GABA-from Inhibition to Cognition: Emerging Concepts.

Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA.

Neurobiological after-effects of non-invasive brain stimulation.

BACKGROUND: In recent years, many studies have evaluated the effects of noninvasive brain stimulation (NIBS) techniques for the treatment of several neurological and psychiatric disorders. Positive results led to approval of NIBS for some of these conditions by the Food and Drug Administration in the USA. The therapeutic effects of NIBS have been related to bi-directional changes in cortical excitability with the direction of change depending on the choice of stimulation protocol. Although after-effects are mostly short lived, complex neurobiological mechanisms related to changes in synaptic excitability bear the potential to further induce therapy-relevant lasting changes. OBJECTIVE: To review recent neurobiological findings obtained from in vitro and in vivo studies that highlight molecular and cellular mechanisms of short- and long-term changes of synaptic plasticity after NIBS. FINDINGS: Long-term potentiation (LTP) and depression (LTD) phenomena by itself are insufficient in explaining the early and long term changes taking place after short episodes of NIBS. Preliminary experimental studies indicate a complex scenario potentially relevant to the therapeutic effects of NIBS, including gene activation/regulation, de novo protein expression, morphological changes, changes in intrinsic firing properties and modified network properties resulting from changed inhibition, homeostatic processes and glial function. CONCLUSIONS: This review brings into focus the neurobiological mechanisms underlying long-term after-effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) recently obtained from in vitro and in vivo studies, both in animals and humans.

Ten Years of Theta Burst Stimulation in Humans: Established Knowledge, Unknowns and Prospects.

BACKGROUND/OBJECTIVES: Over the last ten years, an increasing number of authors have used the theta burst stimulation (TBS) protocol to investigate long-term potentiation (LTP) and long-term depression (LTD)-like plasticity non-invasively in the primary motor cortex (M1) in healthy humans and in patients with various types of movement disorders. We here provide a comprehensive review of the LTP/LTD-like plasticity induced by TBS in the human M1. METHODS: A workgroup of researchers expert in this research field review and discuss critically ten years of experimental evidence from TBS studies in humans and in animal models. The review also includes the discussion of studies assessing responses to TBS in patients with movement disorders. MAIN FINDINGS/DISCUSSION: We discuss experimental studies applying TBS over the M1 or in other cortical regions functionally connected to M1 in healthy subjects and in patients with various types of movement disorders. We also review experimental evidence coming from TBS studies in animals. Finally, we clarify the status of TBS as a possible new non-invasive therapy aimed at improving symptoms in various neurological disorders.

Outcome of fetuses with gastroschisis after modification of prenatal management strategies : Prenatal management and outcome of gastroschisis.

PURPOSE: To improve the outcome of fetuses with gastrochisis several studies evaluated prenatal predictors. But there are different guidelines established and therefore the prenatal care is not standardized. With our study we wanted to evaluate the outcome of fetuses with gastroschisis after modification of prenatal management strategies at the Department of Obstetrics and Gynecology of the University Hospital Münster. METHODS: In this explorative retrospective study of 39 fetuses with gastroschisis, we compare the clinical outcome between two management groups. In the first group (group 1, n = 14) prenatal indication for delivery was confirmed by a subjective evaluation of the small bowel diameter and the wall thickness without established cut-off values for these parameters. In the second group (group 2, n = 25) certain limits for the small bowel diameter (25 mm) and the wall thickness (2.5 mm) were used for fetal surveillance. RESULTS: Noticeable differences between the two groups regarding birth weight, weight centile, arterial pH, small bowel diameter, wall thickness, adverse bowel condition and re-operations could not be observed. In group 2, delivery was earlier (p = 0.011), and a lower rate of prenatal complications was observed (p = 0.016). CONCLUSION: To avoid adverse prenatal complications we recommend the observation of fetuses with gastroschisis by sonographic monitoring of the small bowel diameter and the wall thickness.

The Barmer study: impact of standardized warming of the injection site to enhance insulin absorption and reduce prandial insulin requirements and hypoglycemia in obese patients with diabetes mellitus.

BACKGROUND: The primary objective of this prospective controlled study was to investigate the impact of standardized injection-site warming on prandial rapid acting insulin dose and glycemic control when studied under real-world conditions. METHODS: All 145 participating patients (51 female, 94 male, 13 type 1 and 132 type 2 patients, age: 61.6 ± 8.4 yrs, HbA1c: 7.19 ± 0.50%) were treated with intensive insulin glargine and short-acting insulin analog therapy. After a 4 week treatment optimization run-in period, patients were randomized to continue therapy for three months without (control) or with a local injection-site warming device (InsuPad * ). Observation parameters included HbA1c, insulin dose, frequency of hypoglycemia, body weight and adverse events. RESULTS: HbA1c improved in both arms until study end (control group: 6.3 ± 0.5%; injection-site warming device: 6.3 ± 0.5%; both p < 0.001 vs. baseline). To achieve this good control, patients in the control group needed to increase the daily prandial insulin dose by 8.1% (from 66 ± 31 U to 71 ± 38 U, p < 0.05) with stable basal insulin requirements. Patients who used the injection-site warming device required less prandial insulin (70 ± 43 U to 55 ± 34 U; -19%, p < 0.001) and slightly more basal insulin (+3.9%). Total daily insulin dose increased in the control group (+3.7%) and decreased with warming device use (-8.6%, p < 0.001). The number of hypoglycemic events (<63 mg/dL) during the observation period was higher in the control group (6.2 ± 9.9/patient vs. injection-site warming device: 3.3 ± 4.8/patient, p < 0.05). Main study limitations can be seen in the open label design reliability of the collected dose information and the very obese patient cohort. CONCLUSION: When treating obese patients to target with insulin therapy, use of an injection-site warming device for 3 months resulted in a lower frequency of hypoglycemic events and a reduction in prandial insulin analog requirements. If these results are confirmed in other patient populations, an injection-site warming device may be useful in achieving treatment targets with a safer and more efficient basal bolus therapy in insulin-treated patients with type 1 and type 2 diabetes.

Synthesis and modeling of polysiloxane-based salt-in-polymer electrolytes with various additives.

The effect of both nanoparticles and low molecular weight borate esters on the ionic conductivity of cross-linked polysiloxanes was systematically investigated by means of measuring conductivity spectra in the impedance regime at temperatures between -30 and 90 degrees C. Salt-in-polymer electrolytes were prepared by dissolving lithium triflate (LiSO(3)CF(3)) in comblike polysiloxanes bearing one methyl and one oligoether side group per silicon. An amount of 10 mol % of the oligoether side groups exhibited a terminal allytrimethoxysilane serving as a cross-linker moiety (T(0.1)OPS). Thus prepared polymer electrolyte membranes were completely amorphous and mechanically stable with an optimum conductivity value of 5.7 x 10(-5) S x cm(-1) at 15 wt % of lithium triflate (LiSO(3)CF(3)) at room temperature (T(0.1)OPS + 15 wt % LiSO(3)CF(3)). Further investigations concerned the influence of additives, i.e., nanosized ceramic fillers (alpha-Al(2)O(3) and SiO(2), up to 10 wt %) as well as two low molecular weight borate esters (tris(2-(2-methoxyethoxy)ethyl) borate (B2) and tris(2-(2-(2-methoxyethoxy)ethoxy)ethyl) borate (B3)) with maximum concentrations of 40 wt % as referred to polysiloxane T(0.1)OPS. The addition of borate esters resulted in a considerable increase of the conductivity, while still maintaining the mechanical stability. Optimum conductivities of 3.7 x 10(-5) and 1.6 x 10(-4) S x cm(-1) were measured for B2 and B3, respectively, at room temperature. A fit of the temperature-dependent DC conductivity by the empirical Vogel-Tammann-Fulcher (VTF) equation showed that there was an increased number density of mobile charge carriers in the case of borate esters as additives. However, the shape of the conductivity spectra in the dispersive regime changed considerably in going from nanoparticles as additives to borate esters. A careful and consistent modeling of the conductivity spectra and of the temperature dependence of the DC conductivity was done within the framework of the MIGRATION concept. The result was that the addition of borate esters to the polymer host most probably increased both number density of mobile charge carriers as well as their mobility.

Pressure-dependent diffusion coefficients and haven ratios in cation-conducting glasses.

The influence of hydrostatic pressure on diffusion and ionic conduction is providing deeper insights into the atomistic mechanisms of ionic motion in glasses. We have studied the tracer diffusion of 22Na in a sodium borate glass and of 86Rb in a rubidium borate glass as functions of hydrostatic pressures. The activation volumes of tracer diffusion are DeltaVD(Rb) = 33.5 cm3 mol-1 and DeltaVD(Na) = 6.1 cm3 mol-1. In comparison, the activation volumes of charge diffusion obtained recently from the pressure dependence of conductivity are smaller: DeltaVsigma(Rb) = 7.2 cm3 mol(-1) and DeltaVsigma(Na) = 2.8 cm3 mol(-1). These differences, where (DeltaVD - DeltaVsigma) > 0, imply that the Haven ratios decrease with pressure. This effect is particularly significant for the rubidium borate glass. Starting from basic equations of linear response theory for mass and charge transport, we develop a model that accounts for these experimental findings. The difference between the activation volumes, DeltaVD and DeltaVsigma, and the pressure-dependent Haven ratios are consequences of collective movements of ions in glass, implying a concerted motion of ions in a chain- or caterpillar-like fashion. In our treatment, it is a vacant site (with ions jumping into it successively) that moves along an extended pathway. Hence, we regard vacant sites as the carriers of charge and ions as the carriers of diffusing matter. The decrease of the Haven ratio with pressure is attributed to the influence of pressure on the topology of the conduction pathways, which are progressively straightened out with increasing pressure.

Correlated ionic hopping processes in crystalline and glassy electrolytes resulting in MIGRATION-type and nearly-constant-loss-type conductivities.

Solid electrolytes with disordered structures may be crystalline or glassy. Their complex ionic conductivity displays a characteristic frequency dependence. Modelling the dynamics of the mobile ions, we have developed the MIGRATION concept, the acronym standing for MIsmatch Generated Relaxation for the Accommodation and Transport of IONs. With the help of the MIGRATION concept it is possible to reproduce frequency-dependent experimental conductivities and permittivities including their scaling behaviour. Scaling is a property typically observed in and below the radio frequency regime. At sufficiently high frequencies and low temperatures, however, conductivity spectra of crystals and glasses are often found to contain a second component which displays the so-called nearly-constant-loss (NCL) behaviour. Suitably modifying the MIGRATION concept, we are able to explain this feature and to show that it is caused by a displacive or hopping ionic motion that stays completely localised. Here, as in the unmodified MIGRATION concept, interactions between the ions play an essential role. Experimentally, interesting differences are detected between the NCL-type dynamics in a crystalline and in a glassy ion conductor. In crystalline gamma-RbAg4I5 we find the same elementary rates for the MIGRATION-type and NCL-type hopping movements of the ions, suggesting identical barrier heights for the respective processes. On the other hand, the two rates are found to differ markedly from each other in glassy AgI-AgPO3, not only with regard to their absolute value but also in their temperature dependence. We suggest that the NCL effect in the glass results from dynamic localised displacements involving both the silver ions and negatively charged entities such as iodide ions and/or non-bridging oxygen ions.

[Patient classification and analysis of risk profiles for type 2 diabetics as the main focus point in practice. Results of the TEMPO study]. / Patientenklassifikation und Risikoprofilanalysen bei Typ-2-Diabetikern in der Schwerpunktpraxis. Ergebnisse der TEMPO-Studie.

BACKGROUND AND OBJECTIVE: Disease management programs (DMP) e. g. for diabetes mellitus, should be the clinical and economic basis for a structured treatment. This article shows results of specialized outpatient treatment using a risk factor depending patient classification. PATIENTS AND METHODS: Diabetes associated co-morbidities, micro- and macrovascular complications, the results and findings of blood pressure and metabolism of glucose and lipids, as well as all treatment-associated costs of 5245 type 2 diabetics were collected for a period of 12 months, accompanied by different measures of quality control. For documentation in the centres, all available original data were used as local data sources. RESULTS: The patient classification system, on which diabetic risk profiles are based, covered 74.3 % of all type 2 diabetic patients. Daily direct costs for all treatment measures ranged between EUR 4.79 (primary prevention) and EUR 8.96 for patients suffering from advanced diabetic foot syndrome. Most of the treatment costs arose from prescriptions of pharmaceuticals, other remedies and aids. Specific strategies of therapy were both related to the severity of co-morbidities and the time since manifestation of diabetes (r = 0.486; p < 0.01, two-sided). The share of patients receiving diet and exercise only decreased from 22.8 % (primary prevention) to below 10 % of patients suffering from microvascular complications. Simultaneously, the share of patients receiving insulin increased up to 81.8 % of patients suffering from advanced diabetic retinopathy. CONCLUSION: The risk profile specific variation in the results clearly shows the need of a risk factor depending classification system for type 2 diabetes, which could be useful to reform and focus the system of compensating payments between health insurance companies more and more on morbidity, or on risk profiles.

Changes of contrast gain in cat dorsal lateral geniculate nucleus by dopamine receptor agonists.

The modulatory effects of dopamine (DA) on the contrast gain of retino-geniculate transmission were tested with local micro-iontophoretical application of DA and the DA receptor agonists SKF38393 (SKF, D1/D5) and quinpirole (QUIN, D2/D3/D4) while recording visually induced spike activity of relay cells of the dorsal aspect of cat lateral geniculate nucleus (dLGN) in the anesthetised and paralyzed preparation. DA and QUIN could either facilitate or inhibit visual activity in a dose-dependent fashion: small amounts caused a facilitation while larger quantities resulted in a more (DA) or less (QUIN) strong inhibition. The effect of SKF was almost always suppressive and increased with the amount of drug applied. The absolute change in activity was depending on stimulus contrast and the strength of the elicited response: facilitation and inhibition of activity was proportional to stimulus contrast and response strength and thus resulted in a changed contrast gain. The results indicate that the visual deficits found in Parkinson's disease patients my be not solely related to retinal dysfunctions.

Changes in response modulation of cat perigeniculate neurons related to EEG state and application of neuromodulators.

Spike activity of single perigeniculate (PGN) neurons was recorded in the anaesthetized (N2O/halothane) and paralysed cat during presentation of moving gratings of optimal spatial frequency. Typically, the ongoing (tonic, spontaneous) activity of PGN cells increased during a rise in EEG delta power accompanied by a reduction and often a total loss of spike rate modulation by the moving grating. The opposite behaviour was found when the EEG delta power vanished. Micro-iontophoretically applied acetylcholine (ACh) had an effect similar to a decrease in EEG delta power, decreasing ongoing activity but increasing the response modulation depth. The opposite effect could be achieved with the excitatory action of serotonin (5-HT), mimicking a strengthened EEG delta power. These data support previous data indicating that PGN neurons contribute to spatio-temporal tuning of subcortical visual activity in a state-dependent way.

Quantitative aspects of the state-dependent co-variation of cat lateral geniculate and perigeniculate visual activity.

The quantitative relationship between EEG-related changes in the visual activity of perigeniculate (PGN) and lateral geniculate (LGN) neurons with overlapping receptive fields was analyzed in the anesthetized and paralyzed cat. While transient response peaks were independent of the EEG state, we found opposite changes in spontaneous activity and tonic visual responses, with PGN cells increasing and LGN cells decreasing their spontaneous/tonic activity with increasing EEG delta activity in most cases. The tonic firing rates of PGN and LGN cell pairs were clearly correlated with a slope of about -0.5. Thus, LGN firing was low when PGN activity was high and vice versa. With a change from low to high EEG delta activity the difference between the tonic responses of PGN and LGN cells increased on average by 50 spikes/s, both for the whole population and at the single cell level, indicating that state-dependent changes in retino-geniculate transmission are regulated by a distinct ratio of PGN-LGN activity.

The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin.

The androgen receptor (AR) gene, located on the X-chromosome at Xq11-12, contains in exon 1 a polymorphic CAG repeat which codes for a polyglutamine tract. Contractions of the CAG repeat are said to be related to prostate cancer. In contrast, sizeable expansion of the CAG repeat can cause spinal and bulbar muscular atrophy (SBMA). In infertile patients of Chinese origin and in a Melbourne multinational population impaired sperm production has been postulated to be related to moderate expansions of the polyglutamine tract. In a study of a Swedish population of infertile patients these findings could not be corroborated. The aim of our investigation was to examine the correlation between the length of the CAG repeat and impaired sperm production in an infertile Caucasoid patient sample of German ethnic origin. We found no statistically significant relationship between the size of the CAG repeat or polyglutamine tract and idiopathic impaired sperm production in the population studied. The variability of the results by various investigators may be attributed to different ethnic origins and hence different genetic modifiers of the populations studied and/or to the high probability that these infertile males may represent a heterogeneous group with respect to the causes of defective spermatogenesis.

High-frequency (300-800 Hz) components in cat geniculate (dLGN) early visual responses.

We analysed the early visual responses of relay cells of the dorsal part of cat lateral geniculate nucleus (dLGN) for the occurrence and characteristics of high-frequency (>300 Hz) spike patterns comparable to the high-frequency oscillations (HFO) found in the human somatosensory system. By using a special algorithm for correcting response latency, we can show that the vast majority of dLGN visual responses which were elicited by a sudden change in contrast show HFOs in the range of 300 to more than 800 Hz. After response time correction these HFOs are clearly visible in summed responses, indicating that these patterns are highly reproducible by identical stimuli. On this basis we analysed the HFOs in more detail. We found the oscillation frequency to increase with stimulus contrast and the area of the receptive field centre covered by an excitatory stimulus. Inhibition reduces the oscillation frequency as demonstrated with additional stimulation of the antagonistic surround of the receptive field and by blocking inhibition with micro-iontophoretical application of bicuculline methiodide. The HFO was almost independent of the state of the system as estimated from the EEG pattern. Based on these findings we discuss whether bursts of action potentials triggered by the low-threshold calcium spike (LTS) can contribute to this pattern of visual thalamic activity.

Correlated variations in EEG pattern and visual responsiveness of cat lateral geniculate relay cells.

1. Simultaneous recordings of the EEG and the visual activity of cat dorsal lateral geniculate nucleus (dLGN) relay cells were analysed for covariance. Sliding time-window analyses were performed in parallel for the EEG power spectrum and single unit visual activity. The EEG power ratio (EEG-PR) of low (1-8 Hz) to high (20-40 Hz) frequencies was chosen to achieve a quantitative measure of the EEG which could be compared with the spike rate of a dLGN unit at any time. A high EEG-PR value indicates a synchronized EEG dominated by low frequencies (delta waves and sleep spindles), a low value indicates a less synchronized EEG. 2. In the anaesthetized animal, two different underlying patterns of activity in the EEG-PR were found: slow gradual changes (slow gradations) and oscillatory changes. In many cases both were accompanied by correlated variations in dLGN spike rate, either for overall activity or for burst firing. 3. The slow gradations appear for long time periods of up to 200 s and, in most cases (76.3 %), show a negative correlation between EEG-PR and overall spike rate, but predominantly a positive correlation for burst firing (85.1 %). 4. The oscillatory changes, which have not previously been reported, appear as temporally well-coupled variations in EEG-PR and spike rate with a stable cycle length within the range 4-10 s. In about 77 % of correlated changes the temporal delay between the change in EEG-PR and that of the spike rate was less than +/- 1.0 s. 5. During simultaneous recordings from two dLGN cells the variations in spike rate tend to show the same sign of correlation with respect to the EEG pattern. This relationship is more pronounced with the slow gradations than with the oscillatory changes. 6. Slow gradations in the spectral composition of the EEG may indicate global transitions between different stages within the sleep-wake cycle, reflecting the well-known influences of the brainstem arousal system. The oscillations in the spectral composition of the EEG are accompanied by gradual variations in thalamic transmission mode and are more likely to be due to involvement of a local feedback system via the thalamo-cortico-thalamic loop. The difference between the effects on overall and burst firing activity supports the notion that phasic (burst firing) and tonic visual responses may play distinctive roles in information processing, which are functionally related to the animal's behavioural state.

The dynamic spatio-temporal behavior of visual responses in thalamus and cortex.

Due to eye and object movements the visual world changes on a rather fast time scale and the neuronal network of the primary visual pathway has to immediately react to these changes. Accordingly the neuronal activity patterns in the visual thalamus and cortex show a pronounced dynamic behavior which reenters the circuitry such that the actual cell responses are also guided by the activation history of the network. Thus, spatial and temporal aspects of visual receptive fields change not only by means of the actual visual stimulation hut also as a consequence of the state of the network. In this short review we summarize the different aspects which can influence the temporal firing patterns of cells in the visual thalamus (lateral geniculate nucleus, LGN) mainly by demonstrating how their inter-spike interval distributions will change. We then show that these firing patterns are able to change the spatial shape of receptive fields in the visual cortex (see Fig. 12 for a summary diagram). Finally, by means of a biophysical model, we will argue that the observed changes could serve to adjust the temporal and spatial resolution within the primary visual pathway to the different demands for information processing in an attentive as compared to a non-attentive state.

State-dependent receptive-field restructuring in the visual cortex.

To extract important information from the environment on a useful timescale, the visual system must be able to adapt rapidly to constantly changing scenes. This requires dynamic control of visual resolution, possibly at the level of the responses of single neurons. Individual cells in the visual cortex respond to light stimuli on particular locations (receptive fields) on the retina, and the structure of these receptive fields can change in different contexts. Here we show experimentally that the shape of receptive fields in the primary visual cortex of anaesthetized cats undergoes significant modifications, which are correlated with the general state of the brain as assessed by electroencephalography: receptive fields are wider during synchronized states and smaller during non-synchronized states. We also show that cortical receptive fields shrink over time when stimulated with flashing light spots. Finally, by using a network model we account for the changing size of the cortical receptive fields by dynamically rescaling the levels of excitation and inhibition in the visual thalamus and cortex. The observed dynamic changes in the sizes of the cortical receptive field could be a reflection of a process that adapts the spatial resolution within the primary visual pathway to different states of excitability.

Inverse correlation of firing patterns of single topographically matched perigeniculate neurons and cat dorsal lateral geniculate relay cells.

Action potentials of single perigeniculate (PGN) cells and relay cells of the dorsal lateral geniculate nucleus (dLGN) with topographically matched or at least partially overlapping receptive fields (RF) were simultaneously recorded in the anesthetized and paralyzed cat during visual stimulation with moving gratings or flashing light spots of different size. In many cases, PGN cells showed an activity pattern which appeared like a mirror image of distinct periods of dLGN activity. Flashing spots evoked transient volleys of activity in PGN cells which increased in strength and shortened in latency with increasing size of the stimulus. These responses were temporally matched with inhibitory phases in the early part of visual responses in the dLGN. The spatio-temporal properties of the RFs were established by reverse correlation of the spike activity with the spatially random presentation of bright and dark spots within an array of 20 x 20 positions. Anticorrelated firing patterns of such kind could also be elicited as interocular inhibition with stimulation of the perigeniculate RF in the nondominant eye. Inversely correlated changes in spontaneous and visually induced activity were also visible during spontaneous changes in EEG pattern. With increasing synchronization of the EEG (predominance of delta-waves) the strength of geniculate visual responses declined while maintained perigeniculate activity increased. A weakened interocular and monocular inhibition of dLGN relay cells during visual stimulation of PGN RFs could be achieved with local reversible inactivation of PGN areas topographically matched with the dLGN recording sites. The results indicate that the PGN contributes to the state-dependent control of retino-geniculate transmission and to the monocular and interocular inhibitory processes that shape the visual responses in the dLGN.

The influence of corticofugal feedback on the temporal structure of visual responses of cat thalamic relay cells.

1. Visually driven single-unit activity was recorded in the dorsal lateral geniculate nucleus (dLGN) of the anaesthetized cat while inactivating or stimulating the corticofugal feedback from area 17/18 by means of cortical cooling or application of GABA (inactivation), or application of glutamate or quisqualate (Glu, Quis; stimulation) to layer VI. 2. Manipulations of the corticofugal feedback primarily affected the multimodal interspike interval pattern previously reported to be present in the tonic component of visual responses elicited by spot-like stimuli. 3. Sixty-three per cent of all neurons could be influenced, and temporally localized interspike interval distributions were measured which commonly consisted of one fundamental interval peak (leftmost peak) and integer multiples thereof (higher order peaks). During blockade of the corticofugal feedback, interspike intervals were redistributed into the higher order peaks in about 70 % of the cases, accompanied by a reduced mean firing rate. During stimulation the reverse effect occurred in 69 % of cases. 4. Increased synchronization of the EEG (increased power in the delta-wave range, 1-4 Hz) had an effect similar to cortex inactivation. The specificity of corticofugal effects was verified by consideration of these EEG effects and by dLGN double recordings with one dLGN cell topographically matched with the cortical inactivation/activation site and the second cell outside this area. Clear effects due to manipulation of the corticofugal feedback were found only for the matched dLGN site. 5. In addition we observed that the peaks of the interval distributions were narrower during active corticofugal feedback, such that the temporal dispersion of the signal transmission to the cortex was reduced. 6. The mechanisms underlying this effect were further analysed in a biophysically realistic model demonstrating that the timing of the spikes in the dLGN is improved as soon as the cortical feedback is active. The high degree of convergence/divergence between neurons along the closed feedback loop thereby leads to a temporal averaging effect which reduces the interval dispersion and also introduces synchronization between dLGN cells. 7. Such a mechanism may thus counteract the deterioration of spike timing accuracy which would otherwise occur as a consequence of synaptic noise and other uncorrelated sources of activity at a given neuron.

On the significance of temporally structured activity in the dorsal lateral geniculate nucleus (LGN).

Higher organisms perceive information about external or internal physical or chemical stimuli with specialized sensors that encode characteristics of that stimulus by a train of action potentials. Usually, the location and modality of the stimulus is represented by the location and specificity of the receptor and the intensity of the stimulus and its temporal modulation is thought to be encoded by the instantaneous firing rate. Recent studies have shown that, primarily in cortical structures, special features of a stimulus also are represented in the temporal pattern of spike activity. Typical attributes of this time structure are oscillatory patterns of activity and synchronous discharges in spatially distributed neurons that respond to inputs evoked by a coherent object. The origin and functional significance of this kind of activity is less clear. Cortical, subcortical and even very peripheral sources seem to be involved. Most of the relevant studies were devoted to the mammalian visual system and cortical findings on temporally structured activity were reviewed recently (Eckhorn, 1994, Progr. Brain Res., Vol. 102, pp. 405-426; Singer and Gray, 1995, Annu. Rev. Neurosci., Vol. 18, pp. 555-586). Therefore, this article is designed to give an overview, especially of those studies concerned with the temporal structure of visual activity in subcortical centers of the primary visual pathway, which are the retina and the dorsal lateral geniculate nucleus (LGN). We discuss the mechanisms that possibly contribute to the generation and modulation of the subcortical activity time structure and we try to relate to each other the subcortical and cortical patterns of sensory activity.