Does oral antipsychotic pre-treatment influence outcome of a switch to long-acting injectable risperidone in patients with schizophrenia?

INTRODUCTION: The objective of this open-label study was to evaluate treatment benefits of risperidone long-acting injectable (RLAI) in patients with schizophrenia following direct transition from oral risperidone (RIS) compared with transition from other oral second generation antipsychotics. METHODS: Stable in- or outpatients (n=206) receiving RIS or OQAZ (olanzapine, quetiapine, amisulpride, ziprasidone) were transitioned to RLAI for 12 weeks. The primary outcome was the between-group treatment difference in change in PANSS total score from baseline to endpoint. Secondary outcomes included health-related quality-of-life and therapeutic alliance. RESULTS: Mean between-group difference in the change in PANSS total score from baseline to endpoint was -6.1 (CI: -17.6, 5.4), suggesting greater improvement in OQAZ than RIS patients. Due to the pre-specified non-inferiority margin of 5.1, it could not be concluded that OQAZ pre-treatment results in an at least non-inferior PANSS reduction versus RIS pre-treatment. Patient satisfaction with medication and change in quality-of-life subscores showed advantages for OQAZ patients. DISCUSSION: Compared to RIS pre-treatment, clinically stable patients with schizophrenia who are pre-treated with OQAZ might draw a stronger clinical benefit from direct transition to RLAI.

Asymmetry pays: visual lateralization improves discrimination success in pigeons.

Functional cerebral asymmetries, once thought to be exclusively human, are now accepted to be a widespread principle of brain organization in vertebrates [1]. The prevalence of lateralization makes it likely that it has some major advantage. Until now, however, conclusive evidence has been lacking. To analyze the relation between the extent of cerebral asymmetry and the degree of performance in visual foraging, we studied grain-grit discrimination success in pigeons, a species with a left hemisphere dominance for visual object processing [2,3]. The birds performed the task under left-eye, right-eye or binocular seeing conditions. In most animals, right-eye seeing was superior to left-eye seeing performance, and binocular performance was higher than each monocular level. The absolute difference between left- and right-eye levels was defined as a measure for the degree of visual asymmetry. Animals with higher asymmetries were more successful in discriminating grain from grit under binocular conditions. This shows that an increase in visual asymmetry enhances success in visually guided foraging. Possibly, asymmetries of the pigeon's visual system increase the computational speed of object recognition processes by concentrating them into one hemisphere while preventing the other side of the brain from initiating conflicting search sequences of its own.

Impaired learning of a color reversal task after NMDA receptor blockade in the pigeon (Columba livia) associative forebrain (neostriatum caudolaterale).

The neostriatum caudolaterale (NCL) in the pigeon (Columba livia) forebrain is a multisensory associative area and a functional equivalent to the mammalian prefrontal cortex (PFC). To investigate the role of N-methyl-D-aspartate (NMDA) receptors in the NCL for learning flexibility, the authors trained pigeons in a color reversal task while locally blocking NMDA receptors with D,L-2-2-amino-5-phosphonovalerate (AP-5). Controls received saline injections. AP-5-treated pigeons made significantly more errors and showed significantly stronger perseveration in a learning strategy applied by both groups but were unimpaired in initial learning. Results indicate that NMDA receptors in the NCL are necessary for efficient performance in this PFC-sensitive task, and that they are involved in extinction of obsolete information rather than in acquiring new information.

Impairment in a discrimination reversal task after D1 receptor blockade in the pigeon "prefrontal cortex".

Dopamine (DA) is known to modulate cognitive functions of the prefrontal cortex (PFC) of mammals, especially via D1 receptor mechanisms. Like the PFC, the neostriatum caudolaterale (NCL) of birds is characterized by dopaminergic input, and NLC and PFC lesions cause similar deficits. The significance of DA in a color discrimination reversal was assessed by evaluating the effects of bilateral infusions of the D1 receptor antagonist SCH 23390 into the NCL of pigeons (Columba livia). Reversal deficits were qualitatively similar to those in mammals. At a low dose, perseveration occurred predominantly to the incorrect stimulus. Higher doses caused additional spatial perseveration. The data demonstrate, for the first time, that D1 receptor mechanisms in the NCL of pigeons contribute substantially to its function in cognitive processes. Thus, the avian NCL and mammalian PFC could represent functionally equivalent neural networks under control of the DA system.

Post-hatch activity-dependent modulation of visual asymmetry formation in pigeons.

The embryonically induced visual lateralization in pigeons can be modified by occlusion of one eye after hatching. Here we show that this deprivation effect could be also attained by short-term blocking of retinal activity with tetrodotoxin (TTX), leading to a dominance of the ipsilateral hemisphere in a visual discrimination task. This lateralization pattern resulted from a performance increase conveyed by the non-deprived hemisphere, while performance with the TTX-injected eye did not differ from that of saline-injected controls. Thus, post-hatch modulation of visual lateralization is mediated by TTX-sensitive, activity-dependent neuronal mechanisms. The transient silencing of one visual input alters the activity balance between the left and right eye system, enhancing visuoperceptive skills in the relatively higher active hemisphere.

Evidence for physiological asymmetries in the intertectal connections of the pigeon (Columba livia) and their potential role in brain lateralisation.

In pigeons, visual object processing is lateralised with a dominance of the left tectofugal system. To test the hypothesis, that avian visual lateralisation may arise, at least in part, from asymmetric interhemispheric inhibition, the intertectal modulation was quantified in 19 pigeons. Field potentials were recorded from intratectal electrodes in response to a stroboscope flash to the contralateral eye. Electrical stimulation of the contralateral tectum changed these flash-evoked potentials. This change was taken as a measure of intertectal modulation. It was found that the left-to-right tectotectal modulation was more pronounced than vice versa, supporting the hypothesis of an asymmetric modulation between the tecta of both hemispheres. It is conceivable that this lateralised interhemispheric crosstalk could constitute an important component of asymmetric visual processing.

Single unit activity during a Go/NoGo task in the "prefrontal cortex" of pigeons.

Single unit activity was recorded during a delayed auditory/visual Go/NoGo task from the neostriatum caudolaterale (NCL) of pigeons, a multimodal associative avian forebrain structure comparable to the prefrontal cortex (PFC). The animals were trained to mandibulate (to open their beak) during the Go period after which they received a drop of water as reward. Neuronal activity changes were observed during the delay period (DELAY) between auditory and visual stimulation, to the onset of the visual stimulus or to the delivery of the reward. In some neurons, responses were related to the behavioral significance of the stimulus such that the neuronal activity was statistically different between Go and NoGo trials. Moreover, some units anticipated the upcoming reward or changed their firing frequency in a correlated manner prior to beak movements. These neuronal activity patterns suggest that the NCL provides a neural network that participates in the integration and processing of external stimuli in order to generate goal directed behavior.

Electrophysiological and anatomical evidence for a direct projection from the nucleus of the basal optic root to the nucleus rotundus in pigeons.

A direct projection of the nucleus of the basal optic root (nBOR) onto the nucleus rotundus (Rt) in the pigeon would link the accessory optic system to the ascending tectofugal pathway and could thus combine self- and object-motion processes. In this study, injections of retrograde tracers into the Rt revealed some cells in central nBOR to project onto the ipsilateral Rt. Contrary, injections into the diencephalic component of the ascending thalamofugal pathway resulted in massive labeling of neurons in dorsal nBOR. Single unit recordings showed that visual nBOR units could be activated by antidromic stimulation through the Rt. Successful collision tests applied to nBOR cells revealed that the connection between nBOR and Rt is direct. These data provide strong evidence for a direct and differential projection of nBOR subcomponents onto the thalamic relays of the two ascending visual pathways.

Lateralized interhemispheric transfer of color cues: evidence for dynamic coding principles of visual lateralization in pigeons.

Visual feature discrimination tasks in pigeons reveal a right eye/left hemisphere dominance at the population level. Anatomical studies and lesion data show this visual lateralization to be related to asymmetries of the tectofugal system, which ascends from the tectum over the n. rotundus to the forebrain. Anatomically, this system is characterized by numerous morphological and connectional asymmetries which result in a bilateral visual representation in the dominant left hemisphere and a mostly contralateral representation in the subdominant right hemisphere. Ontogenetically, visual lateralization starts with an asymmetrical embryonic position within the egg, which leads to asymmetries of light stimulation. Differences in exposure to light stimulation between the eyes result in activity differences between the ascending tectofugal pathways of the left and the right hemisphere, which are transcribed during a critical time span into morphological asymmetries. The asymmetries established after this transient period finally start to determine the lateralized processes of the visual system for the entire life span of the individual. We now can show that these anatomical lateralizations are accompanied by asymmetries of interocular transfer, which enable a faster shift of learned color cues from the dominant right to the left eye than vice versa. In summary, our data provide evidence that cerebral asymmetries are based both on "static" anatomical and on "dynamic" process-dependent principles.

Neuronal processing of conspecific and related calls in the torus semicircularis of Rana r. ridibunda Pall. (Anura): single-unit recordings.

1. Single-unit responses in the torus semicircularis of Rana ridibunda were analyzed with regard to the neuronal mechanisms underlying call identification. Particular attention was directed to the question whether discrimination among the conspecific calls (mating, territorial and release calls), and between these and the mating calls of the related species R. lessonae and of the hybrid R. esculenta, can be explained by differences in the neuronal responses. 2. 75% of the single cells responded to at least one call. 25% of the neurons in this group were selective in the sense that they failed to respond to at least one of the calls. 3. Three of the single cells were selective for one type of call alone, the conspecific mating call in each case. Most of the selective neurons responded to three calls, having a preference either for the conspecific calls or for the amplitude-modulated mating calls. Such responses can be explained by the neurons' operation as either frequency or time filters. 4. Even the neurons that were nonselective, responding in some way to all the calls, differentiated among them with regard to response magnitude; that is, either the territorial and release calls elicited higher discharge rates than the amplitude-modulated mating calls, or the reverse. 69.8% of the single cells exhibited maximal responses to the conspecific mating call. The territorial and release calls elicited maximal responses in only 7.8% of the single cells. 5. In discrimination among the three mating calls, the temporal pattern of the calls plays a role. The differences in pulse-group timing are encoded by the overall response magnitude and not by way of differences in degree of synchronization. 66% of the nonselective neurons responded maximally to one of the three mating calls and very much less intensely to the other two. 6. No correlation was found between the types of call to which the various neurons responded maximally and the CF's of those neurons. Only very few cells represented a frequency and time filter exactly tuned to a particular call.

Midbrain auditory sensitivity in the spring peeper (Pseudacris crucifer): correlations with behavioral studies.

1. We derived audiograms from recordings of multiunit activity in the torus semicircularis of 10 males and 6 females of the spring peeper from central Missouri, USA. We used free-field stimulation with tone bursts that had temporal properties similar to typical advertisement calls and that ranged in frequency from 500-6000 Hz. 2. Audiograms from different electrode positions in the same animal had the same general shape. There was no evidence of tonotopy. 3. Audiograms showed two regions of maximal sensitivity: a low-frequency region (500-700 Hz); and a high-frequency region (2000-4000 Hz). Absolute thresholds and frequencies of maximum sensitivity varied considerably from individual to individual. 4. Audiograms derived from all individuals of each sex indicated that in the high-frequency region, corresponding to the frequency range of advertisement calls, males were more broadly tuned than females. However, tuning in both sexes was relatively weak, and the data predict relatively little selectivity in behavioral responses over the entire range of variation in frequency of the advertisement call in local populations. 5. The results are discussed in terms of behavioral experiments with both males and females from the same populations in central Missouri. We show that merely summarizing the audiograms based on estimates of minimum thresholds of a population or species may mask significant individual differences in tuning. Moreover, most behavioral studies are conducted at playback levels considerably above threshold. For these reasons, behavioral selectivity is not always accurately predicted by inspection of "average" audiograms.

Selective phonotaxis to advertisement calls in the grey treefrog Hyla versicolor: behavioral experiments and neurophysiological correlates.

1. The significance of particular acoustic properties of advertisement calls for selective phonotaxis by the gray treefrog, Hyla versicolor (= HV), was studied behaviorally and neurophysiologically. Most stimuli were played back at 85 dB SPL, a level typically measured at 1-2 m from a calling male. 2. Females preferred stimuli with conspecific pulse shapes at 20 degrees and 24 degrees C, but not at 16 degrees C. Tests with normal and time-reversed pulses indicated the preferences were not influenced by the minor differences in the long-term spectra of pulses of different shape. 3. Pulse shape and rate had synergistic or antagonistic effects on female preferences depending on whether the values of one or both of these properties in alternative stimuli were typical of those in HV or heterospecific (H. chrysoscelis = HC) calls. 4. More auditory neurons in the torus semicircularis were temporally selective to synthetic calls (90%) than to sinusoidally AM tones and noise (< 70%). 5. Band-pass neurons were tuned to AM rates of 15-60 Hz. Neurons were more likely to be tuned to HV AM rates (< 40 Hz) when stimuli had pulses with HV rather than HC shapes. 6. Sharp temporal tuning was uncommon and found only in neurons with band-pass or low-pass characteristics. 7. Many neurons differed significantly in response to HV and HC stimulus sets. Maximum spike rate was more often elicited by an HV stimulus (74%) than by an HC stimulus (24%). 8. Differences in spike rates elicited by HV and HC stimuli were attributable to combinations of differences in the rise times and shapes of the pulses.