Defining a left-lateralized response specific to intelligible speech using fMRI.

Functional imaging studies of language have shown bilateral superior temporal activations in response to 'passive' perception of speech when the baseline condition did not control for the acoustic complexity of speech. Controlling for this complexity demonstrates speech-specific processing lateralized to the left temporal lobe, and our recent positron emission tomography study has emphasized a role for left anterolateral temporal cortex in speech comprehension. This contrasts with the more usual view that relates speech comprehension to left temporal-parietal cortex, the ill-defined area of Wernicke. This study attempted to reconcile these differences, using a more sensitive 3 T functional magnetic resonance imaging system, and a sparse sampling paradigm. We found left lateralized activations for intelligible speech with two distinct foci, one in the anterior superior temporal sulcus and the other on the posterior temporal lobe. Therefore, the results demonstrate that there are neural responses to intelligible speech along the length of the left lateral temporal neocortex, although the precise processing roles of the anterior and posterior regions cannot be determined from this study.

Selective cytotoxic lesions of the retrohippocampal region produce a mild deficit in social recognition memory.

Although a number of studies have implicated the hippocampal formation in social recognition memory in the rat, a recent study in this laboratory has demonstrated that selective cytotoxic lesions, confined to the hippocampus proper (encompassing the four CA subfields and the dentate gyrus), are without effect on this behaviour. This finding suggests that the hippocampus proper does not subserve social recognition memory in the rat, but does not preclude the possibility that other areas of the hippocampal formation, such as the entorhinal cortex or subiculum, could support this form of learning. The present study addressed this issue by examining the effects of selective cytotoxic retrohippocampal (RHR) lesions (including both the entorhinal cortex and subiculum) on social recognition memory in the rat. RHR lesions produced a mild social recognition memory impairment, although lesioned animals still displayed a reduction in investigation time between the first and second exposure to the juvenile. This result is consistent with other studies which have implicated the retrohippocampal or parahippocampal area in olfactory recognition memory processes. It also suggests, however, that other areas, out with the retrohippocampal region, are also likely to play an important role in social recognition memory.

The role of the entorhinal cortex in two forms of spatial learning and memory.

It is generally acknowledged that the rodent hippocampus plays an important role in spatial learning and memory. The importance of the entorhinal cortex (ERC), an area that is closely interconnected anatomically with the hippocampus, in these forms of learning is less clear cut. Recent studies using selective, fibre-sparing cytotoxic lesions have generated conflicting results, with some studies showing that spatial learning can proceed normally without the ERC, suggesting that this area is not required for normal hippocampal function. The present study compared cytotoxic and aspiration ERC lesions with both fimbria fornix (FFX) lesions and sham-operated controls on two spatial learning tasks which have repeatedly been shown to depend on the hippocampus. Both groups of ERC lesions were impaired during non-matching-to-place testing (rewarded alternation) on the elevated T-maze. However, neither of these lesions subsequently had any effect on the acquisition of a standard spatial reference memory task in the water maze. FFX lesions produced a robust and reliable impairment on both of these tasks. A second experiment confirmed that cytotoxic ERC lesions spared water maze learning but disrupted rewarded alternation on the T-maze, when the order of behavioural testing was reversed. These results confirm previous reports that ERC-lesioned animals are capable of spatial navigation in the water maze, suggesting that the ERC is not a prerequisite for normal hippocampal function in this task. The present demonstration that ERC lesions disrupt non-matching-to-place performance may, however, be consistent with the possibility that ERC lesions affect attentional mechanisms, for example, by increasing the sensitivity to recent reward history.

Contextual fear conditioning is disrupted by lesions of the subcortical, but not entorhinal, connections to the hippocampus.

Recent studies have questioned the importance of the entorhinal cortex (ERC) for normal hippocampal function. For example, fibre-sparing ERC lesions have been found to have no effect on spatial learning in the watermaze. There is also doubt as to the importance of the ERC for contextual fear conditioning, with previous studies having yielded conflicting results. In an attempt to resolve this issue, the present study compared aspiration and cytotoxic ERC lesioned rats, along with fimbria-fornix (FFX) lesioned animals and sham operated controls, on an unsignalled contextual fear conditioning paradigm. The results of the present study show that whereas lesions of the FFX disrupted contextual freezing, neither aspiration nor cytotoxic ERC lesions had any effect on this behaviour. Aspiration ERC lesioned rats, however, like FFX lesioned animals, did display hyperactivity prior to the delivery of footshock. These results suggest that whereas projections between the hippocampus and subcortical structures are important for normal levels of contextual freezing, projections from the entorhinal cortex are not essential.

A neuropsychological investigation of prefrontal cortex involvement in acute mania.

OBJECTIVE: Mania has received little attention from a contemporary neuropsychological perspective despite its clear resemblance to the disinhibition syndrome sometimes seen after frontal brain injury, particularly injury to the inferior aspect of the prefrontal cortex. The purpose of this investigation was to describe the neuropsychological profile of severe acute mania by using a range of tasks selected primarily for the detection of localized neural disruption within the prefrontal cortex. METHOD: Fifteen acutely manic inpatients were compared with 30 nonpsychiatric subjects on tasks from the Cambridge Automated Neuropsychological Test Battery (Tower of London, spatial working memory, intradimensional-extradimensional attentional shift, and rapid visual information processing tasks) and on the Iowa Gambling Task, Stroop Color and Word Test, a verbal fluency task, and the California Verbal Learning Test. RESULTS: Discriminant function analysis identified deficits in sustained attention (on the rapid visual information processing task) and verbal learning (on the California Verbal Learning Test) as the best indicators of manic performance, rather than deficits on any of the tests of executive functioning. The model correctly classified 91% of subjects overall and 87% of manic subjects. Manic patients did not resemble patients with ventromedial prefrontal cortex damage in their performance on the Iowa Gambling Task. CONCLUSIONS: Acute mania is characterized by core deficits in verbal memory and sustained attention against a background of milder impairments in functions that are traditional measures of prefrontal cortex integrity (attentional set shifting, planning, working memory). The data do not implicate ventral prefrontal cortex disruption as a locus of pathology in acute mania. Verbal memory and sustained attention deficits may relate differentially to the state and trait characteristics of bipolar disorder.

Detection of audio-visual integration sites in humans by application of electrophysiological criteria to the BOLD effect.

Electrophysiological studies in nonhuman primates and other mammals have shown that sensory cues from different modalities that appear at the same time and in the same location can increase the firing rate of multisensory cells in the superior colliculus to a level exceeding that predicted by summing the responses to the unimodal inputs. In contrast, spatially disparate multisensory cues can induce a profound response depression. We have previously demonstrated using functional magnetic resonance imaging (fMRI) that similar indices of crossmodal facilitation and inhibition are detectable in human cortex when subjects listen to speech while viewing visually congruent and incongruent lip and mouth movements. Here, we have used fMRI to investigate whether similar BOLD signal changes are observable during the crossmodal integration of nonspeech auditory and visual stimuli, matched or mismatched solely on the basis of their temporal synchrony, and if so, whether these crossmodal effects occur in similar brain areas as those identified during the integration of audio-visual speech. Subjects were exposed to synchronous and asynchronous auditory (white noise bursts) and visual (B/W alternating checkerboard) stimuli and to each modality in isolation. Synchronous and asynchronous bimodal inputs produced superadditive BOLD response enhancement and response depression across a large network of polysensory areas. The most highly significant of these crossmodal gains and decrements were observed in the superior colliculi. Other regions exhibiting these crossmodal interactions included cortex within the superior temporal sulcus, intraparietal sulcus, insula, and several foci in the frontal lobe, including within the superior and ventromedial frontal gyri. These data demonstrate the efficacy of using an analytic approach informed by electrophysiology to identify multisensory integration sites in humans and suggest that the particular network of brain areas implicated in these crossmodal integrative processes are dependent on the nature of the correspondence between the different sensory inputs (e.g. space, time, and/or form).

Cytotoxic lesions of the hippocampus increase social investigation but do not impair social-recognition memory.

A number of studies have implicated the hippocampal formation in social-recognition memory in the rat. The present study addressed this issue directly by assessing the effects of cytotoxic lesions confined to the hippocampus proper, encompassing the four CA subfields and the dentate gyrus, on this behavioural task. Ibotenate-induced hippocampal lesions led to locomotor hyperactivity and a marked spatial working-memory impairment on the elevated T-maze. In addition, they also led to increased social investigation. However, despite these clear effects, there was no effect of the lesions on social-recognition memory. These results suggest that the hippocampus proper does not subserve social-recognition memory; but does not, however, preclude the possibility that other areas of the hippocampal formation (e.g. entorhinal cortex or subiculum) may support this memory process.

The influence of positive and negative mood states on risk taking, verbal fluency, and salivary cortisol.

BACKGROUND: significant frontal cortex dysfunction. It is hypothesised that performance on frontal lobe tasks may be sensitive to induced fluctuations in mood state in non-clinical samples. METHODS: Subjects performed one of two neuropsychological tasks immediately subsequent to a musical mood induction procedure designed to induce either elation or depression. Mood was assessed using self-report measures. Salivary cortisol levels were also measured in an attempt to objectively validate mood induction effects. The tasks used were verbal fluency and Damasio's Gambling Game. Two groups of subjects were recruited: a group with previous (subclinical) hypomanic experience (n=23) and a control group without previous hypomanic experience (n=23). RESULTS: The positive and negative mood inductions produced robust and contrasting effects on self-reported mood, but had no significant differential effects on salivary cortisol levels and neuropsychological performance. LIMITATIONS: The findings are restricted by the absence of a neutral mood control condition. CONCLUSIONS: Salivary cortisol recording does not provide a simple and reliable method of validating psychological mood induction. Performance on frontal lobe tests appears to be insensitive to normal mood fluctuations, which supports the argument that the deficits in mood disorder patient groups may instead reflect core disturbances of neurobiological processes.

The time course of the hyperactivity that follows lesions or temporary inactivation of the fimbria-fornix.

Lesions of the hippocampus or the fimbria-fornix produce a pronounced hyperactivity in rats. This effect is thought to be due to the loss of glutamatergic hippocampal inputs to the nucleus accumbens, although the mechanisms involved remain unclear. It has been suggested that the hyperactivity is due to changes in accumbens dopamine receptors, possibly involving the gradual development of denervation supersensitivity. Consistent with this possibility, the present study found that fimbria-fornix transection produced hyperactivity which, although undetectable immediately after surgery, gradually became apparent and then continued to increase over the course of several days. This does not, however, preclude the possibility that there is an immediate increase in activity which is masked by the after effects of surgery. To address this issue, local anaesthetic was infused into the fimbria-fornix via chronic indwelling cannulae, in order to silence the hippocampal inputs to the nucleus accumbens. This procedure impaired spatial working memory on the elevated T-maze and resulted in immediate hyperactivity, suggesting that there may be at least two components to fornix lesion-induced hyperactivity, and that the immediate effects of mechanical fornix lesions on activity levels may be masked by the after effects of surgery per se.

Psychomotor-activating effects mediated by dopamine D(2) and D(3) receptors in the nucleus accumbens.

The contribution made by specific dopamine receptor subtypes to the induction of motor behaviors has not been firmly established. Here, we first characterized the behavioral effects induced by a D(2)-class receptor agonist, bromocriptine, following injections into the nucleus accumbens (Acb). Bromocriptine showed an atypical D(2)-class receptor agonist profile, having no observable effect on a range of motor behaviors. However, when coadministered with the D(1)-class receptor agonist SKF 38393, bromocriptine showed a typical D(2)-class receptor agonist profile, enhancing locomotor activity and suppressing spontaneous yawning. We then administered the dopamine receptor antagonists L-741626 and nafadotride, which possess relative selectivity for D(2) and D(3) receptors, respectively, prior to injections of dopamine agonists into the Acb. Nafadotride significantly reduced the locomotor-enhancing effects elicited by the coadministration of SKF 38393 and the D(2)-class receptor agonist (+)-PD 128907 into the Acb, and also attenuated the effects induced by the combination of SKF 38393 and bromocriptine, although not significantly so. L-741626 mildly attenuated the locomotor effects elicited by both drug combinations. Taken together, these results suggest that both D(2) and D(3) receptors in the Acb contribute to the expression of heightened psychomotor activation.

Dynamic dopamine receptor interactions in the core and shell of nucleus accumbens differentially coordinate the expression of unconditioned motor behaviors.

Many neurochemical and behavioral functions mediated by dopamine require the dynamic interaction between dopamine receptors. We examined the behavioral effects evoked by microinjections of drugs with relative selectivity for specific dopamine receptors into the nucleus accumbens (Acb). The results showed that, at behaviorally inactive doses, the dopamine D1-class receptor agonist SKF 38393 switched the behavioral profile induced by injections of the dopamine D2-class receptor agonist quinpirole into the Acb, from sedation, yawning, and motor inhibition to hyperactive-like behavior. Further, the effects of injections of the dopamine D2-class receptor agonist (+)-PD 128907 into the shell of Acb, including suppression of rearing, locomotion, and grooming, and induction of oral dyskinesia, yawning, and sedation, could not be distinguished from those elicited by (+)-PD 128907 following infusions into the core of Acb. However, the behavioral effects elicited by coadministration of SKF 38393 and (+)-PD 128907 into the core or the shell of Acb showed a striking anatomical specificity. The infusion of SKF 38393 plus (+)-PD 128907 into the core, but not into the shell, of Acb modified the pattern of responses induced by (+)-PD 128907, inducing behavioral hyperactivity. These results suggest critical differences in the functional interaction between dopamine receptors in the core and the shell of the Acb and reveal a mechanism of behavioral switching in the core of Acb by virtue of which dopamine D1-class receptors regulate the transition from states of behavioral suppression to states of heightened psychomotor arousal.

The role of nigral and thalamic output pathways in the expression of oral stereotypies induced by amphetamine injections into the striatum.

Microinjections of amphetamine into the ventrolateral striatum (VLS) elicit a striking behavioral syndrome characterized by compulsive oral and forelimb motor stereotypies. The neural pathways that mediate these behavioral responses downstream from the striatum have not yet been identified. In a series of experiments, we investigated the involvement of the substantia nigra pars reticulata (SNr) and the ventromedial nucleus of the thalamus (VMT) in the mediation of this behavioral syndrome. We demonstrated that lidocaine-induced reversible inactivation of the SNr reduced amphetamine-induced stereotyped biting and gnawing behaviors, suggesting that the nigral output pathway plays a significant role in the expression of these behavioral responses. In turn, injections of lidocaine into the VMT only transiently reduced amphetamine-stimulated biting and increased stereotyped gnawing and paw nibbling, suggesting that the expression of oral stereotypies induced by amphetamine injections into the VLS is not dependent on thalamocortical feedback.

Response amplification in sensory-specific cortices during crossmodal binding.

Integrating information across the senses can enhance our ability to detect and classify stimuli in the environment. For example, auditory speech perception is substantially improved when the speaker's face is visible. In an fMRI study designed to investigate the neural mechanisms underlying these crossmodal behavioural gains, bimodal (audio-visual) speech was contrasted against both unimodal (auditory and visual) components. Significant response enhancements in auditory (BA 41/42) and visual (V5) cortices were detected during bimodal stimulation. This effect was found to be specific to semantically congruent crossmodal inputs. These data suggest that the perceptual improvements effected by synthesizing matched multisensory inputs are realised by reciprocal amplification of the signal intensity in participating unimodal cortices.

Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions.

Rats with complete cytotoxic hippocampal lesions exhibited spatial memory impairments in both the water maze and elevated T maze. They were hyperactive in photocell cages; swam faster in the water maze; and were less efficient on a nonspatial, differential reinforcement of low rates (DRL) task. Performance on both spatial tasks was also impaired by selective dorsal but not ventral lesions; swim speed was increased by ventral but not dorsal lesions. Both partial lesions caused a comparable reduction in DRL efficiency, although these effects were smaller than those of complete lesions. Neither partial lesion induced hyperactivity when rats were tested in photocell cages, although both complete and ventral lesion groups showed increased activity after footshock in other studies (Richmond et al., 1999). These results demonstrate possible functional dissociations along the septotemporal axis of the hippocampus.

The pharmacology of memory.

Neurotransmitters play a critical role in the brain circuits involved in various aspects of memory. The importance of acetylcholine is illustrated by the psychopathology of Alzheimer's disease. Cholinergic replacement therapy is now available for treating the cognitive decline associated with this form of degenerative disease. Dopamine in the prefrontal cortex also contributes to information storage, particularly working memory. In both cases efforts have been made to identify the receptor subtype involved and such information is essential if pharmacologically specific drugs are to be developed for cognitive enhancement.

Behavioural topography in the striatum: differential effects of quinpirole and D-amphetamine microinjections.

Behavioural evidence has accumulated that supports the hypothesis that specific territories of the striatum contribute differentially to the control of motor behaviours. The present experiments compare the behavioural effects of microinjections of amphetamine (20 microg/0.5 microl) with those elicited by the D2-class dopamine receptor agonist quinpirole (3 microg/0.5 microl) following direct microinjection into three anatomically distinct sectors of the striatum: the nucleus accumbens, the ventrolateral striatum and the anterodorsal striatum. Our findings demonstrate that site-specific behavioural responses are induced by microinjections of amphetamine, but not of quinpirole, into the striatum. Our results suggest that widespread areas of the striatum are implicated in the induction of a syndrome of sedation, yawning and motor inhibition, observed readily following microinjections of quinpirole into the striatum. This evidence supports both homogeneity and segregation of function in the striatum at the behavioural level. Further, the results suggest that the elicitation of site-specific action sequences at the level of the striatum seems to require cooperative interactions between D1-class and D2-class dopamine receptors.

Crossmodal identification.

Everyday experience involves the continuous integration of information from multiple sensory inputs. Such crossmodal interactions are advantageous since the combined action of different sensory cues can provide information unavailable from their individual operation, reducing perceptual ambiguity and enhancing responsiveness. The behavioural consequences of such multimodal processes and their putative neural mechanisms have been investigated extensively with respect to orienting behaviour and, to a lesser extent, the crossmodal coordination of spatial attention. These operations are concerned mainly with the determination of stimulus location. However, information from different sensory streams can also be combined to assist stimulus identification. Psychophysical and physiological data indicate that these two crossmodal processes are subject to different temporal and spatial constraints both at the behavioural and neuronal level and involve the participation of distinct neural substrates. Here we review the evidence for such a dissociation and discuss recent neurophysiological, neuroanatomical and neuroimaging findings that shed light on the mechanisms underlying crossmodal identification, with specific reference to audio-visual speech perception.

Hemifield-specific visual recognition memory impairments in patients with unilateral temporal lobe removals.

Recent evidence on visual neglect suggests that each hemisphere maintains a retinotopically organized representation of the visual world contralateral to the current fixation point and that this representation is based not only on analysis of the current retinal input but, equally importantly, on information retrieved from memory. This idea predicts that unilateral damage to memory systems should produce a lateralized impairment of memory for the retinotopically contralateral visual world. To test this prediction we examined visual recognition memory performance in the left and right visual hemifields of patients who had undergone partial unilateral temporal lobe removals for the relief of epilepsy, either in the left hemisphere (n = 5) or the right (n = 5). The patients were given complex artificial scenes to remember, constructed of independent left and right halves, and were then tested for recognition of the left and the right halves separately. Stimuli were exposed tachistoscopically throughout and fixation was maintained on a central position. Patients made significantly more errors with half-scenes in the hemifield contralateral to their removal than in the ipsilateral hemifield, an increase of 50% in the error rate on average. The effect was seen equally in patients with left and right removals. This finding supports the idea that visual memory retrieval is retinotopically organized.