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.

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.

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.

Developmental amnesia and its relationship to degree of hippocampal atrophy.

Two groups of adolescents, one born preterm and one with a diagnosis of developmental amnesia, were compared with age-matched normal controls on measures of hippocampal volume and memory function. Relative to control values, the preterm group values showed a mean bilateral reduction in hippocampal volume of 8-9% (ranging to 23%), whereas the developmental amnesic group values showed a reduction of 40% (ranging from 27% to 56%). Despite equivalent IQ and immediate memory scores in the two study groups, there were marked differences between them on a wide variety of verbal and visual delayed memory tasks. Consistent with their diagnosis, the developmental amnesic group was impaired relative to both other groups on nearly all delayed memory measures. The preterm group, by contrast, was significantly impaired relative to the controls on only a few memory measures, i.e., route following and prospective memory. We suggest that early hippocampal pathology leads to the disabling memory impairments associated with developmental amnesia when the volume of this structure is reduced below normal by approximately 20-30% on each side. Whether this is a sufficient condition for the disorder or whether abnormality in other brain regions is also necessary remains to be determined.

Developmental amnesia: effect of age at injury.

Hypoxic-ischemic events sustained within the first year of life can result in developmental amnesia, a disorder characterized by markedly impaired episodic memory and relatively preserved semantic memory, in association with medial temporal pathology that appears to be restricted to the hippocampus. Here we compared children who had hypoxic-ischemic events before 1 year of age (early group, n = 6) with others who showed memory problems after suffering hypoxic-ischemic events between the ages of 6 and 14 years (late group, n = 5). Morphometric analyses of the whole brain revealed that, compared with age-matched controls, both groups had bilateral abnormalities in the hippocampus, putamen, and posterior thalamus, as well as in the right retrosplenial cortex. The two groups also showed similar reductions (approximately 40%) in hippocampal volumes. Neuropsychologically, the only significant differences between the two were on a few tests of immediate memory, where the early group surpassed the late group. The latter measures provided the only clear indication that very early injury can lead to greater functional sparing than injury acquired later in childhood, due perhaps to the greater plasticity of the infant brain. On measures of long-term memory, by contrast, the two groups had highly similar profiles, both showing roughly equivalent preservation of semantic memory combined with marked impairment in episodic memory. It thus appears that, if this selective memory disorder is a special syndrome related to the early occurrence of hypoxia-induced damage, then the effective age at injury for this syndrome extends from birth to puberty.

MRI analysis of an inherited speech and language disorder: structural brain abnormalities.

Analyses of brain structure in genetic speech and language disorders provide an opportunity to identify neurobiological phenotypes and further elucidate the neural bases of language and its development. Here we report such investigations in a large family, known as the KE family, half the members of which are affected by a severe disorder of speech and language, which is transmitted as an autosomal-dominant monogenic trait. The structural brain abnormalities associated with this disorder were investigated using two morphometric methods of MRI analysis. A voxel-based morphometric method was used to compare the amounts of grey matter in the brains of three groups of subjects: the affected members of the KE family, the unaffected members and a group of age-matched controls. This method revealed a number of mainly motor- and speech-related brain regions in which the affected family members had significantly different amounts of grey matter compared with the unaffected and control groups, who did not differ from each other. Several of these regions were abnormal bilaterally, including the caudate nucleus, which was of particular interest because this structure was also found to show functional abnormality in a related PET study. We performed a more detailed volumetric analysis of this structure. The results confirmed that the volume of this nucleus was reduced bilaterally in the affected family members compared with both the unaffected members and the group of age-matched controls. This reduction in volume was most evident in the superior portion of the nucleus. The volume of the caudate nucleus was significantly correlated with the performance of affected family members on a test of oral praxis, a test of non-word repetition and the coding subtest of the Wechsler Intelligence Scale. These results thus provide further evidence of a relationship between the abnormal development of this nucleus and the impairments in oromotor control and articulation reported in the KE family.

Dissociations in cognitive memory: the syndrome of developmental amnesia.

The dearth of studies on amnesia in children has led to the assumption that when damage to the medial temporal lobe system occurs early in life, the compensatory capacity of the immature brain rescues memory functions. An alternative view is that such damage so interferes with the development of learning and memory that it results not in selective cognitive impairments but in general mental retardation. Data will be presented to counter both of these arguments. Results obtained from a series of 11 amnesic patients with a history of hypoxic ischaemic damage sustained perinatally or during childhood indicate that regardless of age at onset of hippocampal pathology, there is a pronounced dissociation between episodic memory, which is severely impaired, and semantic memory, which is relatively preserved. A second dissociation is characterized by markedly impaired recall and relatively spared recognition leading to a distinction between recollection-based versus familiarity-based judgements. These findings are discussed in terms of the locus and extent of neuropathology associated with hypoxic ischaemic damage, the neural basis of 'remembering' versus 'knowing', and a hierarchical model of cognitive memory.

MRI-Based evaluation of locus and extent of neurotoxic lesions in monkeys.

To minimize the variability in the extent of lesions made by injections of the excitotoxin ibotenic acid in rhesus monkeys, we developed and validated an MRI-based method to determine the efficacy of the injections soon after surgery. T2-weighted MR images were obtained 6-11 days after surgery from 17 brain hemispheres of monkeys that had received bilateral lesions of either the hippocampal formation (HF), perirhinal cortex, or parahippocampal cortex. The extent of lesion estimated from the hypersignal that appeared in and outside of the targeted area on these MR images was compared with the extent of damage assessed histologically after survival periods ranging from 120-370 days. Highly significant correlations (r values between 0.85-0.99) were found between these two measures for several regions in the medial temporal lobe. Based on this finding, lack of hypersignal in the targeted area of some Ss was followed by successful reinjection of the neurotoxin to create more complete cell loss prior to the postoperative phase of the study. We also assessed the relationship between a postoperative reduction in HF volume, measured from T1-weighted MR images, and the extent of damage determined histologically in 14 hemispheres of monkeys with bilateral excitotoxic HF lesions. The HF volume decreases sharply after surgery until 40-50 days postoperatively, after which there is only a minor further decrease. Based on this finding, we obtained T1-weighted MR images at least 44 days but in most cases close to 1 year after surgery. A highly significant positive correlation (r = 0.95, P < 0.001) was found between neuronal damage and volume reduction, with nearly complete neuronal damage (96-99%) corresponding to a volume reduction of 68-79%. These MRI-based methods thus provide an accurate in vivo evaluation of the locus and extent of neurotoxic lesions. Application of these methods can ensure that each animal in the experiment is used effectively.

Neither perirhinal/entorhinal nor hippocampal lesions impair short-term auditory recognition memory in dogs.

Visual, tactile, and olfactory recognition memory in animals is mediated in part by the perirhinal/entorhinal (or rhinal) cortices and, possibly, the hippocampus. To examine the role of these structures in auditory memory, we performed rhinal, hippocampal, and combined lesions in groups of dogs trained in auditory delayed matching-to-sample with trial-unique sounds. The sample sound was presented through a central speaker and, after a delay, the sample sound and a different sound were played alternately through speakers placed on either side of the animal; the animal was rewarded for responding to the side emitting the sample sound. None of the lesion groups showed significant impairment in comparison either to their own preoperative performance or to the performance of intact control dogs. This was the case both for relearning the delayed matching rule at a delay of 1.5 s and for task performance at variable delays ranging from 10 to 90 s. From these findings we suggest that the tissue critical for auditory recognition memory is located outside both the perirhinal/entorhinal cortices and the hippocampus.

Brain activity evidence for recognition without recollection after early hippocampal damage.

Amnesic patients with early and seemingly isolated hippocampal injury show relatively normal recognition memory scores. The cognitive profile of these patients raises the possibility that this recognition performance is maintained mainly by stimulus familiarity in the absence of recollection of contextual information. Here we report electrophysiological data on the status of recognition memory in one of the patients, Jon. Jon's recognition of studied words lacks the event-related potential (ERP) index of recollection, viz., an increase in the late positive component (500--700 ms), under conditions that elicit it reliably in normal subjects. On the other hand, a decrease of the ERP amplitude between 300 and 500 ms, also reliably found in normal subjects, is well preserved. This so-called N400 effect has been linked to stimulus familiarity in previous ERP studies of recognition memory. In Jon, this link is supported by the finding that his recognized and unrecognized studied words evoked topographically distinct ERP effects in the N400 time window. These data suggest that recollection is more dependent on the hippocampal formation than is familiarity, consistent with the view that the hippocampal formation plays a special role in episodic memory, for which recollection is so critical.

Effects of selective neonatal temporal lobe lesions on socioemotional behavior in infant rhesus monkeys (Macaca mulatta).

Normal infant monkeys and infant monkeys with neonatal damage to either the medial temporal lobe or the inferior temporal visual area were assessed in dyadic social interactions at 2 and 6 months of age. Unlike the normal infant monkeys, which developed strong affiliative bonds and little or no behavioral disturbances, the lesioned monkeys (each of which was observed with an unoperated control) exhibited socioemotional abnormalities and aberrant behaviors. The socioemotional changes predominated at 6 months of age and were particularly severe in monkeys with medial temporal lesions. In both the pattern and time course, the socioemotional deficits produced by the neonatal medial temporal lesions bear a striking resemblance to the behavioral syndrome in children with autism. Further analysis of these lesion-induced abnormalities in nonhuman primates may therefore provide insight into this debilitating human developmental disorder.

Neurotoxic lesions of perirhinal cortex impair visual recognition memory in rhesus monkeys.

Recent excitotoxic lesion studies in monkeys have shown that the recognition memory deficits originally attributed to amygdalo-hippocampal damage were due in whole or in part to the accompanying damage to surrounding tissue, including fibers of passage. Here we show that the same conclusion does not apply to the visual recognition impairment produced by aspiration lesions of perirhinal cortex inasmuch as equally severe impairment was found after excitotoxic lesions of this cortex. The finding demonstrates that damage limited to perirhinal neurons is sufficient to impair visual memory and that damage to fibers of passage neither caused nor exacerbated the effect described initially.

Learning increases stimulus salience in anterior inferior temporal cortex of the macaque.

With experience, an object can become behaviorally relevant and thereby quickly attract our interest when presented in a visual scene. A likely site of these learning effects is anterior inferior temporal (aIT) cortex, where neurons are thought to participate in the filtering of irrelevant information out of complex visual displays. We trained monkeys to saccade consistently to one of two pictures in an array, in return for a reward. The array was constructed by pairing two stimuli, one of which elicited a good response from the cell when presented alone ("good" stimulus) and the other of which elicited a poor response ("poor" stimulus). The activity of aIT cells was recorded while monkeys learned to saccade to either the good or poor stimulus in the array. We found that neuronal responses to the array were greater (before the saccade occurred) when training reinforced a saccade to the good stimulus than when training reinforced a saccade to the poor stimulus. This difference was not present on incorrect trials, i.e., when saccades to the incorrect stimulus were made. Thus the difference in activity was correlated with performance. The response difference grew over the course of the recording session, in parallel with the improvement in performance. The response difference was not preceded by a difference in the baseline activity of the cells, unlike what was found in studies of cued visual search and working memory in aIT cortex. Furthermore, we found similar effects in a version of the task in which any of 10 possible pairs of stimuli, prelearned before the recording session, could appear on a given trial, thereby precluding a working memory strategy. The results suggest that increasing the behavioral significance of a stimulus through training alters the neural representation of that stimulus in aIT cortex. As a result, neurons responding to features of the relevant stimulus may suppress neurons responding to features of irrelevant stimuli.

Preserved recognition in a case of developmental amnesia: implications for the acquisition of semantic memory?

We report the performance on recognition memory tests of Jon, who, despite amnesia from early childhood, has developed normal levels of performance on tests of intelligence, language, and general knowledge. Despite impaired recall, he performed within the normal range on each of six recognition tests, but he appears to lack the recollective phenomenological experience normally associated with episodic memory. His recall of previously unfamiliar newsreel events was impaired, but gained substantially from repetition over a 2-day period. Our results are consistent with the hypothesis that the recollective process of episodic memory is not necessary either for recognition or for the acquisition of semantic knowledge.

The effects of bilateral hippocampal damage on fMRI regional activations and interactions during memory retrieval.

Using functional magnetic resonance imaging (fMRI) we examined successful retrieval of real-world memories in a patient (Jon) with selective bilateral hippocampal pathology resulting from perinatal hypoxia compared with healthy control subjects. Jon activated the same brain regions during memory retrieval as control subjects, both medial and lateral on the left. In contrast to controls, Jon also activated many homologous regions on the right. In spite of having 50% volume loss bilaterally in his hippocampi, retrieval in Jon was associated with increased activation of the hippocampi. Furthermore, hippocampal activity, as with the controls, was differential, being most responsive to retrieval of autobiographical events compared with other memory types (autobiographical facts, public events, general knowledge). Jon made a distinction between events that the control subjects did not make, namely that some of the autobiographical and public events he clearly remembered, while others he found that he knew about but did not truly remember. His hippocampi and medial frontal cortex were significantly more active during retrieval of events for which he had clear and conscious recollection compared with those he knew as much about, including the context, but could not remember experiencing. Although Jon activates the same network of brain regions as the controls (albeit bilaterally), and with the same pattern of response in the hippocampus, the communication between regions differs from controls with regard to hippocampal-cortical connectivity. In controls there was increased effective connectivity between parahippocampal cortex and hippocampus, specifically during the retrieval of autobiographical events. In contrast, this increase was not apparent in Jon; rather, retrieval of autobiographical events elicited greater interaction between the hippocampus and retrosplenial cortex, and also increased interaction between retrosplenial and medial frontal cortex. This study underlines the value of scanning patients using fMRI while they undertake tasks they can perform, in this case allowing us to confirm the functionality of remaining tissue in the damaged hippocampi, and to appreciate the neural basis of a distinction (remember/know) that control subjects do not make. Besides refining our knowledge of the hippocampal role in autobiographical event memory, this study indicates that recruitment of bilateral regions during memory retrieval, and altered patterns of effective connectivity between brain regions may be important indicators of disordered memory.

Visual habit formation in monkeys with neurotoxic lesions of the ventrocaudal neostriatum.

Visual habit formation in monkeys, assessed by concurrent visual discrimination learning with 24-h intertrial intervals (ITI), was found earlier to be impaired by removal of the inferior temporal visual area (TE) but not by removal of either the medial temporal lobe or inferior prefrontal convexity, two of TE's major projection targets. To assess the role in this form of learning of another pair of structures to which TE projects, namely the rostral portion of the tail of the caudate nucleus and the overlying ventrocaudal putamen, we injected a neurotoxin into this neostriatal region of several monkeys and tested them on the 24-h ITI task as well as on a test of visual recognition memory. Compared with unoperated monkeys, the experimental animals were unaffected on the recognition test but showed an impairment on the 24-h ITI task that was highly correlated with the extent of their neostriatal damage. The findings suggest that TE and its projection areas in the ventrocaudal neostriatum form part of a circuit that selectively mediates visual habit formation.

Developmental amnesia associated with early hypoxic-ischaemic injury.

We recently reported on three young patients with severe impairments of episodic memory resulting from brain injury sustained early in life. These findings have led us to hypothesize that such impairments might be a previously unrecognized consequence of perinatal hypoxic-ischaemic injury. Neuropsychological and quantitative magnetic resonance investigations were carried out on five young patients, all of whom had suffered hypoxic-ischaemic episodes at or shortly after birth. All five patients showed severe impairments of episodic memory (memory for events), with relative preservation of semantic memory (memory for facts). However, none had any of the major neurological deficits that are typically associated with hypoxic-ischaemic injury, and all attended mainstream schools. Quantitative magnetic resonance investigations revealed severe bilateral hippocampal atrophy in all cases. As a group, the patients also showed bilateral reductions in grey matter in the regions of the putamen and the ventral part of the thalamus. On the basis of their clinical histories and the pattern of magnetic resonance findings, we attribute the patients' pathology and associated memory impairments primarily to hypoxic-ischaemic episodes sustained very early in life. We suggest that the degree of hypoxia-ischaemia was sufficient to produce selective damage to particularly vulnerable regions of the brain, notably the hippocampi, but was not sufficient to result in the more severe neurological and cognitive deficits that can follow hypoxic-ischaemic injury. The impairments in episodic memory may be difficult to recognize, particularly in early childhood, but this developmental amnesia can have debilitating consequences, both at home and at school, and may preclude independent life in adulthood.

Effects of neonatal inferior prefrontal and medial temporal lesions on learning the rule for delayed nonmatching-to-sample.

The ability of rhesus monkeys to master the rule for delayed nonmatching-to-sample (DNMS) has a protracted ontogenetic development, reaching adult levels of proficiency around 4 to 5 years of age (Bachevalier, 1990). To test the possibility that this slow development could be due, at least in part, to immaturity of the prefrontal component of a temporo-prefrontal circuit important for DNMS rule learning (Kowalska, Bachevalier, & Mishkin, 1991; Weinstein, Saunders, & Mishkin, 1988), monkeys with neonatal lesions of the inferior prefrontal convexity were compared on DNMS with both normal controls and animals given neonatal lesions of the medial temporal lobe. Consistent with our previous results (Bachevalier & Mishkin, 1994; Málková, Mishkin, & Bachevalier, 1995), the neonatal medial temporal lesions led to marked impairment in rule learning (as well as in recognition memory with long delays and list lengths) at both 3 months and 2 years of age. By contrast, the neonatal inferior convexity lesions yielded no impairment in rule-learning at 3 months and only a mild impairment at 2 years, a finding that also contrasts sharply with the marked effects of the same lesion made in adulthood. This pattern of sparing closely resembles the one found earlier after neonatal lesions to the cortical visual area TE (Bachevalier & Mishkin, 1994; Málková et al., 1995). The functional sparing at 3 months probably reflects the fact that the temporo-prefrontal circuit is nonfunctional at this early age, resulting in a total dependency on medial temporal contributions to rule learning. With further development, however, this circuit begins to provide a supplementary route for learning.