Neocerebellar Crus I Abnormalities Associated with a Speech and Language Disorder Due to a Mutation in FOXP2.

Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the 'KE family', who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene's early and prominent expression in the cerebellum and the evidence for reciprocal cerebellum-basal ganglia connectivity, very little is known about cerebellar abnormalities in affected KE members. Using cerebellum-specific voxel-based morphometry (VBM) and volumetry, we provide converging evidence from subsets of affected KE members scanned at three time points for grey matter (GM) volume reduction bilaterally in neocerebellar lobule VIIa Crus I compared with unaffected members and unrelated controls. We also show that right Crus I volume correlates with left and total caudate nucleus volumes in affected KE members, and that right and total Crus I volumes predict the performance of affected members in non-word repetition and non-verbal orofacial praxis. Crus I also shows bilateral hypo-activation in functional MRI in the affected KE members relative to controls during non-word repetition. The association of Crus I with key aspects of the behavioural phenotype of this FOXP2 point mutation is consistent with recent evidence of cerebellar involvement in complex motor sequencing. For the first time, specific cerebello-basal ganglia loops are implicated in the execution of complex oromotor sequences needed for human speech.

Novelty preference in patients with developmental amnesia.

To re-examine whether or not selective hippocampal damage reduces novelty preference in visual paired comparison (VPC), we presented two different versions of the task to a group of patients with developmental amnesia (DA), each of whom sustained this form of pathology early in life. Compared with normal control participants, the DA group showed a delay-dependent reduction in novelty preference on one version of the task and an overall reduction on both versions combined. Because VPC is widely considered to be a measure of incidental recognition, the results appear to support the view that the hippocampus contributes to recognition memory. A difficulty for this conclusion, however, is that according to one current view the hippocampal contribution to recognition is limited to task conditions that encourage recollection of an item in some associated context, and according to another current view, to recognition of an item with the high confidence judgment that reflects a strong memory. By contrast, VPC, throughout which the participant remains entirely uninstructed other than to view the stimuli, would seem to lack such task conditions and so would likely lead to recognition based on familiarity rather than recollection or, alternatively, weak memories rather than strong. However, before concluding that the VPC impairment therefore contradicts both current views regarding the role of the hippocampus in recognition memory, two possibilities that would resolve this issue need to be investigated. One is that some variable in VPC, such as the extended period of stimulus encoding during familiarization, overrides its incidental nature, and, because this condition promotes either recollection- or strength-based recognition, renders the task hippocampal-dependent. The other possibility is that VPC, rather than providing a measure of incidental recognition, actually assesses an implicit, information-gathering process modulated by habituation, for which the hippocampus is also partly responsible, independent of its role in recognition.

Amygdalectomy impairs crossmodal association in monkeys.

Monkeys trained on both visual and tactual versions of an object memory task (delayed nonmatching-to-sample) received bilateral ablations of either the amygdaloid complex or the hippocampal formation of the brain. Although both groups performed well on the two intramodal versions (visual-to-visual and tactual-to-tactual), the amygdalectomized monkeys were severely impaired relative to the hippocampectomized monkeys on a crossmodal version (tactual-to-visual). The findings suggest that the amygdala is critical for certain forms of crossmodal association and that the loss of such associations underlies many of the bizarre behaviors that make up the Klüver-Bucy syndrome.

The neuroanatomy of amnesia: amygdala-hippocampus versus temporal stem.

Using a task known to be sensitive to human amnesia, we have evaluated two current hypotheses about which brain regions must be damaged to produce the disorder. Monkeys with bilateral transections of the white matter of the temporal stem were unimpaired, but monkeys with conjoint amygdala-hippocampal lesions exhibited a severe memory deficit. The results indicate that the hippocampus, amygdala, or both, but not the temporal stem, are involved in memory in the monkey and suggest that a rapprochement between the findings for the human and the nonhuman primate may be close at hand.

Physiological evidence for serial processing in somatosensory cortex.

Removal of the representation of a specific body part in the postcentral cortex of the macaque resulted in the somatic deactivation of the corresponding body part in the second somatosensory area. In contrast, removal of the entire second somatosensory area had no grossly detectable effect on the somatic responsivity of neurons in the postcentral cortex. This direct electrophysiological evidence for serial cortical processing in somesthesia is similar to that found earlier for vision and, taken together with recent anatomical evidence, suggests that there is a common cortical plan for the processing of sensory information in the various sensory modalities.

Opiate receptor gradients in monkey cerebral cortex: correspondence with sensory processing hierarchies.

In order to obtain information on the possible functions of endogenous opiates in the primate cerebral cortex, we assessed the distribution of mu-like opiate receptors (which selectively bind 3H-labeled naloxone) and delta-like opiate receptors (which selectively bind 3H-labeled D-Ala2, D-Leu5-enkephalin) throughout the cerebral cortex of the rhesus monkey. Stereospecific [3H]naloxone binding sites increased in a gradient along hierarchically organized cortical systems that sequentially process modality-specific sensory information of a progressively more complex nature. Specific [3H]enkephalin binding sites, in contrast, were relatively evenly distributed throughout the cerebral cortex. These results, in combination with electrophysiological studies of monkeys and humans, suggest that mu-like opiate receptors may play a role in the affective filtering of sensory stimuli at the cortical level, that is, in emotion-induced selective attention.

Mapping the primate visual system with [2-14C]deoxyglucose.

The [2-14C]deoxyglucose method was used to identify the cerebral areas related to vision in the rhesus monkey (Macaca mulatta). This was achieved by comparing glucose utilization in a visually stimulated with that in a visually deafferented hemisphere. The cortical areas related to vision included the entire expanse of striate, prestriate, and inferior temporal cortex as far forward as the temporal pole, the posterior part of the inferior parietal lobule, and the prearcuate and inferior prefrontal cortex. Subcortically, in addition to the dorsal lateral geniculate nucleus and superficial layers of the superior colliculus, and structures related to vision included large parts of the pulvinar, caudate, putamen, claustrum, and amygdala. These results, which are consonant with a model of visual function that postulates an occipito-temporo-prefrontal pathway for object vision and an occipito-parieto-prefrontal pathway for spatial vision, reveal the full extent of those pathways and identify their points of contact with limbic, striatal, and diencephalic structures.

Massive cortical reorganization after sensory deafferentation in adult macaques.

After limited sensory deafferentations in adult primates, somatosensory cortical maps reorganize over a distance of 1 to 2 millimeters mediolaterally, that is, in the dimension along which different body parts are represented. This amount of reorganization was considered to be an upper limit imposed by the size of the projection zones of individual thalamocortical axons, which typically also extend a mediolateral distance of 1 to 2 millimeters. However, after extensive long-term deafferentations in adult primates, changes in cortical maps were found to be an order of magnitude greater than those previously described. These results show the need for a reevaluation of both the upper limit of cortical reorganization in adult primates and the mechanisms responsible for it.

Differential effects of early hippocampal pathology on episodic and semantic memory.

Global anterograde amnesia is described in three patients with brain injuries that occurred in one case at birth, in another by age 4, and in the third at age 9. Magnetic resonance techniques revealed bilateral hippocampal pathology in all three cases. Remarkably, despite their pronounced amnesia for the episodes of everyday life, all three patients attended mainstream schools and attained levels of speech and language competence, literacy, and factual knowledge that are within the low average to average range. The findings provide support for the view that the episodic and semantic components of cognitive memory are partly dissociable, with only the episodic component being fully dependent on the hippocampus.

Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex.

'What' and 'where' visual streams define ventrolateral object and dorsolateral spatial processing domains in the prefrontal cortex of nonhuman primates. We looked for similar streams for auditory-prefrontal connections in rhesus macaques by combining microelectrode recording with anatomical tract-tracing. Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole (area 10), rostral principal sulcus (area 46) and ventral prefrontal regions (areas 12 and 45), whereas the caudal belt was mainly connected with the caudal principal sulcus (area 46) and frontal eye fields (area 8a). Thus separate auditory streams originate in caudal and rostral auditory cortex and target spatial and non-spatial domains of the frontal lobe, respectively.

Stimulus recognition.

This review covers recent research on the neural process through which a novel stimulus becomes familiar. Lesion and recording studies have provided data sufficient to outline a tentative stimulus-recognition circuit and to suggest how the circuit might operate to form the new and relatively lasting stimulus traces that must underlie delayed stimulus recognition. The research has reached a stage where further progress could well be hastened by interaction between experiment and the formal, neurobiologically constrained models that are beginning to appear.

Anatomical pathways for auditory memory II: information from rostral superior temporal gyrus to dorsolateral temporal pole and medial temporal cortex.

Auditory recognition memory in non-human primates differs from recognition memory in other sensory systems. Monkeys learn the rule for visual and tactile delayed matching-to-sample within a few sessions, and then show one-trial recognition memory lasting 10-20 min. In contrast, monkeys require hundreds of sessions to master the rule for auditory recognition, and then show retention lasting no longer than 30-40 s. Moreover, unlike the severe effects of rhinal lesions on visual memory, such lesions have no effect on the monkeys' auditory memory performance. The anatomical pathways for auditory memory may differ from those in vision. Long-term visual recognition memory requires anatomical connections from the visual association area TE with areas 35 and 36 of the perirhinal cortex (PRC). We examined whether there is a similar anatomical route for auditory processing, or that poor auditory recognition memory may reflect the lack of such a pathway. Our hypothesis is that an auditory pathway for recognition memory originates in the higher order processing areas of the rostral superior temporal gyrus (rSTG), and then connects via the dorsolateral temporal pole to access the rhinal cortex of the medial temporal lobe. To test this, we placed retrograde (3% FB and 2% DY) and anterograde (10% BDA 10,000 mW) tracer injections in rSTG and the dorsolateral area 38 DL of the temporal pole. Results showed that area 38DL receives dense projections from auditory association areas Ts1, TAa, TPO of the rSTG, from the rostral parabelt and, to a lesser extent, from areas Ts2-3 and PGa. In turn, area 38DL projects densely to area 35 of PRC, entorhinal cortex (EC), and to areas TH/TF of the posterior parahippocampal cortex. Significantly, this projection avoids most of area 36r/c of PRC. This anatomical arrangement may contribute to our understanding of the poor auditory memory of rhesus monkeys.

Light exposure reduces and pinealectomy virtually stops urinary excretion of 6-hydroxymelatonin by rhesus monkeys.

The major metabolite of the pineal hormone melatonin, conjugated 6-hydroxymelatonin, was hydrolyzed, separated from the urine of rhesus monkeys, and assayed mass spectrometrically. The daily excretion pattern reflected pineal melatonin synthetic activity, being 5- to 16-fold higher at night than during the day. Progressive lengthening of the daily photoperiod beyond 12 h decreased the daily excretion of 6-hydroxymelatonin proportional to the increase duration of light exposure. Constant light reduced daily excretion by 90%, and pinealectomy reduced daily excretion by 96%. These results demonstrate the absence of significant extrapineal contributions to the urinary melatonin metabolite and confirm the use of 6-hydroxymelatonin excretion rates as a valid index of pineal gland melatonin synthesis.

Age differences in recognition memory of the rhesus monkey (Macaca mulatta).

Aging is accompanied by a gradual decline in memory in both humans and nonhuman primates. To determine whether the impairment in nonhuman primates extends to recognition memory, which is a sensitive index of the integrity of the limbic system, we trained rhesus monkeys of four different age groups (3-6, 14-17, 20-24, and 25-29 years of age) on a delayed nonmatching-to-sample task with trial-unique objects. After the animals had learned the task, which required recognition of single objects presented ten seconds earlier, memory demands were increased by gradually lengthening delay intervals (to 120 seconds) and list lengths (to ten objects). With increasing age, only marginal impairments in learning the basic task were observed. However, clear age-related differences did emerge when either delays or list lengths were increased, with the oldest group of monkeys demonstrating the greatest impairments. The decline in visual recognition ability in aging monkeys parallels the decline in memory observed with advancing age in humans.

Aged monkeys exhibit behavioral deficits indicative of widespread cerebral dysfunction.

To determine whether the decline of behavioral abilities with aging in monkeys is selective or widespread, we examined 18 monkeys ranging from 3 to 34 years of age on a wide variety of tests with the ultimate goal of correlating behavioral deficits with age-related changes in the brain. In our initial study we found impaired visual recognition ability in the aged monkeys (43). In the present study, we assessed the same animals on tests of spatial memory, visual habit formation, visuospatial orientation, visually guided reaching, motor skill learning, and reaction time, these categories having been chosen to test the integrity of different cerebral systems. There were three major findings. First, age-related impairments were observed in nearly all test categories, though often not on easy versions of the tests, suggesting that the deficits observed were in the specific abilities measured and not an artifact of lowered motivation or other general disability. Second, the behavioral decline began in the late teens for certain spatial abilities but did not affect other abilities until the late 20's, suggesting that although the cerebral dysfunction eventually becomes widespread, the cerebral systems underlying spatial abilities are compromised by aging earlier than others. Finally, the finding of correlations between scores of aged animals primarily within test categories as opposed to across categories suggests that different animals have different patterns of cerebral involvement.

The striate projection zone in the superior temporal sulcus of Macaca mulatta: location and topographic organization.

In the rhesus monkey, the caudal portion of the superior temporal sulcus (STS) receives a direct projection from lateral striate cortex, the striate are representing central vision. The present study was undertaken to determine whether STS also receives a direct projection from areas of striate cortex representing peripheral vision, with the intent of defining the entire striate projection zone in STS as well as providing information regarding a possible topographic organization within this secondary visual area. A series of five rhesus monkeys was prepared with unilateral lesions of lateral, posterior, or medial striate cortex, such that, collectively, the lesions in the series included all of striate cortex with little or no invasion of prestriate cortex. The monkeys were sacrificed seven days after surgery and their brains were processed by the Fink-Heimer procedure. An analysis of the distribution of terminal degeneration within STS indicated: (1) All areas of striate cortex project to a restricted region along the caudal portion of STS. The ventral limit of this region can be demarcated by an imaginary line connecting the ventral tips of the lunate and intraparietal sulci; from this limit the region extends dorsocaudally for approximately 12 mm to the point at which STS frequently bifurcates, sending one spur forward into the inferior parietal lobule. (2) Within this portion of STS there is an orderly mapping of the visual field; progression from central vision to the far periphery is represented by a progression down the posterior bank of STS and continuing along the entire floor, or insula-like portion, of the sulcus. (3) Projections from striate cortex to STS terminate predominantly in layer IV and the deep part of layer III. (4) There is a distinctive pattern of myelination contained within the striate projection zone of STS. These anatomical findings concerning the striate projection zone of STS in the rhesus monkey are remarkably similar to those that have been described for the middle temporal visual area (MT) in New World monkeys, and thus support earlier proposals that the two areas are homologous.

Projections of the amygdala to the thalamus in the cynomolgus monkey.

The projections of the amygdala to the thalamus in cynomolgus monkeys (Macaca fascicularis) were studied with both anterograde and retrograde axonal tracing techniques. Horseradish peroxidase (HRP) was injected into medial and midline thalamic sites in five animals, and tritiated amino acids were injected into selected amygdaloid regions in a total of 13 hemispheres in ten animals. The findings from the two types of tracer experiments demonstrated the origins, course, and terminal pattern of amygdaloid projections to two thalamic nuclei--medialis dorsalis (MD) and reuniens. Almost all of the amygdaloid nuclei contribute projections to MD, though the greatest proportion arise from the basal group and terminate in discrete, interlocking patches within the medial, magnocellular portion of MD. In addition to this major projection, the central and medial amygdaloid nuclei send a lighter projection to the lateral portion of nucleus reuniens. The amygdalothalamic projections took a variety of routes out of the amygdala before the large majority joined the inferior thalamic peduncle and entered the rostral head of the thalamus where they turned caudally toward their targets. A small number of amygdalothalamic fibers may also run in the stria terminalis.

The locus and cytoarchitecture of the projection areas of the olfactory bulb in Macaca mulatta.

A study was made of the normal and experimental anatomy of the olfactory system of the young adult male rhesus monkey. The cytoarchitecture of the central olfactory areas was studied with cell and fiber stains, while the extent and pattern of the projections of the olfactory bulb were determined by the Fink-Heimer and autoradiographic methods. The brain of one animal that had sustained damage to the olfactory bulb two days prior to sacrifice, and of one that had a transection of the olfactory tract ten days prior to sacrifice, were processed with the Fink-Heimer technique. The first of these and four others received injections of 3H-proline or 3H-leucine into the olfactory bulb, and following a survival period of 18 hours, or 2, 4, 12, or 20 days, their brains were processed with the autoradiographic technique. The results were the same for both experimental methods and for all survival periods. The projections of the olfactory bulb in this microsmatic animal are entirely ipsilateral. All of the structures that receive direct olfactory afferents have a laminar organization except for the anterior olfactory nucleus, which is laminated only in its anterior, peduncular, portion. While the olfactory bulb projects to the entire extent and depth of the anterior olfactory nucleus, the olfactory afferents of all other structures are confined to layer IA of the plexiform layer. These structures are: all divisions of the olfactory tubercle; the frontal and temporal prepiriform cortices; the oral, medial, and dorsal divisions of the superficial amygdaloid nucleus; and polar and anterior entorhinal cortex. The rhesus monkey does not have a recognizable accessory olfactory bulb, and no projections were seen to one of its targets, the nucleus of the stria terminalis. Also, no projections were seen to the taenia tecta or the ventral division of the superficial amygdaloid nucleus. With these exceptions, the projections of the olfactory bulb in the rhesus monkey are similar to those in macrosmatic species.

The origin, course, and termination of the hippocampothalamic projections in the macaque.

The projections from the hippocampal formation to the thalamus were investigated with both anterograde and retrograde tracers. Horseradish peroxidase was injected into medial and midline thalamic sites in six cases, and tritiated amino acids were injected into the hippocampal formation in nine others, five of which had prior transections of the fornix. Only the subicular and entorhinal cortices were found to project to the thalamus. From the subicular cortex, dense bilateral projections were traced through the fornix to the anterior nuclei, while lighter fornical projections terminated in other rostral midline sites, including the nuclei reuniens, centralis latocellularis, and paraventricularis. These projections arose predominantly from the polymorphic cells which are located in the deepest cellular layers of the subiculum and prosubiculum. In addition, the subicular cortex was found to project to the nucleus lateralis dorsalis. The latter projection, which showed evidence of a crude topographic organization, ran either through the fornix or, unlike the other subicular efferents, through the sublenticular limb of the internal capsule to form part of the temporopulvinar bundle of Arnold. The nonfornical projection to the nucleus lateralis dorsalis passed through the medial pulvinar, where there was some additional termination. Few, if any, projections from the entorhinal cortex to the thalamus travelled in the fornix. Rather, the entorhinal efferents were carried in the inferior thalamic peduncle to the magnocellular portion of the nucleus medialis dorsalis, and in the internal capsule and bundle of Arnold to the medial pulvinar and the nucleus lateralis dorsalis.

Serial and parallel processing in rhesus monkey auditory cortex.

Auditory cortex on the exposed supratemporal plane in four anesthetized rhesus monkeys was mapped electrophysiologically with both pure-tone (PT) and broad-band complex sounds. The mapping confirmed the existence of at least three tonotopic areas. Primary auditory cortex, AI, was then aspirated, and the remainder of the cortex on the supratemporal plane was remapped. PT-responses in the caudomedial area, CM, were abolished in all animals but one, in which they were restricted to the high-frequency range. Some CM sites were still responsive to complex stimuli. In contrast to the effects on CM, no significant changes were detectable in the rostral area, R. After mapping cortex in four additional monkeys, injections were made with different tracers into matched best-frequency regions of AI, R, and CM. Injections in AI and R led to retrograde labeling of neurons in all three subdivisions of the medial geniculate (MG) nucleus (MGv, MGd, and MGm), as well as nuclei outside MG, whereas CM injections led to only sparse labeling of neurons in a restricted zone of the lateral MGd and, possibly, MGm, in addition to labeling in non-MG sites. The combined results suggest that MGv sends direct projections in parallel to areas AI and R, which drive PT-responses in both areas. PT-responses in area CM, however, appear to be driven by input relayed serially from AI. The direct input to CM from MGd and other thalamic nuclei may thus be capable of mediating responses only to broad-band sounds.