Innovative solutions to novel drug development in mental health.

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.

Orbitofrontal morphology in people at high risk of developing schizophrenia.

BACKGROUND: Abnormalities of orbitofrontal cortex (OFC) sulcogyral patterns have been reported in schizophrenia, but it is not known if these predate psychosis. METHODS: Hundred and forty-six subjects at high genetic risk of schizophrenia, 34 first episode of schizophrenia patients (SZ) and 36 healthy controls were scanned and clinically assessed. Utilising the classification system proposed by Chiavaras, we categorised OFC patterns and compared their distribution between the groups, as well as between those high risk subjects who did, and did not develop schizophrenia. The relationship between OFC pattern and schizotypy was explored in high risk subjects. RESULTS: We refined Chiavaras' classification system, with the identification of a previously unreported variant of OFC surface structure. There were significant differences in distribution of OFC patterns between high risk subjects who did or did not develop schizophrenia as well as between the first episode of schizophrenia group and healthy controls. Within the high risk group, possession of OFC Type III was associated with higher ratings on the Structured Inventory for Schizotypy (SIS) psychotic factor. CONCLUSIONS: Our results suggest that OFC Type III is associated with psychotic features before the development of schizophrenia. Characterisation of OFC morphology may have a role in the identification of those at greatest risk of developing schizophrenia.

Quality of life in Parkinson's disease: movement disorders clinic vs general medical clinic--a comparative study.

OBJECTIVES: to determine the effect of attending a movement disorders (MD) clinic on quality of life (QOL) outcomes for patients with Parkinson's disease (PD). METHODS: Postal questionnaire study of forty-two patients with Parkinson's disease attending either a movement disorders clinic or more conventional general medical clinic were selected consecutively to complete the Parkinson's Disease Quality of Life Questionnaire (PDQL). All patients were diagnosed by a consultant physician with an interest in Parkinson's disease (S.B.R.) and had attended either the movement disorders clinic or the general medical clinic on at least three occasions. Questionnaires were completed independently of the examiners and returned by post. RESULTS: Mean PDQL score was 124.1 [5.16] in the movement disorders clinic and 95.9 [5.86] in the general medical clinic. Analysis of covariance revealed that those subjects attending the MD clinic reported a significantly higher QOL than those subjects in general medical care (F(1,39)= 161.98, P < 0.001). CONCLUSION: These data indicate that the quality of life of respondents attending the movement disorders clinic is significantly higher than those attending the general medical clinic.

Voluntary saccadic eye movements in humans studied with a double-cue paradigm.

In the classic double-step paradigm, subjects are required to make a saccade to a visual target that is briefly presented at one location and then shifted to a new location before the subject has responded. The saccades in this situation are "reflexive" in that they are made in response to the appearance of the target itself. In the present experiments we adapted the double-step paradigm to study "voluntary" saccades. For this, several identical targets were always visible and subjects were given a cue to indicate that they should make a saccade to one of them. This cue was then changed to indicate another of the targets before the subject had responded: double-cue (DC) paradigm. The saccadic eye movements in our DC paradigm had many features in common with those in the double-step paradigm and we show that apparent differences can be attributed to the spatio-temporal arrangements of the cues/targets rather than to any intrinsic differences in the programming of these two kinds of eye movements. For example, a feature of our DC paradigm that is not seen in the usual double-step paradigm is that the second cue could cause transient delays of the initial saccade, and these delays still occurred when the second cue was reflexive--provided that it was at the fovea (as in our DC paradigm) and not in the periphery (as in the usual double-step paradigm). Thus, the critical factor for the delay was the retinal (foveal) location of the second cue/target--not whether it was cognitive or reflexive--and we argue that the second cue/target is here acting as a distractor. We conclude that the DC paradigm can be used to study the programming of voluntary saccades in the same way that the double-step paradigm can be used to study reflexive saccades.

The effect of excitotoxic lesions of the pedunculopontine tegmental nucleus on performance of a progressive ratio schedule of reinforcement.

The pedunculopontine tegmental nucleus has connections with sites in both dorsal and ventral striatum, and a number of studies have suggested that it has a role in reward-related behaviour. The present experiment aimed to investigate the perception of reward in pedunculopontine tegmental nucleus-lesioned rats responding for food under a progressive ratio schedule, which measures willingness to work for a given reward. Rats were trained on a progressive ratio-5 schedule for food reward, then given ibotenic acid or sham lesions of the pedunculopontine tegmental nucleus. Their performance under this schedule was examined again following recovery from surgery. Compared with sham-lesioned rats, those with lesions of the pedunculopontine tegmental nucleus showed significantly reduced breaking points and significantly longer post-reinforcement pauses. However, there was no difference between the groups in their latency to collect food pellets once earned, suggesting that pedunculopontine tegmental nucleus excitotoxin and sham-lesioned rats were equally motivated by the presence of food. Excitotoxin-lesioned rats made significantly more responses on the control lever and more entries to the food hopper as progressive ratio increment increased, but did not differ from controls when the schedule requirement was low. These results are interpreted as indicating no global loss of motivation, since lesioned rats performed normally at low schedule requirements, and were as fast as controls to collect pellets. But as the schedule requirement increased, excitotoxin-lesioned rats showed reductions in responding on the active lever (that is, a reduction in breaking point) and an increase in inappropriate responses towards the food hopper and the control lever.We consider these data to indicate that the behavioural deficits in pedunculopontine-lesioned rats arise not from a sensory or hedonic change, but from alteration in the control of motor output.

Cholinergic neurotransmission influences covert orientation of visuospatial attention in the rat.

RATIONALE: Both monkey and human studies have suggested that attentional orienting may be mediated by the cholinergic neurotransmitter system. OBJECTIVES: The purpose of the present study was to examine whether the cholinergic agonist (nicotine) and/or antagonist (scopolamine) influence covert orientation in the rat. METHODS: Rats carried out a visual reaction time task to measure covert orienting of attention following systemic administration of nicotine or scopolamine. RESULTS: Nicotine reduced reaction times, abolishing the validity effect by differentially speeding the reaction times for invalidly cued targets. Conversely, scopolamine increased the validity effect by disproportionately lengthening reaction times to invalidly cued targets. CONCLUSIONS: Taken together, these data indicate that cholinergic transmission represents an important neurochemical substrate of visuospatial attention, specifically influencing disengagement or movement of attention.

Medial frontal cortex mediates perceptual attentional set shifting in the rat.

If rodents do not display the behavioral complexity that is subserved in primates by prefrontal cortex, then evolution of prefrontal cortex in the rat should be doubted. Primate prefrontal cortex has been shown to mediate shifts in attention between perceptual dimensions of complex stimuli. This study examined the possibility that medial frontal cortex of the rat is involved in the shifting of perceptual attentional set. We trained rats to perform an attentional set-shifting task that is formally the same as a task used in monkeys and humans. Rats were trained to dig in bowls for a food reward. The bowls were presented in pairs, only one of which was baited. The rat had to select the bowl in which to dig by its odor, the medium that filled the bowl, or the texture that covered its surface. In a single session, rats performed a series of discriminations, including reversals, an intradimensional shift, and an extradimensional shift. Bilateral lesions by injection of ibotenic acid in medial frontal cortex resulted in impairment in neither initial acquisition nor reversal learning. We report here the same selective impairment in shifting of attentional set in the rat as seen in primates with lesions of prefrontal cortex. We conclude that medial frontal cortex of the rat has functional similarity to primate lateral prefrontal cortex.

Anticipatory errors after unilateral lesions of the subthalamic nucleus in the rat: evidence for a failure of response inhibition.

The nature of anticipatory responding in rats with unilateral subthalamic nucleus lesions was examined. Rats were trained to respond toward visual targets that were preceded by 1 of 4 different cues. For normal rats, a cue invokes an involuntary attentional orienting that enhances processing of the target at the location of attention. The cue is also a salient stimulus to which a response must be suppressed. Therefore, this task was used to investigate possible attentional impairments, as well as the ability of a lesioned rat to suppress competing motor programs. Responding under target control was not affected by the lesion. There was an increase in anticipatory responses before target onset, which could be accounted for by a failure to inhibit contralateral responses.

Thalamic reticular nucleus activation reflects attentional gating during classical conditioning.

All senses, except olfaction, are routed through the thalamus to cerebral cortex. Thus, the thalamus is often referred to as the sensory gateway to cortex. Located between thalamus and cortex is a thin lamina of neurons called the thalamic reticular nucleus, which may function as an attentional gate. The phenomenon of blocking in classical conditioning provides an opportunity to test whether an attended stimulus activates the thalamic reticular nucleus more than an unattended stimulus: when a second stimulus is presented together with a previously conditioned stimulus, conditioned responding to the second stimulus is inhibited. Different groups of rats were given conditioning sessions with a single stimulus, a light or a tone, and then given conditioning sessions with compound (light and tone) stimuli. Blocking was confirmed using probe trials of single stimulus presentations. After a final test session of compound stimulus presentations, the brains were processed for the presence of Fos protein. Here we show that Fos-positive neurons were more numerous in the sector of the thalamic reticular nucleus associated with the attended conditioned stimulus than in the sector associated with the unattended stimulus. Thus, we provide evidence for an involvement of the thalamic reticular nucleus in selective attention.

Attentional orienting is impaired by unilateral lesions of the thalamic reticular nucleus in the rat.

The thalamic reticular nucleus (TRN) has been implicated in attentional processes based on its anatomical, electrophysiological, and neurochemical relationships with the sensory nuclei of the thalamus and corresponding sensory areas of cortex. This study examined the possibility that the TRN is involved in covert orienting of attention. Attention can be summoned to a spatial location in the absence of an overt orienting response. The reaction time to a visual target is faster when attention has been drawn to the location of the target by a preceding cue in that location (valid cue) compared with when the cue misdirects attention (invalid cue) away from the location of the subsequent target. This reaction time difference is referred to as the "validity effect." Rats were trained to perform such a reaction time task with visual cues and targets presented in poke holes to either side of the rat's head, which had to be maintained centrally and still. If the rat made an overt orienting response to the cue, the trial was aborted. Unilateral lesions were made by injection of ibotenic acid in the TRN. After surgery, there was no bias apparent in their responding; they were as likely to initiate responses and were equally accurate to either side. There was, however, a complete abolition of the validity effect for responses to contralateral targets. The data are discussed in terms of a role for the TRN in attentional processing.

Reaction time performance following unilateral striatal dopamine depletion and lesions of the subthalamic nucleus in the rat.

The akinesia resulting from Parkinson's disease or striatal dopamine depletion in experimental animals can be ameliorated or reversed by inactivation of the subthalamic nucleus. This inactivation might be effective by restoring balance to the basal ganglia motor circuits. Alternatively, new movement-related deficits might be introduced which mask the original impairments (e.g. hyperkinesia might replace hypokinesia). In the present study, striatal dopamine depletion was effected unilaterally, in order to dissociate generalized effects, e.g. hyperkinesia, from response-specific initiation effects. Rats were trained in a lateralized visual reaction time task and then assigned to one of four groups: striatal dopamine depletion; cell body lesion of the subthalamic nucleus; combined striatal dopamine depletion and subthalamic nucleus lesion; or control. As expected, rats with striatal dopamine depletion exhibited slower reaction time and a bias to respond to the ipsilateral side. The subthalamic nucleus lesion resulted in no reaction time change (in particular, there was no evidence of faster reaction times), but there was an increase in anticipatory responding. The group with the combined striatal dopamine depletion and subthalamic nucleus lesion had no reaction time impairment. This group showed an increase in anticipatory errors and a contralateral response bias. These data demonstrate that lesions of the subthalamic nucleus do not merely cancel the akinesia which follows striatal dopamine depletion by the addition of a hyperkinetic impairment. Rather, there appears to be a change in the balance of the motor system.

Mechanisms underlying attentional set-shifting in Parkinson's disease.

Patients with Parkinson's disease (PD) show impairments on tasks that require them to switch attention between two perceptual dimensions (extradimensional (ED) shifting). It has been suggested that ED shifting deficits can be caused by two separate mechanisms, 'learned irrelevance' and 'perseveration'. This study set out to test the hypothesis that enhanced learned irrelevance is present in medicated patients with PD. An enhancement of learned irrelevance in PD patients should result in increased errors on a 'deficit' shift relative to controls and decreased errors on an 'improvement' shift. A similar pair of deficit and improvement shifts were used to detect possible enhanced perseveration in patients. Instead of showing the predicted patterns of deficit and improvement, patients displayed a consistent deficit on those shifts that required that they switch their attention to a different dimension (ED shifts). In contrast, patients were not impaired on shifts that required no such shift of attention (intradimensional shifts). Although there was an increase in errors at the learned irrelevance deficit shift, a similar increase at the learned irrelevance improvement shift shows that enhanced learned irrelevance is not responsible for either of these results. Patients were no more distractible than controls, but displayed increased 'loss of set' as measured by errors generated after a rule was learned. These results point to the existence of exaggerated, rigid selective attention in patients with PD rather than a breakdown in the ability to selectively attend. There was no evidence for the existence of enhanced learned irrelevance in the patients.

Simple and choice reaction-time performance following occlusion of the anterior cerebral arteries in the rat.

Focal cerebral ischemia in the rat has traditionally been studied by examining the consequences of middle-cerebral artery occlusion. However, the anteriorcerebral arteries of the rat may now also be bilaterally occluded by stereotaxic injection of the vasoconstrictor endothelin-1, resulting in ischemic damage to medial prefrontal cortex and the anteromedial basal forebrain. The behavioural consequences of anterior-cerebral artery occlusion (ACAo) were studied in two experiments using simple and choice reaction-time tasks designed to dissociate response impairments from dysfunction of motivation and attention, respectively. Following ACAo, reaction-time increased post-surgery in the choice, but not simple reaction-time task. There was also an increase in incorrect choices in the choice reaction-time task. However, the impairments were independent of motivational or attentional function, which remained intact. Although the ACAo-induced ischemic damage did not disrupt motivation or attention, the results suggest that the lesion results in an executive impairment in selecting and initiating responses.

Effects of excitotoxic lesions of the rat ventral striatum on the perception of reward cost.

This study examined the possibility that lesions of the nucleus accumbens in rats impair the perception of the "cost of reward", as defined by the number of operant responses needed to obtain a food pellet. In a first experiment, visual cues indicated the cost of reward under a multiple-ratio schedule of reinforcement. In a second experiment, the number of lever presses required for each reward incremented with each trial in a progressive-ratio schedule of reinforcement. Lesions of the nucleus accumbens altered the behavioral response to the increasing cost of reward when there was an absence of external cues. There was no change in the ability of the lesioned rats to respond to visual cues that indicated reward availability. The results are considered in terms of the traditional idea of the nucleus accumbens as a limbic-motor interface: it is suggested that, if the nucleus accumbens serves such a function, it is limited to only some contexts.

Reaction time deficits and Parkinson's disease.

Controversy surrounds the existence and nature of reaction time deficits in Parkinson's disease. Three areas of research are reviewed: the use of precues to speed movement (motor preprogramming), the effects of medication on reaction time, and simple reaction times. No evidence is found for a motor preprogramming deficit, and the presence of a parkinsonian reaction time deficit after medication withdrawal is found to be dependent upon experimental design and the withdrawal method used. Parkinson's disease is found to cause a consistent deficit in simple reaction time. A quantitative analysis of past studies reveals that a parkinsonian reaction time deficit is more likely to be present in tasks that controls can perform with a fast reaction time. This relationship between deficit and control group reaction time applies to choice, but not simple, reaction time tasks. Many studies compare patient and control choice reaction times across experimental conditions that cause control reaction time to vary. The authors of these studies should consider whether their results can be explained in terms of the simple relationship between patient reaction time deficit and control reaction time before drawing more complex conclusions from their data.

Excitotoxic lesions of the subthalamic nucleus ameliorate asymmetry induced by striatal dopamine depletion in the rat.

We investigated the effect of unilateral dorsal striatal dopamine depletion (by intrastriatal infusion of 6-OHDA), ibotenic acid lesions of the subthalamic nucleus (STN) and combined dopamine depletion and STN lesions on sensorimotor asymmetry using a test of somatosensory asymmetry [T. Schallert et al., Pharmacol. Biochem. Behav. 16 (1982) 455-462]. The unilateral striatal dopamine depletion resulted in a somatosensory asymmetry. This asymmetry was ameliorated in the rats with combined dopamine depletion and STN lesion. indicating the potential beneficial nature of STN inactivation in rats with striatal dopamine depletion.

On the relationships between the striatum and the pedunculopontine tegmental nucleus.

In this essay we consider the role of the pedunculopontine tegmental nucleus as a striatal output station. We review the relevant anatomical, electrophysiological, behavioral, and pathological studies and conclude that the pedunculopontine tegmental nucleus occupies an important position in striatal outflow, receiving motor output from the dorsal striatum and information from the ventral striatum relating to limbic processes of motivation and reinforcement. The hypothesis we present is that the pedunculopontine tegmental nucleus is at the very least an integral component of the limbic-motor interface, although in discussing this concept we also assess the likelihood that the limbic-motor interface is in fact a distributed system-that is, that limbic-motor interfacing is not all done by a single structure in the central nervous system but that different aspects of it are served by different systems. We present the hypothesis that the pedunculopontine tegmental nucleus is one critical site through which limbic information concerned with motivation, reinforcement, and the construction of novel associations can gain access to a stream of motor outflow coming from the caudate-putamen and directed toward pontomedullary systems without reference back to the cerebral cortex. This hypothesis is important because it highlights striatal outflow, which is not processed through the cortical re-entry systems, and also emphasizes the importance of pontine systems in cognitive processing.

Assessment of sensorimotor neglect after occlusion of the middle cerebral artery in the rat.

Evaluating the efficacy of neuroprotective drugs in rat models of focal cerebral ischemia has involved histological and behavioral batteries to examine treatment outcome. However, the behavioral tests used to date provide little insight into the nature of the neurological impairments. To provide an analysis of a possible "neglect" syndrome after occlusion of the middle cerebral artery, M. I. Posner's (1980) visual attentional paradigm was adapted for use in the rat. A paw-reaching task and a test of somatosensory "neglect" also were used to assess forelimb sensorimotor function. The lesion group displayed unilateral deficits; however, there was no evidence of attentional dysfunction. Results are consistent with the conclusion that the behavioral deficits identified arise from a somatosensory deficit rather than hemineglect due to dysfunctional spatial attention.