U-100, pH-Neutral formulation of VIAject(®) : faster onset of action than insulin lispro in patients with type 1 diabetes.

AIMS: VIAject® is a formulation of human insulin with a very fast onset of action. Previous studies used VIAject in a concentration of 25 U/ml and a pH of 4 [VIAject 25 (VJ25)]. Objective of this double blind, three-way crossover study was to compare the pharmacodynamic/pharmacokinetic properties of a novel formulation of VIAject with a concentration of 100 U/ml and a neutral pH [VIAject 7 (VJ7)] with VJ25 and insulin lispro (LIS). METHODS: Forty-three patients with type 1 diabetes [aged 43 (21-65) years, BMI 24.1 (20-28) kg/m(2) and HbA1c 7.5 (5.7-9.5) %] participated in this study. They received subcutaneous injections of 12 U of each insulin formulation under euglycaemic glucose clamp conditions. RESULTS: VJ7 was bioequivalent to VJ25 [90% confidence interval (CI) of the ratios for total insulin AUCs and maximum insulin concentration (C(INS max) ) was within 0.80-1.25]. VJ7 showed a faster absorption compared to LIS [time to C(INS max) 23 vs. 60 min; difference (CI) -30 (-35 to -23)] and faster onset of action [time to early half-maximal glucose infusion rate (GIR) 25 vs. 44 min; -18 (-26 to -10)], and a higher AUC of glucose infusion rate (AUC(GIR) ) in the first 60 min after injection [176 vs. 107 mg/kg; ratio 1.65 (1.27 to 2.14)], contributing to a slightly higher value for AUC(GIR 0-480) [1263 vs. 1095 mg/kg; 1.15 (1.06 to 1.26)]. Maximum GIR was similar between VJ7 and LIS [6.1 vs.6.6 mg/kg/min; ratio 0.93 (0.86 to 1.01)], whereas the duration of action (t(GIR50%-late) ) was longer with VJ7 [274 vs. 228 min; 50 (25 to 73)]. CONCLUSIONS: This formulation of VIAject is bioequivalent to the previously used formulation and has a faster absorption/onset of action than LIS.

Standard antiepileptic drugs fail to block epileptiform activity in rat organotypic hippocampal slice cultures.

BACKGROUND AND PURPOSE: Earlier studies had demonstrated that tonic-clonic seizure-like events (SLEs) resembling electrographic correlates of limbic seizures in animals and humans can be induced in organotypic hippocampal slice cultures (OHSCs). We have explored OHSCs for their suitability to serve as in vitro models of limbic seizures for studying seizure mechanisms and screening new antiepileptic compounds. EXPERIMENTAL APPROACH: OHSCs were cultivated according to the interface method. Neuronal activity and extracellular potassium concentration were recorded under submerged conditions. SLEs were induced by lowering magnesium concentration or by applying the potassium channel blocker 4-aminopyridine. The effects of standard antiepileptic drugs (AEDs), carbamazepine, phenytoin, valproic acid, clonazepam, diazepam and phenobarbital sodium on SLEs were analysed. KEY RESULTS: In more than 93% of OHSCs, AEDs did not prevent the induction of SLEs or stop ongoing seizure activity even when toxic concentrations were applied. This pharmacoresistance was independent of the method of seizure provocation, postnatal age at explantation (P2-P10) and cultivation time in vitro (2 months). SLEs were reversibly blocked by glutamate antagonists or the GABA(A)-agonist muscimol. CONCLUSIONS AND IMPLICATIONS: We present a simple to establish in vitro model of tonic-clonic SLEs that is a priori pharmacoresistant and thus has an advantage over animal models of pharmacoresistant seizures in which responders and non-responders can be sorted out only after an experiment. OHSCs could be suitable for exploring mechanisms of pharmacoresistant seizures and be used for the identification of new anticonvulsive compounds eventually effective in drug refractory epilepsy.

Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison.

BACKGROUND: Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatment-refractory. In this study, the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia. METHODS: Twenty-one patients (mean [+/-SD] age, 14.0 +/- 2.3 years) with onset of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition-defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study. Patients were randomized to a 6-week double-blind parallel comparison of clozapine (mean [+/-SD] final dose, 176 +/- 149 mg/d), or haloperidol, (16 +/- 8 mg/d). RESULTS: Clozapine was superior to haloperidol on all measures of psychosis (P = .04-.002). Positive and negative symptoms of schizophrenia improved. However, neutropenia and seizures were major concerns. To date, one third of the group has discontinued using clozapine. CONCLUSIONS: Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia. However, due to possibly increased toxic effects in this pediatric population, close monitoring for adverse events is essential.

Brain anatomic magnetic resonance imaging in childhood-onset schizophrenia.

BACKGROUND: Early-onset schizophrenia (first psychotic symptoms by age 12 years) has been the subject of a small number of studies, and its biological continuity with later-onset disorder has not been established. In this study quantitative anatomic brain magnetic resonance images of children and adolescents with early-onset schizophrenia were compared with those of matched controls. Brain abnormalities in childhood-onset schizophrenia were examined in relation to those reported for later-onset schizophrenics. METHODS: Anatomic brain magnetic resonance imaging scans were obtained for 21 patients (mean +/- SD age, 14.6 +/- 2.1 years; range, 10 to 18 years) with childhood-onset schizophrenia (13 males, eight females) and 33 age-, sex-, height-, and weight-matched normal controls. Quantitative measurements were obtained for the cerebrum, anterior frontal region, lateral ventricles, thalamus, caudate, putamen, and globus pallidus. RESULTS: Total cerebral volume and midsagittal thalamic area were smaller in the patients (analysis of variance, P = .002, and analysis of covariance, P = .03, respectively); the caudate, putamen, and globus pallidus were larger in the patients (analysis of covariance, P = .05, P = .007, and P < .001, respectively); and the lateral ventricles tended to be larger in the patients (analysis of covariance, P = .06). Globus pallidus enlargement correlated with neuroleptic exposure and with age of onset of psychosis. The magnitude of abnormalities compared with controls was similar to that reported in adult studies, although there was a trend toward relatively smaller cerebral volumes for the childhood-onset group compared with controls. CONCLUSION: Brain anatomic abnormalities in childhood-onset schizophrenia are similar to those reported for adult populations, indicating overall continuity between these rare childhood cases and the adult schizophrenia populations.

Childhood-onset schizophrenia: brain MRI rescan after 2 years of clozapine maintenance treatment.

OBJECTIVE: The effect of clozapine on striatal morphology was examined in adolescents with childhood-onset schizophrenia. METHOD: Eight adolescent patients with onset of psychosis before age 12 and eight matched comparison subjects had initial and 2-year follow-up brain magnetic resonance imaging scans. Basal ganglia and lateral ventricle volumes were measured. The patients were on a clozapine regimen during the 2-year interim. RESULTS: Caudate volume was larger in the patients at the initial scanning, decreased in the patients between scans, and did not differ significantly between the patients and the comparison subjects at the second scanning. CONCLUSIONS: Caudate enlargement in patients with childhood-onset schizophrenia who are taking typical neuroleptics appears to be secondary to medication exposure. Rescanning to examine basal ganglia morphology is indicated for these patients when they are taking an atypical neuroleptic.

Divergence of single axons in afferent projections to the cat's visual cortical areas 17, 18, and 19: a parametric study.

The proportions of neurons projecting via axon collaterals to two areas in the cat's occipital cortex (diverging neurons) were determined quantitatively in subcortical and cortical afferents by making use of the retrograde axonal transport of two different tracers. The proportions of diverging neurons were determined for that part of the afferent sites in which neurons filled with tracers from both injected areas occurred (overlap zone). A number of experimental variables were tested for their role in possibly influencing the results of quantitative double-label experiments, among them the types and the combinations of retrograde tracers, the position of the injections, the survival time, and the histological procedure. The most important variable was the position of the cortical injection, which had to be restricted clearly to the cortical grey matter and to one cortical area in order to avoid false-positive double labeling. Other experimental variables affected the total number of retrogradely labeled neurons and/or the ratio between neurons labeled with the two different tracers rather than the proportions of double-labeled neurons. In particular DL proportions were largely independent of the number and density of labeled neurons. They only deviated significantly from mean values in those sections in which the number of labeled neurons amounted to less than 20% of the maximal number of labeled neurons found in one section throughout the overlap zone. Our results show that divergence is common in afferents to the cat visual cortex. The amount of divergence, however, varies considerably according to the origin of the afferent projection. The proportion of diverging neurons expressed as the percentage of the total number of neurons projecting to areas 17 and 18 was 3% in the A-laminae of the dorsal part of the lateral geniculate nucleus, about 8% in the posteromedial lateral suprasylvian area, and about 15% in the C-laminae of the dorsal part of the lateral geniculate nucleus, in the medial interlaminar nucleus, in the lateral part of the lateral posterior nucleus, and in the claustrum. The proportions of diverging neurons in the afferent projections to areas 17 and 19, and to areas 18 and 19 were about 10%. Diverging neurons were also found in the projections of the intralaminar thalamic nuclei to the visual cortex.(ABSTRACT TRUNCATED AT 400 WORDS)

Rapid rearrangement of intrinsic tangential connections in the striate cortex of normal and dark-reared kittens: lack of exuberance beyond the second postnatal week.

Clustered intrinsic connections in the kitten striate cortex originate from an unclustered, diffusely organized pattern prevailing during the first postnatal week. We have studied the progress of this reorganization and its dependence on visual input by determining the topographies of the intrinsic tangential connections at various postnatal ages by means of axonal tracing methods. Neurons were labeled either by diffusion of the carbocyanin dye DiI in animals ranging in age between 1 day and 30 days, or by retrograde transport of fluorescent microspheres in animals ranging in age between 7 days and 11 months. Quantitative evaluation of retrogradely labeled neurons revealed that during the first postnatal week, intrinsic tangential connections are organized in an unclustered fashion. During the second postnatal week a rapid rearrangement of connections occurs and is complete around postnatal day 11. The main events taking place during the course of this rearrangement are a decrease in the density of tangential connections and an arrangement of them in a clustered fashion. Once the clusters have been formed, the periodicity of the clustered pattern of connections and the size and distinctness of the clusters do not change. This means that the system of clustered tangential connections is adult-like at the end of the second postnatal week. Dark rearing affects neither the rapid rearrangement of horizontal connections into an adult-like system of clusters, nor the integrity of this clustered topography until the end of the first postnatal month. The overall distribution and the lateral extent of the tangential connections remain about the same during the postnatal period and are not affected by dark rearing until the end of the first postnatal month. We conclude that the clustered system of tangential connections in the cat's striate cortex is determined innately.

The distribution of pontine projection cells in visual and association cortex of the cat: an experimental study with horseradish peroxidase.

The projections from the visual and association areas of the cat's neocortex to the pons were investigated with horseradish peroxidase as retrograde tracer. Small injections were made into the pars basalis of the pons, along its entire rostrocaudal extent. The cortical areas considered were areas 17, 18, 19, 20, 21, and the lateral suprasylvian areas (LSA); the posterior (PMSA), and the anterior middle suprasylvian association area (AMSA), the anterior lateral association area (ALA) and the anterior suprasylvian association area (ASA). A pontine projection was found for all the areas investigated; however, areas differ in the relative strength of their projection, in their intraareal distribution of projection cells, and in the location of their projection zones within the pons. A low to moderate density of projection cells is seen in the areas 17, 18, 19, 20, 21, and in PMSA. The posterior part of LSA contains only a few projection cells, whereas in more anterior parts of LSA the density of projection cells is moderate to high. A relatively dense distribution of projection cells also appears in AMSA, ALA, and ASA. In those areas which are retinotopically organized (17, 18, 19, LSA) the representation of the center of gaze contains far fewer projection cells than the representation of peripheral vision. In the association areas the distribution of projection cells appears even. The projection zones from areas 17, 18, and 19 overlap with the zones from LSA in the anterior half of the basal pons. The projection zones from areas 20 and 21 and from ALA and ASA are located in the middle third and the projection zones from PMSA and AMSA spread throughout the entire rostrocaudal extent of the basal pons. Our findings indicate that efferent impulses from the visual cortical areas and from the association areas on the middle suprasylvian gyrus are relayed to the cerebellum exclusively via the basal pontine nuclei. The findings further suggest that the visual corticopontine projections carry a map of the visual field in which the cortical magnification factor is reduced.

Examination of the effects of cholecystokinin 26-33 and neuropeptide Y on responses of visual cortical neurons of the cat.

Extracellular recordings were made from 160 neurons in area 17 (n = 120) and area 18 (n = 40) of the visual cortex of anesthetized cats. Cells were classified according to their receptive field properties and their intracortical positions were evaluated histologically. Cholecystokinin 26-33, antagonists, (cholecystokinin 27-32, cholecystokinin 27-33 and proglumide), amino acids, neuropeptide Y and solvent vehicle (control), were administered to cells by microiontophoresis (cholecystokinin and neuropeptide Y) or by pressure (neuropeptide Y). The results of the tests with cholecystokinin 26-33 fell into four categories: enhancement (31%), suppression (24%), mixed, i.e. either biphasic responses or dose-related alterations in the direction of effect (20%), and no effect (25%). Enhancements of the visually elicited response were more prevalent in simple (43%) and unimodal/movement-sensitive (34%) cells than in complex (7%) cells. The converse was true for suppressions: 19% of simple cells, 24% of unimodal/movement-sensitive cells, and 31% of complex cells were suppressed. Thirty per cent of the unaffected cells were complex or unimodal/movement-sensitive; only 14% were simple. Cells in layers II-IV were more likely to have firing enhanced than suppressed by cholecystokinin 26-33. The converse was true for cells in layers V and VI, where 50% of responses were suppressed and only 22% were enhanced. Unaffected cells were found predominantly in layer III of areas 17, and the lower part of layer III and layer IV of area 18. Cholecystokinin 26-33 sometimes exerted delayed, response-suppressant effects; it also occasionally elevated responsiveness preferentially within the upper ranges (10-20 degrees/s) of velocity tuning curves. Cholecystokinin 26-33 altered the response-suppressant action of GABA in 11 of 19 visually sensitive cells. The peptide potentiated the visual responsiveness in half of the cells where cholecystokinin 26-33 diminished the GABA-induced suppressions (n = 8). The presumed antagonists either exerted no effect on firing or on cholecystokinin 26-33-induced effects, or had cholecystokinin 26-33-like actions themselves. There was a reversible partial antagonism of the effects of cholecystokinin 26-33 on only two of 11 cells tested. Neuropeptide Y injected by pressure or administered iontophoretically had variable and inconsistent effects on the visually evoked responses of 29 additional neurons from those described above. These effects were indistinguishable from those of the vehicle whether spontaneous activity, magnitude of the visually elicited response, spatial integrity of the RF substructure, orientation or velocity tuning was assessed.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response.

BACKGROUND: Plasma clozapine and haloperidol concentrations were studied in adolescents being treated for childhood-onset schizophrenia. METHOD: Eleven patients (9 boys, 2 girls; mean age = 14.1 +/- 2.1 years) received a 6-week blinded or open trial of clozapine. Five patients also received 6 weeks of blinded or open haloperidol. Doses were increased on an individual basis to a mean 6-week dose of 5.99 +/- 2.6 mg/kg/day for clozapine and 0.24 +/- 0.20 mg/kg/day for haloperidol. The Brief Psychiatric Rating Scale and Bunney Hamburg Rating Scale were completed weekly for each subject. Weekly blood samples were obtained during therapy and assayed by high performance liquid chromatography. RESULTS: The mean clozapine level at Week 6 was 378.3 ng/mL and ranged from 77.5 to 1050 ng/mL. The mean Week 6 haloperidol level was 23.0 ng/mL (range, 6.2-44.3 ng/mL). The clozapine desmethyl and N-oxide metabolites achieved mean concentrations of 77% and 18%, respectively, of those of the parent compound. The mean ratio of haloperidol/reduced haloperidol was 4.48 (range, 0.76-8.76). Clozapine concentrations versus clinical benefit exhibited a consistent linear relationship among patients (correlation range, 0.26-0.96). Conversely, poor and inconsistent correlations between haloperidol concentrations and clinical effects were observed. No relationships were noted between clozapine or haloperidol dose and clinical effects. CONCLUSION: Adolescents with schizophrenia produce a greater amount of desmethylclozapine than previously seen in adults. Plasma clozapine concentrations appear to be related in a linear fashion to clinical improvement.

Neuropsychological deficits in pediatric patients with childhood-onset schizophrenia and psychotic disorder not otherwise specified.

OBJECTIVE: Children with transient psychotic symptoms and serious emotional disturbances who do not meet current criteria for schizophrenia or other presently recognized diagnostic categories commonly present diagnostic and treatment problems. Clarifying the connections between children with narrowly defined schizophrenia and children with a more broadly defined phenotype (i.e., Psychotic Disorder Not Otherwise Specified, PD-NOS) has implications for understanding the pathophysiology of schizophrenia. In this study, the neuropsychological test performance of a subgroup of children with atypical psychosis was compared with that of patients with childhood-onset schizophrenia (COS). METHOD: Cognitive function was assessed with neuropsychological test battery regimens in 51 neuroleptic-nonresponsive patients within the first 270 at NIMH testing (24 PD-NOS, 27 COS) were included in this analysis. Seventeen (39%) of 44 COS subjects were unavailable for this study as their IQ tested <70. The PD-NOS patients were younger than the COS patients at the time of testing (12.0+/-2.8 vs 14.4+/-1.8years, respectively, p<0.004). The test levels of these groups were compared with each other. RESULTS: The neuropsychological test results for the PD-NOS and COS patients were 1-2standard deviations below normative data across a broad array of cognitive functions. There were no overall differences in the test levels for the six summary scales (F=2.82, df=1, 36, p=0.10) or in the profile shape (F=1.70, df=5, 180, p=0.14) between the PD-NOS and COS groups. For the COS patients, there was a significant difference between their mean full-scale WISC IQ (84.7+/-16.2) and their average standard scores for both the spelling (97.7+/-16.1, n=23, t=4.0, p=0.001) and reading decoding subtests (97.7+/-13.7, n=23, t=3.7, p=0.001) of the Kaufman Test of Educational Achievement. CONCLUSIONS: Treatment-refractory PD-NOS and COS patients share a similar pattern of generalized cognitive deficits, including deficits in attention, learning and abstraction which are commonly observed in adult patients with schizophrenia. These data support a hypothesis that at least some of the PD-NOS cases belong within the schizophrenic spectrum, which is of importance for future genetic studies planned for this cohort.

Performance of real time separation of multi-neuron recordings with a DSP32C microprocessor.

The performance of a method for sorting of waveforms in multi-neuron data (Gädicke and Albus, 1995) is evaluated by using artificial spike patterns generated by the computer and by adding to these spikes noise or free running sine waves of varying frequency and amplitude to simulate EEG-waves. The DSP32C is capable of continuously processing spikes at 183.106 Hz. In addition to real-time sorting the DSP32C also performs a running average of the spikes sorted into each class and transfers data to the host computer. The ability of the system to analyse burst of activity is determined by the FIFO memory buffer (2048 samples, or 32.768 ms at 62.5 kHz sampling rate). Adding a 50 Hz sine wave discrimination worked correctly with sine wave amplitudes of up to 2.5 times that of the smallest spike. Combining spikes with noise revealed errors of inclusion and/or exclusion of less than 0.1% provided the models spikes were determined from noiseless spikes and the spike threshold was set above the noise peak level. When noisy spikes were used to define model spikes about 4% of the smallest amplitude spikes (signal to noise ratio 3.3) were incorrectly classified. For higher amplitude spikes (signal to noise ratio > or = 5) the classification error was on average less than 1%. The artificial patterns used for performance testing are exactly defined and could be used to standardize the comparison between different sorting techniques.

Real-time separation of multineuron recordings with a DSP32C signal processor.

We have developed a hardware and software package for real-time discrimination of multiple-unit activities recorded simultaneously from multiple microelectrodes using a VME-Bus system. Compared with other systems cited in literature or commercially available, our system has the following advantages. (1) Each electrode is served by its own preprocessor (DSP32C); (2) On-line spike discrimination is performed independently for each electrode. (3) The VME-bus allows processing of data received from 16 electrodes. The digitized (62.5 kHz) spike form is itself used as the model spike; the algorithm allows for comparing and sorting complete wave forms in real time into 8 different models per electrode.

Childhood-onset schizophrenia: the severity of premorbid course.

OBJECTIVE: To review the premorbid histories of 23 children meeting DSM-III-R criteria for schizophrenia with onset before age 12 years and to compare these with childhood data of later-onset schizophrenics. METHOD: Premorbid features up to 1 year before onset of first psychotic symptoms were rated from hospital and clinic records, clinical interviews, rating scales, and tests. RESULTS: In keeping with previous studies, specific developmental disabilities and transient early symptoms of autism, particularly motor stereotypies, were common. Comparison with the childhood of later-onset schizophrenics showed greater delay in language development, and more premorbid speech and language disorders, learning disorders, and disruptive behavior disorders. (Sixty percent had received or were estimated to meet criteria for one or more clinical diagnoses.) CONCLUSIONS: Childhood-onset schizophrenia may represent a more malignant form of the disorder, although selection and ascertainment bias cannot be ruled out. The presence of prepsychotic language difficulties focuses attention on the importance of early temporal and frontal lobe development; early transient motor stereotypies suggest developmental basal ganglia abnormalities and extend previous findings seen in the childhood of later-onset patients.

A neuronal subsystem in the cat's area 18 lacks retinotopy.

Single neurones were recorded extracellularly in the visual cortex of anaesthetized and paralyzed cats. In all parts of area 18, neurones with diffuse receptive fields (DRFs) were found. DRFs measured at least 50 degrees in diameter and always included the area centralis and large parts of the ipsi- and contralateral hemifeld; some DRFs even covered the entire visual field. DRF neurones gave phasic responses to diffuse light, and to light spots either presented stationary or moved rapidly across the field; they were not orientation- or direction-sensitive. In contrast to the majority of area 18 neurones, which are part of a retinotopically organized system, DRF neurones constitute a subsystem with only poor retinotopy, or no retinotopy at all. This system might be suitable for detecting sudden changes in global illumination.

Phaclofen antagonizes baclofen-induced suppression of visually evoked responses in the cat's striate cortex.

The suppression of visually evoked responses (VER) in the cat's striate cortex by baclofen was reversibly antagonized by the phosphonic acid derivative of baclofen, phaclofen. The antagonistic effect of phaclofen was seen irrespective of whether it enhanced, suppressed or did not change VER on its own. The suppression of VER by gamma-aminobutyric acid (GABA) was not affected by phaclofen. Our findings support the notion (Kerr et al., Brain Research, 405 (1987) 150-154) that phaclofen is an effective baclofen antagonist in the central nervous system of mammals. Preliminary findings indicate that in spite of its possible action on GABAB receptors, phaclofen does not significantly alter functional properties of striate cortical neurons, in particular direction and orientation sensitivity.

Spiny stellates as cells of origin of association fibres from area 17 to area 18 in the cat's neocortex.

Neurons in the cat's area 17 were stained in Golgi-like fashion following injection of horseradish peroxidase into area 18. Such staining allows classification of neurons on the basis of dendritic morphology. The types of neurons found in area 17 are: pyramidal cells in layers 2, 3 and 4ab; spiny stellate cells in the lower part of layer 3, and in layer 4ab; and a few pyramidal and spindle cells in layer 5. The axons of the spiny stellate cells are finer than those of pyramidal cells; they give off collaterals in deeper cortical layers and may bifurcate when entering the white matter. Spiny stellates in area 17 do not project to area 19; after injections are made into area 17, these neurons are found neither in area 18 nor in area 19. The spiny stellate cell with a long axon is thus categorized as a projection neuron which takes part in the pathway from area 17 to ipsilateral and contralateral area 18.

Cholecystokinin octapeptide-like immunoreactive material in neurons of the intralaminar nuclei of the cat's thalamus.

Cholecystokinin-like immunoreactive material (CCK-IR) was revealed in the cat's thalamus by using the peroxidase-antiperoxidase method. The most dense collection of perikarya containing CCK-IR was seen in the rostral group of the intralaminar nuclei, in rostral parts of the rhomboid nucleus and the anterodorsal nucleus. Cells with CCK-IR were also found in the caudal group of the intralaminar nuclei, in the paraventricular nucleus and the parataenial nucleus. The remaining thalamic nuclei were void of CCK-IR. By combining immunohistochemistry with retrograde transport of horseradish peroxidase, CCK-IR was shown to be present in neurons of the intralaminar nuclei projecting to the neocortex. Our findings suggest that CCK might act as a transmitter in the efferent projections of the intralaminar and midline nuclei of the cat's thalamus.

Orientation bias in the response of kitten LGNd neurons to moving light bars.

The orientation sensitivity to moving light bars was determined for 113 neurons in laminae A, A1 and C of the dorsal part of the lateral geniculate nucleus (LGNd) of kittens 7-42 days old. Forty neurons (35.4%) were biased to contrast orientation (OB neurons), i.e. their response to an optimally oriented bar was 2-10 times stronger than their response to a bar oriented orthogonally to the optimal. The remaining 73 neurons were not sensitive to contrast orientation. Evidence is presented that orientation bias in the LGNd develops prior to visual experience. Orientation biased responses in the LGNd strongly depended on stimulus parameters; preferred stimuli were light bars having a length of 5 degrees or more and moving at velocities slower than 5 degrees/s. Our findings suggest that the OB neurons of the LGNd could be effective in generating the early orientation sensitivity in the visual cortex.

Tachykinins preferentially excite certain complex cells in the infragranular layers of feline striate cortex.

Microiontophoretically administered substance P (SP) affected the visually evoked responses (VER) and the spontaneous firing of 22 (14%) of the 152 neurons recorded from the striate cortex of anaesthetised cats. Enhancing effects were seen in 14 neurons and suppressant actions in 8 neurons. Most of the cells excited by SP were located in infragranular layers and had complex receptive fields; a few belonged to the movement-sensitive class or responded only weakly to visual stimulation. Of the neurons recorded in layer V, about 70% were excited by SP; the respective proportions were 8% in layer VI, and 2% in layer IV. Cells suppressed by SP had either simple or unimodal receptive fields including hypercomplex varieties; most of them were located in layer IVc. The effects of other tachykinins (neurokinin A, neurokinin B) and of the NK-3 receptor agonist Senktide tested in 36 cells were identical to those of SP with respect to types, and intracortical locations, of cells affected. During the enhancement induced by the tachykinins functional parameters of the neurons such as orientation and direction sensitivity were not substantially affected. It seems likely therefore that the effect of tachykinins in the primary visual cortex is not a shaping of receptive field properties, but rather a modulation of the general excitability of neurons projecting to subcortical centers, in particular to the midbrain and pons.