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Pitch and timing abilities in inherited speech and language impairment.
Members of the KE family who suffer from an inherited developmental speech-and-language disorder and normal, age-matched, controls were tested on musical abilities, including perception and production of pitch and rhythm. Affected family members were not deficient in either the perception or production of pitch, whether this involved either single notes or familiar melodies. However, they were deficient in both the perception and production of rhythm in both vocal and manual modalities. It is concluded that intonation abilities are not impaired in the affected family members, whereas their timing abilities are impaired. Neither their linguistic nor oral praxic deficits can be at the root of their impairment in timing; rather, the reverse may be true.
Neural basis of an inherited speech and language disorder.
Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of these same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study [Fisher, S., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168-170] localized the abnormal gene (SPCH1) to a 5. 6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.
Cortical mechanisms and cues for action.
Monkeys have more highly developed brains and are more intelligent than rats; yet rats learn some tasks as efficiently as monkeys. For example, rats are as quick at discovering which of two doors hides food or how to open the doors. Presumably tasks of this sort do not greatly tax cortical associative mechanisms since the animals have only to cumulate facts about objects. It is argued that cortical mechanisms are crucial for the ability to relate together information that is presented at different times or in different places. After removal of parts of frontal cortex monkeys can still associate cues that are presented together but they are poor at relating cues that are presented apart.
Neuronal activity of the supplementary motor area (SMA) during internally and externally triggered wrist movements.
The activity of neurones was recorded from the supplementary motor area (SMA) of monkeys while they were performing a discrete, arbitrary wrist movement. The cells responded similarly whether there was a triggering stimulus at the time of the movement or not. This experiment indicates that SMA neurones are active both in relation to externally triggered and internally initiated (voluntary) actions.
Seeing or doing? Influence of visual and motor familiarity in action observation.
The human brain contains specialized circuits for observing and understanding actions. Previous studies have not distinguished whether this "mirror system" uses specialized motor representations or general processes of visual inference and knowledge to understand observed actions. We report the first neuroimaging study to distinguish between these alternatives. Purely motoric influences on perception have been shown behaviorally, but their neural bases are unknown. We used fMRI to reveal the neural bases of motor influences on action observation. We controlled for visual and knowledge effects by studying expert dancers. Some ballet moves are performed by only one gender. However, male and female dancers train together and have equal visual familiarity with all moves. Male and female dancers viewed videos of gender-specific male and female ballet moves. We found greater premotor, parietal, and cerebellar activity when dancers viewed moves from their own motor repertoire, compared to opposite-gender moves that they frequently saw but did not perform. Our results show that mirror circuits have a purely motor response over and above visual representations of action. We understand actions not only by visual recognition, but also motorically. In addition, we confirm that the cerebellum is part of the action observation network.
Kallmann's syndrome: mirror movements associated with bilateral corticospinal tract hypertrophy.
OBJECTIVE: To investigate the etiology of mirror movements in patients with X-linked Kallmann's syndrome (xKS) through statistical analysis of pooled white matter data from structural MR images. BACKGROUND: Mirror movements occur in 85% of xKS patients. Previous electrophysiologic studies have suggested an abnormal ipsilateral corticospinal tract projection in xKS patients exhibiting mirror movements. However, an alternative hypothesis has proposed a functional lack of transcallosal inhibitory fibers. METHODS: T1-weighted brain scans were normalized into stereotaxic space with segregation of gray and white matter to allow comparison of pooled white matter data on a voxel-by-voxel basis using SPM-96 software. Nine xKS patients were compared with two age-matched groups of nonmirroring individuals: nine patients with autosomal Kallmann's syndrome (aKS) and nine age-matched normal (healthy) men. RESULTS: Hypertrophy of the corpus callosum was found in both Kallmann's syndrome groups: the anterior and midsection in xKS, and the genu and posterior section in aKS. Bilateral hypertrophy of the corticospinal tract was found only in the group of xKS patients exhibiting mirror movements. SPM analysis was validated by an independent region of interest analysis of corpus callosum size. CONCLUSION: Although morphometry on its own cannot determine the cause of mirror movements, the specific finding of a hypertrophied corticospinal tract in xKS is consistent with electrophysiologic evidence suggesting that mirror movements in xKS result from abnormal development of the ipsilateral corticospinal tract fibers.
Touching a rubber hand: feeling of body ownership is associated with activity in multisensory brain areas.
In the "rubber-hand illusion," the sight of brushing of a rubber hand at the same time as brushing of the person's own hidden hand is sufficient to produce a feeling of ownership of the fake hand. We shown previously that this illusion is associated with activity in the multisensory areas, most notably the ventral premotor cortex (Ehrsson et al., 2004). However, it remains to be demonstrated that this illusion does not simply reflect the dominant role of vision and that the premotor activity does not reflect a visual representation of an object near the hand. To address these issues, we introduce a somatic rubber-hand illusion. The experimenter moved the blindfolded participant's left index finger so that it touched the fake hand, and simultaneously, he touched the participant's real right hand, synchronizing the touches as perfectly as possible. After approximately 9.7 s, this stimulation elicited an illusion that one was touching one's own hand. We scanned brain activity during this illusion and two control conditions, using functional magnetic resonance imaging. Activity in the ventral premotor cortices, intraparietal cortices, and the cerebellum was associated with the illusion of touching one's own hand. Furthermore, the rated strength of the illusion correlated with the degree of premotor and cerebellar activity. This finding suggests that the activity in these areas reflects the detection of congruent multisensory signals from one's own body, rather than of visual representations. We propose that this could be the mechanism for the feeling of body ownership.
Relative blindsight in normal observers and the neural correlate of visual consciousness.
By using a paradigm based on metacontrast masking, we created experimental conditions in which the subjective report of consciousness differs but the objectively measured ability to discriminate visual targets does not. This approach allowed us to study the neural correlate of consciousness while having performance levels carefully matched in healthy human subjects. A comparison of the neural activity associated with these conditions as measured by functional MRI showed that conscious perception is associated with spatially specific activity in the mid-dorsolateral prefrontal cortex (area 46). Further analysis confirms that this activation is not only free from any performance confound, but is also not driven by differences in the timing of the physical stimuli. Our results suggest that the prefrontal cortex is important for the essentially subjective aspects of conscious perception.
Threatening a rubber hand that you feel is yours elicits a cortical anxiety response.
The feeling of body ownership is a fundamental aspect of self-consciousness. The underlying neural mechanisms can be studied by using the illusion where a person is made to feel that a rubber hand is his or her own hand by brushing the person's hidden real hand and synchronously brushing the artificial hand that is in full view. Here we show that threat to the rubber hand can induce a similar level of activity in the brain areas associated with anxiety and interoceptive awareness (insula and anterior cingulate cortex) as when the person's real hand is threatened. We further show that the stronger the feeling of ownership of the artificial hand, the stronger the threat-evoked neuronal responses in the areas reflecting anxiety. Furthermore, across subjects, activity in multisensory areas reflecting ownership predicted the activity in the interoceptive system when the hand was under threat. Finally, we show that there is activity in medial wall motor areas, reflecting an urge to withdraw the artificial hand when it is under threat. These findings suggest that artificial limbs can evoke the same feelings as real limbs and provide objective neurophysiological evidence that the rubber hand is fully incorporated into the body. These findings are of fundamental importance because they suggest that the feeling of body ownership is associated with changes in the interoceptive systems.
The prefrontal cortex: response selection or maintenance within working memory?
It is controversial whether the dorsolateral prefrontal cortex is involved in the maintenance of items in working memory or in the selection of responses. We used event-related functional magnetic resonance imaging to study the performance of a spatial working memory task by humans. We distinguished the maintenance of spatial items from the selection of an item from memory to guide a response. Selection, but not maintenance, was associated with activation of prefrontal area 46 of the dorsal lateral prefrontal cortex. In contrast, maintenance was associated with activation of prefrontal area 8 and the intraparietal cortex. The results support a role for the dorsal prefrontal cortex in the selection of representations. This accounts for the fact that this area is activated both when subjects select between items on working memory tasks and when they freely select between movements on tasks of willed action.
Changes in the human brain during rhythm learning.
Subjects were scanned with PET while they learned a complex arbitrary rhythm, paced by visual cues. In the comparison condition, the intervals were varied randomly. The behavioral results showed that the subjects decreased their response time with training, thus becoming more accurate in responding to the pacing cues at the appropriate time. There were learning-related increases in the posterior lateral cerebellum (lobule HVIIa), intraparietal and medial parietal cortex, presupplementary motor area (pre-SMA), and lateral premotor cortex. Learning-related decreases were found in the prestriate and inferior temporal cortex, suggesting that with practice the subjects increasingly came to depend on internal rather than external cues to time their responses. There were no learning-related increases in the basal ganglia. It is suggested that it is the neocortical-cerebellar loop that is involved in the timing and coordination of responses.
Parahippocampal reactivation signal at retrieval after interruption of rehearsal.
Verbal information is maintained on-line within working memory by rehearsal. However, we still can recall the verbal information when rehearsal is interrupted. Here we show that this is achieved by reactivation of maintained information. We used event-related functional magnetic resonance imaging to identify brain activation at encoding, during memory delay, and at retrieval, within the same trial of a verbal working memory task. On half of the trials, retrieval was tested after arithmetic distraction to interrupt rehearsal of the remembered verbal items. We found that the parahippocampal cortex (PHC) was highly active at retrieval on trials with distraction compared with trials without distraction. The PHC did not show sustained activation during the memory delay. By contrast, the dorsolateral prefrontal cortex (DLPF), left superior temporal region (ST), and Broca's area showed sustained activation during the memory delay, suggesting their role in maintenance of verbal items. After arithmetic distraction, the DLPF and ST were engaged in arithmetic processing. Thus, these areas could not maintain the verbal items during the distraction. At retrieval of verbal items after the distraction, the DLPF, ST and Broca's area were also active. The activity was taken to reflect reactivated representation of the verbal items. The primary role of the PHC in retrieval may be to trigger the reactivation of these cortical areas that had maintained the remembered items, thereby reactivating the information that is no longer maintained on-line.
Multiple movement representations in the human brain: an event-related fMRI study.
Neurovascular correlates of response preparation have been investigated in human neuroimaging studies. However, conventional neuroimaging cannot distinguish, within the same trial, between areas involved in response selection and/or response execution and areas specifically involved in response preparation. The specific contribution of parietal and frontal areas to motor preparation has been explored in electrophysiological studies in monkey. However, the associative nature of sensorimotor tasks calls for the additional contributions of other cortical regions. In this article, we have investigated the functional anatomy of movement representations in the context of an associative visuomotor task with instructed delays. Neural correlates of movement representations have been assessed by isolating preparatory activity that is independent from the performance of an actual motor act, or from the presence of a response's target. Movement instruction (specified by visual cues) and motor performance (specified by an auditory cue) were separated by a variable delay period. We have used whole-brain event-related fMRI to measure human brain activity during the performance of such a task. We have focused our analysis on specific preparatory activity, defined as a sustained response over variable delay periods between a transient visual instruction cue and a brief motor response, temporally independent from the transient events. Behavioral and electrophysiological controls ensured that preparatory activity was not contaminated by overt motor responses or working memory processes. We report suggestive evidence for multiple movement representations in the human brain. Specific sustained activity in preparation for an action was found not only in parieto-frontal regions but also in extrastriate areas and in the posterior portion of the superior temporal sulcus. We suggest that goal-directed preparatory activity relies on both visuomotor and visuoperceptual areas. These findings point to a functional-anatomical basis for the integration of perceptual and executive processes.
Converging projections from the mediodorsal thalamic nucleus and mesencephalic dopaminergic neurons to the neocortex in three species.
Previous studies in the rat have shown that the neocortical dopaminergic afferents, originating in the mesencephalon, terminate in those areas of the frontal lobe which receive projections from the mediodorsal thalamic nucleus i.e., the prefrontal cortex. In order to clarify whether this overlap is accidental for the rat or a consistent feature of several species we have compared the projection areas of the ventral tegmental area and the mediodorsal thalamic nucleus in three species, rat, opossum and tree shrew, using HRP injections in combination with glyoxylic acid histofluorescence method. The results have shown, first, that the area innervated by the mediodorsal nucleus of the thalamus is localized in a different part of the frontal lobe in each species: dorsolateral in the opossum, anteromedial, polar and suprarhinal in the rat and frontopolar in the tree shrew. Secondly, this area alone in each species receives projections from the ventral tegmental area. Thirdly, this area alone receives a dense innervation in the deep cortical layers by fluorescent fibres probably containing dopamine. The neighbouring neocortical areas receive afferents neither from the mediodorsal nucleus of the thalamus nor from the ventral mesencephalic tegmentum; their catecholamine innervation is mainly confined to the superficial layers and appears to be of noradrenergic nature. Although the techniques used did not allow a precise determination of the borders of the two projection areas and, therefore, the exact degree of overlap, it appears that mesencephalic dopaminergic innervation is a characteristic feature of the prefrontal cortex in the mammalian brain.
Amygdala activation when one is the target of deceit: did he lie to you or to someone else?
The ability to figure out whether a person is being honest or deceitful is an important part of social competence. Reactions to deceit may however differ depending on whether one is being deceived oneself or observes a deceitful exchange between others. In the present study, we investigated whether personal involvement influenced the neural responses associated with the detection of deceit. Subjects watched videos of actors lifting a box and judged whether the actors had been misled about the real weight of the box. Personal involvement was manipulated by having the participants themselves among the actors. The critical finding was that there was activity in amygdala and fusiform gyrus only for the condition in which participants observed themselves being deceived. In contrast, the superior temporal sulcus and anterior cingulate cortex were activated irrespective of whether the participants detected that the experimenter had deceived themselves or another. These four brain areas are all interconnected and are part of the discrete neural system subserving social cognition. Our results provide direct evidence, using judgments of deceit in a social context, that the crucial factor for amygdala activation is the involvement of the subjects because they are the target of the deceit. We interpret the activation of the amygdala in this situation as reflecting the greater affective reaction when one is deceived oneself. Our results suggest that when one is personally involved, deceit is taken as a potential threat.
Is gray matter volume an intermediate phenotype for schizophrenia? A voxel-based morphometry study of patients with schizophrenia and their healthy siblings.
BACKGROUND: Shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover previously unidentified gray matter volume differences in patients with schizophrenia and their siblings with optimized voxel-based morphometry. METHODS: We studied 169 patients with schizophrenia, 213 of their unaffected siblings, and 212 healthy volunteers from the Clinical Brain Disorders Branch/National Institute of Mental Health Genetic Study of Schizophrenia with magnetic resonance imaging. RESULTS: Patients with schizophrenia had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with healthy volunteers. Their unaffected siblings tended to share gray matter decreases in the medial frontal, superior temporal, and insular cortices, but these decreases were not significant after correction for multiple comparisons, even when we looked at a subgroup of siblings with a past history of mood disorder. As an exploratory analysis, we estimated heritability with regions of interest from the VBM analysis as well as from the hippocampus. Hippocampal volume was significantly correlated within sibling-pairs. CONCLUSIONS: Our findings confirm and extend previous voxel-based morphometry analyses in ill subjects with schizophrenia. Furthermore, these data argue that although siblings might share some regional gray matter decreases with their affected siblings, the pattern of regional differences might be a weak intermediate phenotype for schizophrenia.
Deletion of the GluA1 AMPA receptor subunit impairs recency-dependent object recognition memory.
Deletion of the GluA1 AMPA receptor subunit impairs short-term spatial recognition memory. It has been suggested that short-term recognition depends upon memory caused by the recent presentation of a stimulus that is independent of contextual-retrieval processes. The aim of the present set of experiments was to test whether the role of GluA1 extends to nonspatial recognition memory. Wild-type and GluA1 knockout mice were tested on the standard object recognition task and a context-independent recognition task that required recency-dependent memory. In a first set of experiments it was found that GluA1 deletion failed to impair performance on either of the object recognition or recency-dependent tasks. However, GluA1 knockout mice displayed increased levels of exploration of the objects in both the sample and test phases compared to controls. In contrast, when the time that GluA1 knockout mice spent exploring the objects was yoked to control mice during the sample phase, it was found that GluA1 deletion now impaired performance on both the object recognition and the recency-dependent tasks. GluA1 deletion failed to impair performance on a context-dependent recognition task regardless of whether object exposure in knockout mice was yoked to controls or not. These results demonstrate that GluA1 is necessary for nonspatial as well as spatial recognition memory and plays an important role in recency-dependent memory processes.
Learning associations between places and visual cues without learning to navigate: neither fornix nor entorhinal cortex is required.
Rats with fornix transection, or with cytotoxic retrohippocampal lesions that removed entorhinal cortex plus ventral subiculum, performed a task that permits incidental learning about either allocentric (Allo) or egocentric (Ego) spatial cues without the need to navigate by them. Rats learned eight visual discriminations among computer-displayed scenes in a Y-maze, using the constant-negative paradigm. Every discrimination problem included two familiar scenes (constants) and many less familiar scenes (variables). On each trial, the rats chose between a constant and a variable scene, with the choice of the variable rewarded. In six problems, the two constant scenes had correlated spatial properties, either Allo (each constant appeared always in the same maze arm) or Ego (each constant always appeared in a fixed direction from the start arm) or both (Allo + Ego). In two No-Cue (NC) problems, the two constants appeared in randomly determined arms and directions. Intact rats learn problems with an added Allo or Ego cue faster than NC problems; this facilitation provides indirect evidence that they learn the associations between scenes and spatial cues, even though that is not required for problem solution. Fornix and retrohippocampal-lesioned groups learned NC problems at a similar rate to sham-operated controls and showed as much facilitation of learning by added spatial cues as did the controls; therefore, both lesion groups must have encoded the spatial cues and have incidentally learned their associations with particular constant scenes. Similar facilitation was seen in subgroups that had short or long prior experience with the apparatus and task. Therefore, neither major hippocampal input-output system is crucial for learning about allocentric or egocentric cues in this paradigm, which does not require rats to control their choices or navigation directly by spatial cues.
Modulation of hippocampal dopamine metabolism and hippocampal-dependent cognitive function by catechol-O-methyltransferase inhibition.
Catechol-O-methyltransferase (COMT) catabolises the catecholamine neurotransmitters and influences cognitive function. COMT modulates dopamine levels in the prefrontal cortex and its action in this region is generally invoked to explain its effects on cognition. However, its role in other brain regions important for cognitive function remains largely unexplored. Here, we investigated COMT's impact on dopamine metabolism in the hippocampus and hippocampal-dependent behaviour. We examined the acute effects of a centrally-acting COMT inhibitor, tolcapone (30 mg/kg i.p.), on dopamine metabolism in the rat dorsal hippocampus, assessed both in tissue homogenates and extracellularly, using in vivo microdialysis. Additionally, we investigated the effect of tolcapone on delayed-rewarded alternation and spatial novelty preference, behavioural tasks which are dependent on the dorsal hippocampus. Tolcapone significantly modulated dopamine metabolism in the dorsal hippocampus, as indexed by the depletion of extracellular homovanillic acid (HVA) and the accumulation of dihydroxyphenylacetic acid (DOPAC). Tolcapone also improved performance on the delayed-rewarded alternation and spatial novelty preference tasks, compared to vehicle-treated rats. Our findings suggest that COMT regulates dorsal hippocampal neurochemistry and modulates hippocampus-dependent behaviours. These findings support the therapeutic candidacy of COMT inhibition as a cognitive enhancer, and suggest that, in addition to the prefrontal cortex, the hippocampus might be a key region for mediating these effects.