis of any discretely localized neuronal group which can be identified electrophysiologically, including neurons in cortical columns, cell assemblies or other functional units.

OBJECTIVE To determine the usefulness of endovascular embolization for treatment of dural arteriovenous fistulae of the superior petrosal sinus. METHODS We performed a retrospective review of 18 patients treated during a 16-year period. Transarterial and/or transvenous embolizations were performed as a preoperative adjunct or definitive therapy. Clinical follow-up status was supplemented by telephone interviews to determine Glasgow Outcome Scale scores. RESULTS Fourteen patients (78%) were treated with a combination of endovascular therapy and open surgery, and 4 were treated by embolization alone (22%). Angiographic cure was achieved in all patients (100%). Thirty-day morbidity and mortality were 11 and 0%, respectively. The mean follow-up period was 5.4 years. At the latest follow-up examination, all patients had returned to independent clinical status (Glasgow Outcome Scale scores of 1 or 2). CONCLUSION Endovascular treatment of dural arteriovenous fistulae of the superior petrosal sinus can result in cure when access to the site of the fistula can be achieved. Preoperative embolization is a safe and effective adjunct to minimize bleeding during open neurosurgery.

The striatum and its dense dopaminergic innervation originating in the midbrain, primarily from the substantia nigra pars compacta and the ventral tegmental area, compose the mesostriatal dopamine (DA) systems. The nigrostriatal system is involved mainly in motor coordination and in disorders such as Tourette’s syndrome, Huntington’s disease, and Parkinson’s disease. The dopaminergic projections from the ventral tegmental area to the striatum participate more in the processes that shape behaviors leading to reward, and addictive drugs act upon this mesolimbic system. The midbrain DA areas receive cholinergic innervation from the pedunculopontine tegmentum and the laterodorsal pontine tegmentum, whereas the striatum receives dense cholinergic innervation from local interneurons. The various neurons of the mesostriatal systems express multiple types of muscarinic and nicotinic acetylcholine receptors as well as DA receptors. Especially in the striatum, the dense mingling of dopaminergic and cholinergic constituents enables potent interactions. Evidence indicates that cholinergic and dopaminergic systems work together to produce the coordinated functioning of the striatum. Loss of that cooperative activity contributes to the dysfunction underlying Parkinson’s disease.

The cellular events underlying various retinopathies are poorly understood but likely involve perturbation of retinal glucose metabolism. Current methods for assessing this metabolism are destructive, thus limiting longitudinal studies. We hypothesize that following an intravitreous injection, the clearance rate of a glucose analogue will be a nondestructive index of retinal glucose transport and metabolism in vivo. First, radiolabeled glucose analogues were injected into the vitreous. After 40 min, the dominant clearance path was posterior via the retina and was consistent with a facilitated transport mechanism. Next, either [6,6-2H2]glucose or 3-deoxy-3-fluoro-D-glucose was injected into the vitreous of rabbit eyes, and the clearance rate of each analogue was determined over 40 min using, respectively, 2H or 19F NMR. These rates were interpreted as a function of the retinal glucose transport and consumption. From the NMR data, the rate of retinal glucose consumption was approximately 16 times slower than the transport of glucose. These data demonstrate that NMR measurements of glucose analogue clearance rate from the vitreous can provide a nondestructive index of retinal glucose transport and consumption in vivo.

OBJECTIVE: Arteriovenous malformations (AVMs) can be treated successfully, but treatment can pose unacceptable risks if the AVM is located in eloquent cortex. Because AVMs are developmental lesions, the location of primary cortical function may be deranged. We used magnetic source imaging (MSI) to identify the central suicus and to determine whether primary cortical function was shifted in a set of 30 patients. We correlated these findings with outcome after treatment. METHODS: We retrospectively analyzed the clinical data of 30 patients with AVMs who underwent MSI. Nonparametric statistical comparisons were made to correlate the proximity of AVMs to primary cortex and somatosensory shift to outcome at 12 months. RESULTS: Using MSI, 14 patients (47%) were found to have AVMs involving primary cortex, and 10 patients (33%) were found to have shift in the Somatosensory homunculus. Primary cortical involvement was neither required nor sufficient to cause shift (Mann-Whitney U test, z = -0.02, P = 0.31). Patients with AVMs involving primary cortex fared worse after treatment than did patients with AVMs that spared primary cortex (Mann-Whitney U test, z = -2.3, P = 0.02). The presence or absence of shift did not correlate with outcome after treatment (Mann-Whitney U test, 2 = -0.18, P = 0.48). CONCLUSION: MSI showed that some patients with AVMs have abnormal cortical distribution of function. The involvement of primary cortex correlated with worse outcome after treatment. Our results suggest that preoperative functional imaging may help to better estimate treatment risks and ultimately to guide therapeutic planning.

Summary: Purpose: Deep brain stimulation has been used by several investigators to prevent the occurrence of spontaneous seizures in patients with intractable epilepsy. With the kainic acid rat model of spontaneous recurrent seizures, we examined the consequences of subthreshold electrical stimulation of commissural pathways and perforant path on the synaptic plasticity, rate of interictal epileptiform events (IIEs), and spontaneous seizures in kainic acid (KA)-treated rats epileptic rats. Methods: Recording microelectrodes were implanted bilaterally in the dentate gyrus and entorhinal cortex. Stimulating electrodes were implanted into the rostral part of the right hippocampus and right perforant path. Stimulation was performed daily with 200 Hz/0.5-s duration trains, 10-min duration 1-Hz train, or 2-h, 1-Hz train and 2-h duration, 50-Hz trains. Integrated amplitude of evoked potentials, rate of IIE, and spontaneous seizures was analyzed before and after stimulation. Results: High-frequency tetani evoked long-term potentiation in 50% of epileptic rats compared with 100% of control rats. No long-term depression was observed after 1-Hz train. Decrease rate of IIE was found during 1-Hz and 50-Hz stimulation and returned to the basal level within 30–60 min. No significant change of the spontaneous seizure rate was found. Conclusions: Epileptic brain is less prone to plastic changes compared with the normal brain. Daily 2-h electrical stimulation with either low or high frequency does not have a long-term effect on the rate of interictal events and spontaneous seizures.

The complete striatal axonal arborizations of 16 juxtacellularly stained cortical pyramidal cells were analyzed. Corticostriatal neurons were located in the medial agranular or anterior cingulate cortex of rats. All axons were of the extended type and formed synaptic contacts in both the striosomal and matrix compartments as determined by counterstaining for the mu-opiate receptor. Six axonal arborizations were from collaterals of brain stem-projecting cells and the other 10 from bilaterally projecting cells with no brain stem projections. The distribution of synaptic boutons along the axons were convolved with the average dendritic tree volume of spiny projection neurons to obtain an axonal innervation volume and innervation density map for each axon. Innervation volumes varied widely, with single axons occupying between 0.4 and 14.2% of the striatum (average = 4%). The total number of boutons formed by individual axons ranged from 25 to 2,900 (average = 879). Within the innervation volume, the density of innervation was extremely sparse but inhomogeneous. The pattern of innervation resembled matrisomes, as defined by bulk labeling and functional mapping experiments, superimposed on a low background innervation. Using this sample as representative of all corticostriatal axons, the total number of corticostriatal neurons was estimated to be 17 million, about 10 times the number of striatal projection neurons.

The delayed appearance of motor symptoms in PD poses a crucial challenge for early detection of the disease. We measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [(11)C]PE2I in MPTP-treated macaque monkeys, thus establishing a detailed profile of the nigrostriatal DA status following MPTP intoxication and its relation to induced motor and non-motor symptoms. Clinical score and cognitive performance were followed throughout the study. We measured longitudinally in vivo the non-displaceable binding potential to DAT in premotor, motor-recovered (i.e. both non-symptomatic) and symptomatic MPTP-treated monkeys. Results show an unexpected and pronounced dissociation between clinical scores and [(11)C]PE2I-BP(ND) during the premotor phase i.e. DAT binding in the striatum of premotor animals was increased around 20%. Importantly, this broad increase of DAT binding in the caudate, ventral striatum and anterior putamen was accompanied by i) deteriorated cognitive performance, showing a likely causal role of the observed hyperdopaminergic state (Cools, 2011; Cools and D'Esposito, 2011) and ii) an asymmetric decrease of DAT binding at a focal point of the posterior putamen, suggesting that increased DAT is one of the earliest, intrinsic compensatory mechanisms. Following spontaneous recovery from motor deficits, DAT binding was greatly reduced as recently shown in-vivo with other radiotracers (Blesa et al., 2010, 2012). Finally, high clinical scores were correlated to considerably low levels of DAT only after the induction of a stable parkinsonian state. We additionally show that the only striatal region which was significantly correlated to the degree of motor impairments is the ventral striatum. Further research on this period should allow better understanding of DA compensation at premature stages of PD and potentially identify new diagnosis and therapeutic index.

The red snapper Lutjanus campechanus is an important recreational and commercial fish species in the northern Gulf of Mexico. Management approaches have varied in part because of uncertainty of their longevity. Snapper ages have been based on presumed otolith annuli; however, this methodology has not been validated for all age classes. A recent technique to validate otolith age utilizes the increase in oceanic 14C resulting from atmospheric testing of nuclear bombs during the 1950s and 1960s. Analyses of annuli from living corals and fish otoliths from 1900 to the present have documented that elevated 14C input has occurred throughout the world's oceans. We validated otolith section age estimates through accelerator mass spectrometry analysis of bomb-produced 14C in red snapper (otoliths) hatched before, during, and after the nuclear testing periods. Delta 14C data from the otoliths of red snapper with presumed birth dates between 1960 and 1973 clearly reflect the sharp increase in oceanic radiocarbon attributable to previous nuclear testing. Similarities between the otolith and nearby coral △14C chronologies suggest that annulus-based age estimates of red snapper are valid on average to within 1–3 yr. In addition, this study provides the first carbonate bomb radiocarbon time series from the northern Gulf of Mexico.

Object. Pituitary abscess is a rare but serious intrasellar infection. To better determine the salient signs and symptoms that help in making the diagnosis, and to determine the most appropriate treatment, the authors reviewed their experience in a series of 24 patients treated at the University of California at San Francisco. Methods. Nine of the patients were female and 15 were male, and their mean age was 41.2 years (range 12–71 years). Surprisingly, most patients in our series presented with complaints and physical findings consistent with a pituitary mass, but rarely with evidence of a serious infection. Headache, endocrine abnormalities, and visual changes were the most common clinical indicators; fever, peripheral leukocytosis, and meningismus were present in 33% or fewer of the patients. Imaging tests demonstrated a pituitary mass in all patients, but the features evident on computerized tomography and magnetic resonance studies did not distinguish pituitary abscesses from other, more common intrasellar lesions. Because of the ambiguous clinical features and imaging findings, most abscesses were not diagnosed before treatment; rather, the diagnosis was made during surgical exploration of the sella turcica, when the surgeon encountered a cystic mass containing pus. There were only two deaths in this series (8.3%). Patients presenting with headache and visual changes noted improvement in almost all cases; patients with endocrine dysfunction generally did not recover normal pituitary function, but were easily treated with hormone replacement therapy. Conclusions. Antibiotic therapy is suggested for patients who have symptoms of sepsis, or for patients in whom specific organisms are identified from cultures obtained during surgery. The transsphenoidal approach is recommended over open craniotomy for surgical drainage.

In this study, we evaluate the assumptions for estimating ages with radiometric and elemental analyses of otoliths of red snapper (Lutjanus campechanus) and red drum (Sciaenops ocellatus) from the northern Gulf of Mexico. In whole otoliths of both red snapper and red drum, 226Ra activity was inversely correlated with the otolith mass increase with age, validating the assumption that 226Ra accumulation in otoliths occurs at a rate proportional to that of Ca. 222Rn emanation from otoliths decreased as otolith mass increased. 222Rn loss occurred in all red snapper otolith samples ([Formula: see text]4.1%) and, to a lesser extent, in red drum otolith samples ([Formula: see text]0.6%) and decreased with increasing size (age) of the otolith. For red drum, the assumption that the initial activity ratio of 210Po to 226Ra in otoliths is essentially zero was indirectly validated with elemental analyses of Pb and Ba. Radiometric age estimation of shallow-water fishes from the northern Gulf of Mexico holds great promise, considering that 226Ra activities observed in this study are some of the highest recorded to date for species to which the 210Pb/226Ra dating technique has been applied.

What is the neuronal basis for whether an experience is recalled or forgotten? In contrast to recognition, recall is difficult to study in nonhuman primates and rarely is accessible at the single neuron level in humans. We recorded 128 medial temporal lobe (MTL) neurons in patients implanted with intracranial microelectrodes while they encoded and recalled word paired associates. Neurons in the amygdala, entorhinal cortex, and hippocampus showed altered activity during encoding (9%), recall (22%), and both task phases (23%). The responses of hippocampal neurons during encoding predicted whether or not subjects later remembered the pairs successfully. Entorhinal cortex neuronal activity during retrieval was correlated with recall success. These data provide support at the single neuron level for MTL contributions to encoding and retrieval, while also suggesting there may be differences in the level of contribution of MTL regions to these memory processes.

Spine-like dendritic protrusions (SLDPs) emanating from developing dendrites have been proposed to play an important role in early synaptogenesis. We previously analyzed synaptic termination sites on soma-dendritic membrane of newborn cats and found that corticorubral (CR) axons form synapses preferentially on SLDPs (Saito et al., 1997). In the present study, we examined CR synapses in adult cats to elucidate the maturation process of CR synapses in relation to SLDPs. Electron microscopic observation of serial thin sections of Phaseolus vulgaris-leucoagglutinin–labeled axons revealed that approximately 60% of CR terminals in adult cats formed synapses on dendritic spines. We also found that CR axons terminate on dendritic spines originating from the intermediate or distal dendrites of rubrospinal cells (more than 200 μm apart from the soma), in contrast to kittens in which CR fibers terminate on SLDPs originating from the proximal dendrites (less than 100 μm apart from the soma) of rubrospinal cells (Saito et al. [1997] J. Neurosci. 17:8792–8803). These results suggest that CR synapses undergo remarkable remodeling after initial termination on SLDP during postnatal development. J. Comp. Neurol. 440:236–244, 2001. © 2001 Wiley-Liss, Inc.

Summary: Purpose: The “silent period” is a characteristic of human localization-related symptomatic epilepsy. In mesial temporal lobe epilepsy (MTLE), it follows an initial precipitating injury, and in animal models of MTLE in which brain damage is artificially created, there is also a prolonged interval between injury and the onset of spontaneous seizures. The neuronal reorganization responsible for epileptogenesis presumably takes place during this silent interval; however, the functional correlates of this process are poorly understood. We have previously described high-frequency (250 to 500 Hz) oscillations, called fast ripples (FR), in the hippocampus and entorhinal cortex (EC) of intrahippocampal kainic acid (KA)-injected rats and patients with MTLE that are confined to the region of spontaneous seizure generation. We have proposed, therefore, that FR reflect the mechanisms responsible for epileptogenesis. If this is the case, they should appear during the process of epileptogenesis, before the appearance of spontaneous seizures. The purpose of the present study was to record continuously from rats after KA injection to compare the temporal development of FR with spontaneous seizures. Additional goals were to determine in these rats after spontaneous seizures begin (a) the volume of tissue in which FR can be recorded in hippocampus and EC, (b) the multiple-unit and field potential correlates of FR oscillations, and (c) whether there is an association of FR with mossy fiber sprouting. Methods: After unilateral KA injection in the posterior hippocampus, interictal field epileptic activity and single-unit activity were recorded from freely moving animals using multiple-contact microelectrodes in dentate gyrus (DG) and EC. One group of animals underwent continuous recording to determine the time of onset of both FR oscillations and spontaneous seizures. A second group was implanted after behavioral seizures began to measure the area within which FR could be recorded as well as their unit and field potential correlates. The neo-Timm method was used to reveal mossy fiber sprouting, and gray value analysis was used to measure the intensity of sprouting in the inner molecular layer of DG. Results: In KA-injected rats, FR were observed in hippocampal areas adjacent to the lesion and in the ipsilateral EC 11 to 14 days after injection, whereas spontaneous behavioral seizures occurred 2 to 4 months after injection. Analysis of depth profiles of interictal FR in the DG and EC showed that they were generated in local areas with a volume of about 1.0 mm3, and unit recordings indicated that they reflected fields of hypersynchronous action potentials. FR were found in areas of DG with more intensive mossy fiber sprouting. However, the correspondence was not absolute. Conclusions: The electrophysiological and anatomical data are consistent with the participation of FR oscillations, within small neuronal assemblies, in the development of chronic epileptogenesis. It is hypothesized that small clusters of pathologically interconnected neurons develop after focal hippocampal injury and that these clusters are capable of generating powerful hypersynchronous bursts of action potentials, which initiate epileptogenesis via a kindling effect. As the silent period progresses, a network of such clusters is formed that allows the development of discharges that spread throughout the limbic system. When this network engages brain areas that control motor activity, clinical seizures occur and the silent period ends.

Reciprocally connected glutamatergic subthalamic and GABAergic globus pallidus neurons have recently been proposed to act as a generator of low-frequency oscillatory activity in Parkinson's disease. To determine whether GABAA receptor-mediated synaptic potentials could theoretically generate rebound burst firing in subthalamic neurons, a feature that is central to the proposed oscillatory mechanism, we determined the equilibrium potential of GABAA current ( E GABAA ) and the degree of hyperpolarization required for rebound firing using perforated-patch recording. In the majority of neurons that fired rebounds, E GABAA was equal to or more hyperpolarized than the hyperpolarization required for rebound burst firing. These data suggest that synchronous activity of pallidal inputs could underlie rhythmic bursting activity of subthalamic neurons in Parkinson's disease.

The transphenoidal approach to intracranial lesions is most commonly used for pituitary tumors. It can also be used to biopsy or treat midline skull base lesions from the planum sphenoidale to the clivus. Proper application of this approach requires an understanding of sellar and parasellar anatomy. In this article, we describe our techniques, discuss modifications introduced by others, and review the advantages and pitfalls of transsphenoidal microsurgery. This approach is best suited to extradural lesions that extend no further than 1.5 cm from midline. The most common complications are cerebrospinal fluid leak and endocrinopathy.

✓ Monitoring physiological changes in the brain parenchyma has important applications in the care of neurosurgical patients. A technique is described for measuring extracellular neurochemicals by cerebral microdialysis with simultaneous recording of electroencephalographic (EEG) and single-unit (neuron) activity in selected targets in the human brain. Forty-two patients with medically intractable epilepsy underwent stereotactically guided implantation of a total of 423 intracranial depth electrodes to delineate potentially resectable seizure foci. The electrodes had platinum alloy contacts for EEG recordings and four to nine 40-µm microwires for recording single-unit neuron activity. Eighty-six electrodes also included microdialysis probes introduced via the electrode lumens. During monitoring on the neurosurgical ward, electrophysiological recording and cerebral microdialysis sampling were performed during seizures, cognitive tasks, and sleep—waking cycles. The technique described here could be used in developing novel approaches for evaluation and treatment in a variety of neurological conditions such as head injury, subarachnoid hemorrhage, epilepsy, and movement disorders.

We describe a case of a morbidly obese Jehovah's Witness who sustained a popliteal artery and vein transection after a spontaneous knee dislocation. Following surgical repair, the patient fatally deteriorated, while blood products had to be withheld according to the patient's preoperative request.

Action potentials in neostriatal cholinergic interneurons recordedin vivoare triggered by summation of two or three discrete synaptic depolarizations (Wilson et al., 1990). The ability and precision with which EPSPs and IPSPs regulate action potential timing was therefore investigatedin vitro. Cholinergic interneurons were identified on the basis of morphological and electrophysiological characteristics in neostriatal slices taken from 2- to 3-week-old postnatal rats recorded at 24–26°C.During periods of induced regular firing, intrastriatal stimuli were used to evoke pharmacologically isolated monosynaptic AMPA receptor-mediated EPSPs or GABAAreceptor-mediated IPSPs. EPSPs evoked during the interspike interval (ISI) produced a phase-dependent decrease in the ISI, whereas IPSPs produced a phase-independent prolongation of the ISI. Injection of brief depolarizing currents mimicked the action of EPSPs and revealed an alteration in the input resistance during the ISI. In contrast to IPSPs, the ability of brief hyperpolarizing current injections to delay spike generation was phase-dependent. After blockade of GABAergic and glutamatergic synaptic transmission, stimuli failed to produce a detectable conductance change but could still prolong the subsequent ISI primarily through a D1 dopamine receptor-mediated enhancement of the afterhyperpolarization (AHP).Hence, EPSPs are ideally suited to provide a precise regulation of spike timing in cholinergic cells, whereas IPSPs are more likely to influence the overall level of excitability. The D1-mediated modulation of the AHP may contribute to the prolonged ISI seen in tonically active neuronsin vivoin monkeys trained to respond to a sensory cue.

BACKGROUND Prostate-specific antigen (PSA) cannot differentiate benign prostatic hyperplasia (BPH), from prostatitis, or prostate cancer in the range of 4.0–10 ng/ml. An accurate cytologic or histologic assessment is necessary to confirm the proper diagnosis. The nature of a biopsy tends to make it a selective test not frequently repeated. We are reporting a technique employing semen as a source for the differential diagnosis of prostate epithelial cells. METHODS Eleven vasectomized and nonvasectomized prostate cancer patients provided semen samples (stage T1 to T2). Two patients provided repeat samples. In addition, 15 vasectomized or nonvasectomized individuals without evidence of disease provided semen samples. Three million cells fixed with 50% ethanol were stained by an antibody (7E11.C5) to prostate-specific membrane antigen (PSMA), Hybritech Antibody (399) to PSA, and cytokeratin 8 and 18. In addition to the antibodies described, a DNA stain To-Pro 3 was used to identify 2n-4n DNA containing cells. A dual laser, Becton Dickinson FACSCaliber cytometer, was used to analyze the samples. RESULTS All semen specimens contained diploid, cytokeratin 18–positive epithelial cells regardless of disease status. A clear difference between prostate cancer and normal prostate cell samples was observed using staining with 7E11.C5. The ratio of prostatic cells in the total epithelial cell population (PSMA:cytokeratin ratios) was calculated for each specimen. A retrospective study of sixteen semen samples from 11 prostate cancer patients had a mean PSMA:cytokeratin ratio of 0.57, whereas the samples from 15 patients without evidence of cancer had a mean PSMA:cytokeratin ratio of 0.11. This difference was significant. PSA staining was variable and inconsistent. CONCLUSIONS This report demonstrates that human semen contains prostate cells that can be characterized and used in the clinical diagnosis of prostate cancer. Prostate 36:181–188, 1998. © 1998 Wiley-Liss, Inc.

The distribution of synapses formed by corticostriatal neurons was measured to determine the average connectivity and degree of convergence of these neurons and to search for spatial inhomogeneities. Two kinds of axonal fields, focal and extended, and two striatal tissue compartments, the patch (striosome) and matrix, were analyzed separately. Electron microscopic examination revealed that both kinds of corticostriatal axons made synapses at varicosities that could be identified in the light microscope, and each varicosity made a single synapse. Thus, the distribution of varicosities was a good estimate of the spatial distribution of synapses. The distance between axonal varicosities was measured to determine the density of synaptic connections formed by one axon within the volume occupied by a striatal neuron. Intersynaptic distances were distributed exponentially, except that synapses were rarely located4 microm apart. The mean distance between synapses was approximately 10 microm, so axons made a maximum of 40 synapses within the dendritic volume of a spiny neuron. There are approximately 2840 spiny neurons located within the volume of the dendrites of one spiny cell (Oorschot, 1996), so each axon must contact/=1.4% of all cells in its axonal arborization. Within the same volume there are approximately 30.5 million asymmetric synapses (Ingham et al., 1996), approximately half of which are cortical in origin. Thus, approximately 380,000 cortical axons innervate the volume of the dendritic tree of one spiny cell. Striatal neurons with totally overlapping dendritic volumes have few presynaptic cortical axons in common, and cortical cells with overlapping axons have few striatal target neurons in common. These results explain the absence of redundancy in the responses of neurons located near each other in the striatum.

The hippocampus and its associated structures play a key role in human memory, yet the underlying neuronal mechanisms remain unknown. Here, we report that during encoding and recognition, single neurons in the medial temporal lobe discriminated faces from inanimate objects. Some units responded selectively to specific emotional expressions or to conjunctions of facial expression and gender. Such units were especially prevalent during recognition, and the responses depended on stimulus novelty or familiarity. Traces of exposure to faces or objects were found a few seconds after stimulus removal as well as 10 hr later. Some neurons maintained a record of previous stimulus presentation that was more accurate than the person's conscious recollection. We propose that the human medial temporal lobe constructs a "cognitive map" of stimulus attributes comparable to the map of the spatial environment described in the rodent hippocampus.

The neurochemical changes underlying human emotions and social behaviour are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 and melanin-concentrating hormone, measured in the human amygdala. We show that hypocretin-1 levels are maximal during positive emotion, social interaction and anger, behaviours that induce cataplexy in human narcoleptics. In contrast, melanin-concentrating hormone levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. Melanin-concentrating hormone levels increase at sleep onset, consistent with a role in sleep induction, whereas hypocretin-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized.