Dissection of the Temporofrontal Extreme Capsule Fasciculus Using Diffusion MRI Tractography and Association with Lexical Retrieval.

The well-known arcuate fasciculus that connects the posterior superior temporal region with the language production region in the ventrolateral frontal cortex constitutes the classic peri-Sylvian dorsal stream of language. A second temporofrontal white matter tract connects ventrally the anterior to intermediate lateral temporal cortex with frontal areas via the extreme capsule. This temporofrontal extreme capsule fasciculus (TFexcF) constitutes the ventral stream of language processing. The precise origin, course, and termination of this pathway has been examined in invasive tract tracing studies in macaque monkeys, but there have been no standard protocols for its reconstruction in the human brain using diffusion imaging tractography. Here we provide a protocol for the dissection of the TFexcF in vivo in the human brain using diffusion magnetic resonance imaging (MRI) tractography which provides a solid basis for exploring its functional role. A key finding of the current dissection protocol is the demonstration that the TFexcF is left hemisphere lateralized. Furthermore, using the present dissection protocol, we demonstrate that the TFexcF is related to lexical retrieval scores measured with the category fluency test, in contrast to the classical arcuate fasciculus (the dorsal language pathway) that was also dissected and was related to sentence repetition.

Response selection versus feedback analysis in conditional visuo-motor learning.

Conditional associative sensori-motor learning (i.e. the acquisition of specific arbitrary sensori-motor mappings) involves several processes that depend upon the integrity of the fronto-striatal system. The specific role of the different components of the fronto-striatal system in this type of learning is still unclear and was examined in the present functional Magnetic Resonance Imaging (fMRI) study in humans. The subjects had to learn by trial and error arbitrary associations between visual stimuli and motor responses in an experimental paradigm designed to dissociate between the neuronal substrates specifically involved in the selection of the appropriate response and in the analysis of the feedback obtained during the learning and post-learning periods. First, the results demonstrate that the dorsal premotor (PMd) cortex is the critical structure for the acquisition and execution of arbitrary mappings of visual stimuli to motor responses. Second, they reveal an important shift in activation from the cognitive fronto-striatal network (involving the caudate nucleus, the dorsolateral prefrontal cortex, and the PMd) to the motor fronto-striatal network (involving the putamen and the PMd) as we move from initial learning of sensori-motor relations to the post-learning selection of the responses. Finally, they show that feedback processing, but not response selection, increased activity in the anterior cingulate and orbitofrontal cortical regions, demonstrating the selective involvement of these limbic frontal regions in the processing of the consequences of a given action. Altogether our data suggest that, in conditional visuo-motor learning, the associations are critically regulated by the dorsal premotor cortex and the striatum, with additional brain areas contributing to specific aspects of the learning and performance of such associations.

Cross-modal matching and the primate frontal cortex.

Rhesus monkeys with selective lesions of the prefrontal system were tested on a tactile-visual cross-modal matching task. Monkeys with lesions in the banks and depths of the arcuate sulcus were impaired, while normal controls and monkeys with lesions in the banks and depths of the sulcus principalis and in the anterodorsal part of the head of the caudate nucleus were not.

Mental rotation of the neuronal population vector.

A rhesus monkey was trained to move its arm in a direction that was perpendicular to and counterclockwise from the direction of a target light that changed in position from trial to trial. Solution of this problem was hypothesized to involve the creation and mental rotation of an imagined movement vector from the direction of the light to the direction of the movement. This hypothesis was tested directly by recording the activity of cells in the motor cortex during performance of the task and computing the neuronal population vector in successive time intervals during the reaction time. The population vector rotated gradually counterclockwise from the direction of the light to the direction of the movement at an average rate of 732 degrees per second. These results provide direct, neural evidence for the mental rotation hypothesis and indicate that the neuronal population vector is a useful tool for "reading out" and identifying cognitive operations of neuronal ensembles.

Three-dimensional probabilistic maps of the occipital sulci of the human brain in standardized stereotaxic space.

Developments in functional neuroimaging in normal human subjects, such as functional magnetic resonance imaging (fMRI), have permitted the mapping of several visual areas of the human brain and have already provided provisional identification of some of the visual areas that were first described in nonhuman primates. However, the lack of a detailed description of the sulcal patterns of the human occipital lobe makes it difficult to establish clear relationships between sulcal landmarks and identified visual areas with functional neuroimaging. In the present study we used magnetic resonance images to investigate the morphological variation of the human occipital sulci in both the left and right hemispheres of 40 normal adult human brains. We identified 11 occipital sulci, the parieto-occipital fissure and the temporo-occipital incisure, and their corresponding gray matter voxels were marked in the magnetic resonance volumes which had been transformed into the Montreal Neurological Institute standard proportional stereotaxic space. Probability maps were then constructed for each occipital sulcus. These probability maps provide a quantitative measure of the variability of the occipital sulci in standard stereotaxic space and are a useful tool to identify the location of voxels of other magnetic resonance imaging images transformed in the same stereotaxic space.

Local morphology informs location of activation during navigation within the parahippocampal region of the human brain.

The relationship between the local morphological features that define the entorhinal and parahippocampal cortex in the medial temporal region of the human brain and activation as measured during a navigation task with functional magnetic resonance imaging was examined individually in healthy participants. Two functional activation clusters were identified one within the caudal end of the collateral sulcus proper and the other in the parahippocampal extension of the collateral sulcus, clearly establishing the activation in the posterior parahippocampal cortex. A third activation cluster was identified where the anterior segment of the collateral sulcus proper gives way to the posterior segment, demonstrating also activation within the middle parahippocampal cortex. No activation was observed in the entorhinal cortex that lies medial to the rhinal sulcus or in the anterior part of the parahippocampal cortex along the anterior branch of the collateral sulcus proper. The activations could also be clearly differentiated from the cortex of the fusiform and lingual gyri that lie laterally and posteriorly. These findings demonstrated specific activation in the middle and posterior part of the parahippocampal cortex when information necessary for navigation was retrieved from a previously established cognitive map and demonstrate that the sulci that comprise the collateral sulcal complex represent important landmarks that can provide an accurate localization of activation foci along the parahippocampal cortex and allow identification of subdivisions involved in the processing of spatial information.

Efferent association pathways originating in the caudal prefrontal cortex in the macaque monkey.

The efferent association fibers from the caudal part of the prefrontal cortex to posterior cortical areas course via several pathways: the three components of the superior longitudinal fasciculus (SLF I, SLF II, and SLF III), the arcuate fasciculus (AF), the fronto-occipital fasciculus (FOF), the cingulate fasciculus (CING F), and the extreme capsule (Extm C). Fibers from area 8Av course via FOF and SLF II, merging in the white matter of the inferior parietal lobule (IPL) and terminating in the caudal intraparietal sulcus (IPS). A group of these fibers turns ventrally to terminate in the caudal superior temporal sulcus (STS). Fibers from the rostral part of area 8Ad course via FOF and SLF II to the IPS and IPL and via the AF to the caudal superior temporal gyrus and STS. Some fibers from the rostral part of area 8Ad are conveyed to the medial parieto-occipital region via FOF, to the STS via Extm C, and to the caudal cingulate gyrus via CING F. Fibers from area 8B travel via SLF I to the supplementary motor area and area 31 in the caudal dorsal cingulate region and via the CING F to cingulate areas 24 and 23 and the cingulate motor areas. Fibers from area 9/46d course via SLF I to the superior parietal lobule and medial parieto-occipital region, via SLF II to the IPL. Fibers from area 9/46v travel via SLF III to the rostral IPL and the frontoparietal opercular region and via the CING F to the cingulate gyrus.

Frontal lobes and behaviour.

A number of studies have appeared during the past year that contribute significantly to our understanding of the role of the frontal cortex in learning, memory, and response control. In addition to the traditional approaches that involve the investigation of the behavioural effects of lesions and the recording of the activity of single neurons, important information is now provided by functional activation studies carried out using positron emission tomography on normal human subjects.

Memory and the region of the mammillary bodies.

The contribution of the mammillary region to several classes of learning and memory has been reviewed. There is considerable evidence that lesions of this region of the brain impair performance on tasks that require memory for locations that an animal has visited, but that the deficit depends both on the amount of damage within the region and the difficulty of the task. Such lesions, however, do not appear to impair performance on a variety of spatial conditional associative learning tasks which require the animal to form an association between a place or a scene and a stimulus embedded within it. In addition, damage to the region of the mammillary bodies does not impair the ability to learn a variety of non-spatial memory tasks. These studies suggest that the mammillary region may play a selective role in certain types of spatial learning and memory.

Dissociable roles of mid-dorsolateral prefrontal and anterior inferotemporal cortex in visual working memory.

Functional neuroimaging in human subjects and studies of monkeys with lesions limited to the mid-dorsolateral (MDL) prefrontal cortex have shown that this specific region of the prefrontal cortex is involved in visual working memory, although its precise role remains a matter of debate. The present study compared the effect on visual working memory of lesions restricted to the mid-dorsolateral prefrontal cortex of the monkey with that of lesions to the anterior inferotemporal cortex, a region of the temporal cortex specialized for visual memory. Increasing the delay during which information had to be maintained in visual working memory impaired performance after lesions of the anterior inferotemporal cortex, but not after mid-dorsolateral prefrontal lesions. By contrast, increasing the number of stimuli that had to be monitored impaired the performance of animals with mid-dorsolateral prefrontal lesions, but not that of animals with anterior inferotemporal lesions. This demonstration of a double dissociation between the effects of these two lesions provides strong evidence that the role of the mid-dorsolateral prefrontal cortex in visual working memory does not lie in the maintenance of information per se, but rather in the executive process of monitoring this information. In addition, the present study demonstrated that lesions limited to area 9, which constitutes the superior part of the mid-dorsolateral prefrontal region, give rise to a mild impairment in the monitoring of information, whereas lesions of the complete mid-dorsolateral prefrontal region yield a very severe impairment.

Wisconsin Card Sorting revisited: distinct neural circuits participating in different stages of the task identified by event-related functional magnetic resonance imaging.

The Wisconsin Card Sorting Task (WCST) has been used to assess dysfunction of the prefrontal cortex and basal ganglia. Previous brain imaging studies have focused on identifying activity related to the set-shifting requirement of the WCST. The present study used event-related functional magnetic resonance imaging (fMRI) to study the pattern of activation during four distinct stages in the performance of this task. Eleven subjects were scanned while performing the WCST and a control task involving matching two identical cards. The results demonstrated specific involvement of different prefrontal areas during different stages of task performance. The mid-dorsolateral prefrontal cortex (area 9/46) increased activity while subjects received either positive or negative feedback, that is at the point when the current information must be related to earlier events stored in working memory. This is consistent with the proposed role of the mid-dorsolateral prefrontal cortex in the monitoring of events in working memory. By contrast, a cortical basal ganglia loop involving the mid-ventrolateral prefrontal cortex (area 47/12), caudate nucleus, and mediodorsal thalamus increased activity specifically during the reception of negative feedback, which signals the need for a mental shift to a new response set. The posterior prefrontal cortex response was less specific; increases in activity occurred during both the reception of feedback and the response period, indicating a role in the association of specific actions to stimuli. The putamen exhibited increased activity while matching after negative feedback but not while matching after positive feedback, implying greater involvement during novel than routine actions.

Flow rate of some pharmaceutical diluents through die-orifices relevant to mini-tableting.

The effects of cylindrical orifice length and diameter on the flow rate of three commonly used pharmaceutical direct compression diluents (lactose, dibasic calcium phosphate dihydrate and pregelatinised starch) were investigated, besides the powder particle characteristics (particle size, aspect ratio, roundness and convexity) and the packing properties (true, bulk and tapped density). Flow rate was determined for three different sieve fractions through a series of miniature tableting dies of different orifice diameter (0.4, 0.3 and 0.2 cm) and thickness (1.5, 1.0 and 0.5 cm). It was found that flow rate decreased with the increase of the orifice length for the small diameter (0.2 cm) but for the large diameter (0.4 cm) was increased with the orifice length (die thickness). Flow rate changes with the orifice length are attributed to the flow regime (transitional arch formation) and possible alterations in the position of the free flowing zone caused by pressure gradients arising from the flow of self-entrained air, both above the entrance in the die orifice and across it. Modelling by the conventional Jones-Pilpel non-linear equation and by two machine learning algorithms (lazy learning, LL, and feed-forward back-propagation, FBP) was applied and predictive performance of the fitted models was compared. It was found that both FBP and LL algorithms have significantly higher predictive performance than the Jones-Pilpel non-linear equation, because they account both dimensions of the cylindrical die opening (diameter and length). The automatic relevance determination for FBP revealed that orifice length is the third most influential variable after the orifice diameter and particle size, followed by the bulk density, the difference between bulk and tapped densities and the particle convexity.

Memory for Places and the Region of the Mamillary Bodies in Rats.

Rats with extensive lesions of the mamillary bodies and the immediately adjoining areas exhibited a severe impairment on two spatial memory tasks. In the first task, the animals had to retrieve food from each one of eight separate locations within the daily test session. In the second task, the animals were allowed to visit a particular location and retrieve food from it and, after a variable delay, they had to select between returning to the location they had already visited and a new location that now contained the food. Rats with lesions of the mamillary region were able to perform the task with minimal delay, but their performance was impaired as the delay increased. Finally, rats with mamillary lesions were not impaired in learning a visual discrimination task or its reversal. The results show that extensive damage in the mamillary region can lead to significant and long lasting spatial memory impairments.

Projections to the frontal cortex from the posterior parietal region in the rhesus monkey.

The projections to the frontal cortex from the various subdivisions of the posterior parietal region in the rhesus monkey were studied by means of autoradiographic technique. The rostral superior parietal lobule (area PE) projects to the dorsal areas 4 and 6 on the lateral surface of the frontal lobe as well as to the supplementary motor area (MII) on its medial surface. The caudal area PE sends its connections to dorsal area 6 and MII. The projections from the medial parietal cortex (areas PEc and PGm) are similar to those of the superior parietal lobule but they tend to concentrate in the more rostral part of dorsal area 6, MII, and in the cingulate gyrus (area 24). The most caudal part of the medial parietal cortex also projects to area 8. The anteriormost part of the inferior parietal lobule (area PF) projects to the ventral area 6, including the caudal bank of the lower branch of the arcuate sulcus, to the ventral area 46 below the sulcus principalis, and to the frontal and pericentral opercular cortex. The middle inferior parietal lobule (areas PFG and PG) projects to the ventral part of area 46 and area 8, whilst the posteriormost inferior parietal lobule (caudal PG and area Opt) is connected with both dorsal and ventral area 46, dorsal area 8, as well as the anteriormost dorsal area 6, and the cingulate gyrus (area 24).

Association fiber pathways to the frontal cortex from the superior temporal region in the rhesus monkey.

The projections to the frontal cortex that originate from the various areas of the superior temporal region of the rhesus monkey were investigated with the autoradiographic technique. The results demonstrated that the rostral part of the superior temporal gyrus (areas Pro, Ts1, and Ts2) projects to the proisocortical areas of the orbital and medial frontal cortex, as well as to the nearby orbital areas 13, 12, and 11, and to medial areas 9, 10, and 14. These fibers travel to the frontal lobe as part of the uncinate fascicle. The middle part of the superior temporal gyrus (areas Ts3 and paAlt) projects predominantly to the lateral frontal cortex (areas 12, upper 46, and 9) and to the dorsal aspect of the medial frontal lobe (areas 9 and 10). Only a small number of these fibers terminated within the orbitofrontal cortex. The temporofrontal fibers originating from the middle part of the superior temporal gyrus occupy the lower portion of the extreme capsule and lie just dorsal to the fibers of the uncinate fascicle. The posterior part of the superior temporal gyrus projects to the lateral frontal cortex (area 46, dorsal area 8, and the rostralmost part of dorsal area 6). Some of the fibers from the posterior superior temporal gyrus run initially through the extreme capsule and then cross the claustrum as they ascend to enter the external capsule before continuing their course to the frontal lobe. A larger group of fibers curves round the caudalmost Sylvian fissure and travels to the frontal cortex occupying a position just above and medial to the upper branch of the circular sulcus. This latter pathway constitutes a part of the classically described arcuate fasciculus.

Architectonic analysis of the human retrosplenial cortex.

The architecture of the macaque retrosplenial cortex, including its posteroventral extension around and below the splenium of the corpus callosum, was recently characterized (Morris et al. [1999a] Eur. J. Neurosci. 11:2506-2518.). This analysis was made possible by sectioning the posterior cingulate gyrus radially, i.e., in planes that were orthogonal to its line of curvature and that, therefore, preserved the laminar organization of this region. The aim of the present study was to examine the architecture and the limits of the human retrosplenial cortex. Cross sections through the entire posterior cingulate gyrus were obtained by applying the sectioning technique developed in the monkey, so that an explicit comparison could be made between the architecture of the human and the monkey retrosplenial cortex. The present analysis revealed that, as is the case in the macaque brain, the human retrosplenial cortex is composed of granular areas 29a-c and d, and dysgranular/agranular area 30. The human retrosplenial cortex, like that of the macaque monkey, runs, as an arch, around the splenium of the corpus callosum. In the macaque brain, the retrosplenial cortex remains buried within the callosal sulcus throughout its entire course around the splenium. In the human brain, however, the posteroventral segment of the retrosplenial cortex extends on the medial wall of the cerebral hemisphere to encompass most of the cortical region commonly referred to as the "isthmus of the cingulate gyrus."

Orbitofrontal sulci of the human and macaque monkey brain.

The present study investigated the orbitofrontal sulci in 100 normal adult human cerebral hemispheres by using magnetic resonance images that were transformed into the standardized proportional stereotaxic space most commonly used, that of Talairach and Tournoux (Talairach and Tournoux [1988]. Co-planar stereotaxic atlas of the human brain. New York: Thieme). The patterns formed by the individual sulci were then examined and compared with those of the less convoluted macaque monkey brain. Four sulci forming a similar sulcal pattern were identified in both species. The olfactory sulcus occupies the most medial position forming the lateral border of the gyrus rectus. Lateral to this, the medial, lateral, and transverse orbital sulci form a pattern often resembling an "H," "X," or "K." These sulci divide the orbitofrontal cortex into four major gyri: the medial, lateral, anterior, and posterior orbital gyri. Three major types of sulcal pattern were identified in both species based on the arrangement of these orbital sulci. Additional sulci were observed in the human brain, creating more complex patterns. Probability maps were constructed for the four main orbitofrontal sulci of the human brain. These maps provide a statistical description of the variability of the location of the orbitofrontal sulci within the three-dimensional coordinate system of Talairach and Tournoux (Talairach and Tournoux [1988]. Co-planar stereotaxic atlas of the human brain. New York: Thieme). Because these maps may be directly compared with any image transformed into the same standardized space, they provide a valuable tool for identifying and describing the location of functional or structural changes in the orbitofrontal region of the human brain.

Fiber system linking the mid-dorsolateral frontal cortex with the retrosplenial/presubicular region in the rhesus monkey.

The present study investigated the origin, course, and terminations of the association fiber system linking the frontal cortex with the hippocampal system by means of the cingulum bundle. Injections of tritiated amino acids were placed within individual cytoarchitectonic areas of the frontal cortex in the rhesus monkey. It was demonstrated that the mid-dorsolateral frontal cortex (areas 46, 9/46, and 9) and its medial extension (medial areas 9 and 9/32) is the origin of a specific fiber pathway, running posteriorly as part of the cingulum bundle, and terminating mainly in the retrosplenial area 30 and the posterior presubiculum. This fiber bundle therefore provides the anatomical substrate of a functional interaction between the mid-dorsolateral frontal cortex and the hippocampal memory system for the monitoring of information within working memory.

Visuo-motor conditional associative learning after frontal and temporal lesions in the human brain.

It has been shown that damage to the human lateral frontal cortex results in a severe impairment on conditional associative tasks requiring learning of arbitrary associations between a set of stimuli and a set of responses (Petrides, M., Neuropsychologia, 1985, 23, 601-614; 1990, 28, 137-149). In these studies, which first demonstrated the impairment after frontal lesions, training was by a trial-and-error procedure, during which the subject performed the various responses when a given stimulus was presented and the experimenter provided feedback until the correct response was performed. In the present experiment, patients with unilateral frontal- or temporal-lobe excisions were tested on a visuo-motor conditional associative task with a modified procedure. The subjects had to learn arbitrary associations between a set of coloured stimuli and a set of hand postures. Training in the present experiment consisted of a series of demonstration trials followed by test trials. In the demonstration trials, the experimenter showed the subject the associations between the stimuli and the responses and, in the test trials that followed, the subject was tested on these associations. If an error was made on the test trials, the correct response was demonstrated by the experimenter. Despite these changes in the training procedure, namely the demonstration of the stimulus-response associations and the provision of the correct response immediately following an error, patients with left or right frontal-lobe excisions were severely impaired in learning this task. These findings, together with those of the earlier studies (Petrides, M., Neuropsychologia, 1985, 23, 601-614; 1990, 28, 137-149), demonstrate that the impairment in conditional learning after frontal lesions is not dependent on the type of the training procedure and therefore that it reflects a specific impairment in learning.

Deficits on conditional associative-learning tasks after frontal- and temporal-lobe lesions in man.

Patients with unilateral frontal- or temporal-lobe excisions were tested on a spatial and a nonspatial conditional associative task. These tasks required the learning of arbitrary associations between a set of stimuli and a set of responses. Patients with excisions from the left or right frontal cortex were severely impaired in learning both tasks. Patients with left or right temporal-lobe excisions that did not involve extensive damage to the hippocampal region were not impaired, whilst those with more radical involvement of the hippocampal region exhibited deficits that were material-specific and varied with the side of the lesion.