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We investigated the impact of a congenital prefrontal lesion and its resection on decision making under risk and under ambiguity in a patient with right mediofrontal cortical dysplasia. Both kinds of decision making are normally associated with the medial prefrontal cortex. We additionally studied pre- and postsurgical fMRI activations when processing information relevant for risky decision making. Results indicate selective impairments of ambiguous decision making pre- and postsurgically. Decision making under risk was intact. In contrast to healthy subjects the patient exhibited no activation within the dysplastic anterior cingulate cortex but left-sided orbitofrontal activation on the fMRI task suggesting early reorganization processes.

Neuroimaging studies of right-handed normal volunteers under semantic word generation tasks have consistently reported left lateralized activation of the anterior inferior frontal gyrus (ifg) which decreased during task repetition. This repetition-related activation decrease has been interpreted as the neurophysiological correlate of repetition priming, a mechanism of implicit memory for initial semantic processing. We interfered with left lateralized ifg activation, as identified by O-15-water PET activation, using repetitive transcranial magnetic stimulation (rTMS) in five right-handed male normal subjects, once using new (unprimed) nouns and once using known (primed) nouns for the procedure. All five subjects exhibited clear left lateralized activations of the triangular part of the left ifg in the PET studies. In all subjects, reaction time latencies were significantly longer during rTMS over the activation sites in the left ifg as compared to latencies off stimulation. Latencies were not affected during stimulation of the right ifg or over the vertex. These effects were observed within the group and in each individual, only if lists of primed nouns were used in the verb-generation task. In conclusion, these results demonstrate that the anterior part of the left ifg is not only involved in semantic processing, but is also essential for repetition priming on semantic tasks since successful interference with rTMS was only observed if lists of primed words were used for the generation task.

Pathological gambling (PG) is most likely associated with functional brain changes as well as neuropsychological and personality alterations. Recent research with the Iowa Gambling Task suggests decision-making impairments in PG. These deficits are usually attributed to disturbances in feedback processing and associated functional alterations of the orbitofrontal cortex. However, previous studies with other clinical populations found relations between executive (dorsolateral prefrontal) functions and decision-making using a task with explicit rules for gains and losses, the Game of Dice Task. In the present study, we assessed 25 male PG patients and 25 male healthy controls with the Game of Dice Task. PG patients showed pronounced deficits in the Game of Dice Task, and the frequency of risky decisions was correlated with executive functions and feedback processing. Therefore, risky decisions of PG patients might be influenced by both dorsolateral prefrontal and orbitofrontal cortex dysfunctions.

Extensive neuropsychological testing is reported on two chronic patients with combined temporopolar and prefrontal damage, dominantly left-hemispheric, and, as control, one chronic patient with bi-hemispheric prefrontal damage. The principal finding is that combined temporofrontal damage, but not substantial prefrontal damage alone, results in marked retrograde memory deficits while leaving intelligence and new learning relatively unimpaired. Although their general world knowledge was good, the temporopolar patients demonstrated retrograde memory impairments on several tests of past events and faces of previously famous people. With respect to retrograde autobiographical memory, one of the temporopolar patients was severely impaired and the other was judged to be moderately impaired. The control patient appeared to be normal. These results, together with corresponding data from related single case and dynamic imaging studies, strongly support a crucial role of the temporofrontal junction area in the ecphory of old memories.

A 54 year old patient of average intelligence with a severe and enduring loss of old autobiographical memories after herpes simplex type 1 infection is described. She was tested with a comprehensive neuropsychological battery two years after the infection. Special emphasis was laid on examining different aspects of retrograde memory. The neurological examination involved MRI and SPECT. Brain damage was found mainly in the right temporofrontal region, but minor left sided damage to this region seems possible. The patient was in the normal or slightly subnormal range for all tested anterograde memory functions, but manifested severe retrograde memory deficits with respect to episodic old memories and more moderate deficits in tests of general knowledge (semantic old memories). It is concluded that the ecphory of old autobiographical memories relies heavily on an activation of the right lateral temporofrontal junction area, but that probably only some complementary left hemispheric damage to these regions will lead to major and persistent retrograde amnesia. Alternatively, the disconnection between major prefrontal and posterior cortical regions may provide a basis for retrograde amnesia.

Memory is two-sided like the head of Janus: it looks into the past (retrograde memory) and the future (anterograde memory). While current opinion assumes a strong anatomical interdigitation in the processing of either kind of memory, recent single case reports and results obtained with the positron emission tomographic subtraction method indicate the likely existence of a dissociation: regions of the limbic system are primarily engaged in the encoding of autobiographical and semantic information, while cortical areas in the orbitofrontal and anterolateral temporo-polar regions are principally engaged in information retrieval. Within this retrieval system the right hemisphere may subserve episodic memory retrieval, and the left retrieval from the knowledge system (semantic memory).

An industrial manager had severe retrograde and variable but usually mild anterograde amnesia four years after a head injury. MRI showed damage of both temporal poles and the lateral portion of the right prefrontal cortex. The prefrontal and temporal cortical damage on the right side extended deeply into the white matter while the temporal cortical damage on the left side was much smaller. There was an additional left temporo-parietal lesion. The patient was of average intelligence. His attention, short term memory and learning ability were average or somewhat below average. His old memories were severely affected for the personal-episodic domain and less so for semantic remote memory abilities. Therefore an anatomical dissociation between anterograde and retrograde amnesia is possible at the anterior temporal regions, possibly interacting with the prefrontal cortex; these regions seem necessary for the retrieval of old episodic memories.

Afferents from limbic system-related structures (aside from the cingulate and retrosplenial cortex) to medial and lateral regions of the bush baby's frontal cortex were investigated by means of the somatopetal transport of horseradish peroxidase. The frontopolar region received afferents from the subicular cortex, the lateral nucleus of the amygdala, from hypothalamic nuclei, the ventral tegmental area and other brain stem nuclei. Injections of horseradish peroxidase into other frontal regions usually resulted in labeled cells in brain stem nuclei and in the hypothalamus, but not in telencephalic regions; only the large injection into the posterior part of the frontal cortex was followed by labeled amygdaloid neurons. From these results it is concluded that a small number of limbic system-related telecephalic areas projects to the frontal cortex and that a somewhat larger number of diencephalic and brain stem nuclei reaches this part of the cortex.

On the basis of a previous experiment (Irle & Markowitsch, 1983) in which triple limbic lesions as opposed to double limbic lesions in the cat failed to impair the learning behavior of these animals, the effects of a lesion in a fourth brain structure, in addition to the original ones, were examined. Two groups of cats were given lesions in either the prefrontal cortex alone or in the prefrontal cortex, the anterior thalamus, the mamillary bodies, and the subiculum and subsequently tested in the acquisition of a visual reversal, a delayed alternation, and an active two-way avoidance task. Compared with control cats, cats with prefrontal lesions were strongly impaired in the acquisition of the visual reversal task and the delayed alternation task but only slightly impaired in the acquisition of the active two-way avoidance task. In contrast, animals with combined prefrontal cortical, anterior thalamic, mamillary, and subicular lesions were unimpaired in the acquisition of the visual reversal task, slightly facilitated in the acquisition of the active two-way avoidance task, but impaired in the acquisition of the delayed alternation task similarly to the animals with prefrontal lesions. The superior performance rates of the animals with fourfold lesions are considered to be due to a lesion-induced functional shift acting on intact brain structures which, prior to massive limbic lesions, remain inhibited or otherwise suppressed. The failure of the animals with fourfold lesions in the delayed alternation task indicates that the functions underlying this type of behavior cannot be compensated for or, alternatively, that a prefrontal lesion is not sufficient to disinhibit other structures involved in the same behavior.

The distribution of the afferents to the rat's prefrontal cortex originating in the thalamic mediodorsal nucleus and the amygdala was investigated with two fluorescent tracers. Special emphasis was laid on detecting the loci of neurons which project via axonal collaterals into both lateral and medial portions of the prefrontal cortex. It was found that a high number of neurons of the anterior portion of the basolateral amygdaloid nucleus terminate via collaterals in both the medial and lateral subfields of the prefrontal cortex. On the other hand, only a small number of mediodorsal thalamic cells were found to project to both sides of the prefrontal hemisphere via bifurcating axonal collaterals. These cells were situated exclusively in the lateral part of the medial segment of the mediodorsal nucleus. The majority of both thalamic and amygdaloid neurons with bifurcating axons originate from subregions whose cells innervate primarily the medial prefrontal cortex. In brain-stem, neurons of the nucleus raphé dorsalis also project via collaterals to the medial and lateral prefrontal regions. Furthermore, neurons of the dorsal and ventral premamillary nuclei, the lateral mamillary nucleus, the ventral tegmental area of Tsai, and the ventral tegmental nucleus of Gudden were found to project to the medial prefrontal cortex. Our results indicate a differential collateral organization of thalamic and amygdaloid afferents to prefrontal cortical fields. The anterior basolateral amygdala (which innervates via collaterals both the medial and lateral prefrontal subfields) may add a common input to either subfield, such as information on the significance of incoming stimuli to the animal's behavior, while the mediodorsal nucleus (whose segments are principally connected to only one prefrontal subfield) may add segment-specific information, for example, of a spatial-cognitive nature for the lateral segment and of an emotional nature for the central and medial segments. The existence of a basolateral limbic circuit, composed of the amygdala, the thalamic mediodorsal nucleus, and the prefrontal cortex, is confirmed and knowledge on its interconnectivity is extended. From an anatomical point of view these data provide arguments for both unitary and diverging functions of the prefrontal cortex.

The cortical projection area of the thalamic mediodorsal nucleus (MD) was investigated using the horseradish peroxidase technique. Distinct relationships between subdivisions of MD and of the prefrontal cortex were established: the medial sector of MD projects to sulcal cortex dorsal to the rhinal fissure and to the lateral frontopolar region; the lateral sector of MD reaches mainly cortex within the medial part of the hemisphere from the frontopolar region up to a mid corpus callosal level. The projection area of the lateral sector of MD overlaps with the projection fields of the paratenial and anteromedial nuclei. It is concluded that the guinea pig's prefrontal cortex, defined as the projection area of MD, has strong similarities with the prefrontal cortices of rats and rabbits, that is with the prefrontal cortices of species of two different orders.

The extent of convergence of mediodorsal thalamic and amygdalar afferents on the rat's frontal cortex was studied by tracing retrogradely labeled cells following injections of horseradish peroxidase (HRP). HRP was applied iontophoretically in extremely small injections throughout all areas of the frontal cortex. The following organization was revealed: Converging inputs from the mediodorsal nucleus and the amygdala are observed in the posterior parts of the pre- and infralimbic areas, in the posterior half of the dorsal and ventral agranular insular areas and in the lateral and dorsal precentral areas. Both mediodorsal and amygdaloid afferents reach the dorsal tip of the frontal cortex. Only the mediodorsal afferents were found to terminate in the anterior parts of the pre- and infralimbic areas and in the anterior part of the dorsal division of the anterior cingulate area and in the medial precentral area. On the lateral side of the hemisphere the anterior halves of the dorsal and ventral agranular insular areas receive mediodorsal afferents. Amygdaloid, but not mediodorsal afferents, were found following injections into the more posterior parts of the lateral precentral area. These results are discussed with respect to the extent of the prefrontal cortex in the rat and its definability as a target area of subcortical nuclei. Functional aspects of the anatomical convergence of connections within the so-called basolateral limbic circuit are outlined.

Cortical afferents to the prefrontal cortex were studied in 10 bush babies (Galago senegalensis) by means of somatopetal transport of horseradish peroxidase. The lateral injections invariably labeled neurons in the temporal cortex and in most cases also in the insular and parietal regions. In some of these brains the cingulate and retrosplenial areas contained labeled perikarya. Injections into the medial cortex, on the other hand, consistently labeled cell bodies in the cingulate cortex, but not in the insular, temporal and parietal regions. When both lateral and medial sites of the bush baby's prefrontal cortex are considered together, apparently fewer cortical areas (as defined by Brodmann's cytoarchitectonic maps) project to the prefrontal cortex in the bush baby than in the rhesus monkey. This statement holds for both ipsi- and contralateral projections.

Direct projections from the mediodorsal nucleus of the thalamus to ventral parts of the insular region of the cat's cortex were demonstrated by using the horseradish peroxidase technique.

The sulcal or medial subdivision of the prefrontal cortex of the guinea pig was ablated after the animals had learned a spatial delayed-alternation task. Retention of this task was significantly impaired only after ablation of the medial prefrontal cortex. As the most critical cortical region for delayed-alternation performance in the rat is also situated in the medial prefrontal cortex, our findings suggest a close functional correspondence of the prefrontal cortices of these rodent species.

Efferent projections from the basal forebrain to the prefrontal cortex of the lesser bush baby (Galago senegalensis) were traced with the retrograde horseradish peroxidase technique. Different areas of the prefrontal cortex of six bush babies were injected with small amounts of horseradish peroxidase. The entire basal forebrain was then screened for labeled neurons. Following all six injections, many retrogradely labeled neurons could be detected in the nucleus basalis of Meynert. These results indicate a strong innervation of the bush baby's prefrontal cortex by the nucleus basalis of Meynert. The observed projections seem comparable in strength and topography to those found in another primate species, the rhesus monkey. Anatomical and functional implications of these projections in the bush baby are discussed and related to findings in other primates and species of other orders.

Different areas of the frontal cortex of the cat were injected with small amounts of horseradish peroxidase. The region of labeled cells in the mediodorsal nucleus of the thalamus (MD) were related to the injected areas. Distinct relations between subdivisions of MD and of the prefrontal cortex were established: a rather large central sector of MD projects to the gyrus proreus and the anterior parts of the gyri sigmoideus, rectus, and frontalis. A narrow lateral band of anterior MD neurons projects predominantly to an area on both sides of the sulcus praesylvius, whereas a postero-lateral band sends fibers to a region on the ventral anterior sylvian gyrus. The area between the presylvian sulcus and the sylvian gyrus is apparently free of MD afferents, but not of other thalamic afferents. A fourth sector of MD, situated dorsomedially, projects to the middle parts of the gyri rectus and frontalis. And a fifth sector, located ventrally to the dorsomedial MD sector, projects to the ventral part of the gyrus rectus. The established subfields of MD and of the prefrontal cortex are discussed with respect to previous anatomical research in the cat.

In the mouse small amounts of horseradish peroxidase were injected iontophoretically into different portions of the frontal lobe. Out of a large number of mice, 18 with typical injections which together covered most of the anterior half of the cortex were selected, and their retrogradely labeled thalamic cells were described and illustrated in detail. Special emphasis was laid on the cortical projections of the mediodorsal nucleus which were considered to define locus and extent of the prefrontal cortex. The results reveal that topographically the extent of the mouse, prefrontal cortex closely resembles that of the rat, another species of the rodent order. It includes a small area within and dorsal to the rhinal sulcus and a comparatively larger region within the medial half of the anterior cortex. Furthermore, the dorsal tip of the frontal pole is reached by a considerable number of afferents from the mediodorsal nucleus. Whether this last projection also exists in the rat is still disputed. As in the rat, only the sulcal prefrontal cortex seems to be reached by mediodorsal cells alone, whereas the rest of the prefrontal cortical fields have overlapping projections from the anteromedial nucleus. Though a considerable area within the frontal lobe of the mouse is reached by mediodorsal afferents, the significance and usefulness of this definition of the prefrontal cortex is questioned.

Relationships between the performance in a symmetrically reinforced go-no go task and cellular firing patterns in prefrontal and parietal association areas of the neocortex were studied in six cats. During recordings, animals lay in a box, with their heads fixed to a stereotaxic frame, and performed an auditory go-no go task by pressing a retractable lever in front of them. Units obtained were classified into eight types according to the correlation of their activity changes with aspects of the task and/or with sensory stimuli. These types were (poly-) sensory, reward related, EMG-related, EOG-related, event-related, movement-initiating, expressing expectancy or novelty, and nonspecific or task-unrelated active units. Between the two recording areas a considerable degree of similarity was obtained in unit firing patterns. It was concluded that within the cerebral cortex, and especially within its association areas, a considerable functional overlap exists, that neurons may be involved in the processing of several and rather different phenomena, and that the processing of information at this level of the brain is generally done via widespread, interwoven neuronal nets so that only the average network activity, but not that of a particular, single neuron, represents a stimulus or an event.

A survey of existing atlases of the cat's brain has revealed a lack of coronal sections on the levels of the prefrontal cortex. On the other hand, neurophysiological and behavioral studies of this region have increased greatly in recent years. As the extent of coronal sections through the prefrontal cortex was seen to differ markedly even at separations of 1 mm, a stereotaxic atlas was made on the basis of brain sections of 16 mongrel cats. Brains were cut with the use of the paraffin or freezing method, and stained with cresyl violet, Luxol fast blue, or Kluver-Barrera's combination. Statistical methods were used to yield representative coronal outlines of sections from +20 to +30 mm anterior in 1 mm steps. A comparison with Reinoso-Suarez five coronal sections within this range showed a marked congruence between the two atlases.

The retention performance for learned words was compared in two groups of cortically damaged patients: A group of 14 patients with uni- or bilateral damage to the frontal lobes (group F), and a group of 14 patients with postrolandic damage. The patients learned three lists of words each of which had to be reproduced after 15 min. and after 1 day: one list under free recall, one under cued recall, and one under a recognition condition. While the performance of the two groups of patients was similar under all three conditions when tested after 15 min., group F was significantly inferior in the one day free recall retention test. We interpret this deficit as related in part to the classic "frontal" symptomatology (reduced attention and lack of initiative, drive, and concentration), and in part to a distinct disturbance of long term memory. We base this conclusion on the similar performance levels of frontal and non-frontal patients under all other conditions of testing, in particular under the free recall condition after the 15 min. delay. Reasons are given why attentive and drive related components might be mediated by prefrontal cortical neurons themselves, while mnemonic components might be mediated by mediodorsal thalamic neurons projecting to the prefrontal cortex. No or only minor differences could be established between the side of damage or between uni- versus bilateral frontal damage.

Following horseradish peroxidase (HRP) injections into different areas within the prefrontal cortex (PFC) of the cat, labeled neurons were found in the cingulate and insular cortex. These results demonstrate that the cat's prefrontal cortex is reached directly from these cortical regions, and that the observed cortical projections are similar to those detected in the monkey's prefrontal cortex.

On the basis of new neuroanatomical findings on relationships between subregions of the mediodorsal thalamic nucleus and the prefrontal cortex of the cat, it was attempted to investigate the relative importance of prefrontal subfields with the aim of obtaining evidence in favor of a functional inequality of different prefrontal subfields. Four areas, named presylvian (PRS), proreal (PR), dorsomedial (DM), and orbito-insular (OI) sectors, were ablated successfully in 30 adult animals. Performance of a 10-sec delayed-alternation task was compared pre- and postoperatively. Furthermore, most of the cats had to learn an extension of this task postoperatively, using a 20-sec delay period, and lastly, these animals were subjected to an extinction test. Significant performance differences were obtained between cats of different groups in all three tasks. Lesions of subregion PR, and even more of subregion PRS, led to severe behavioral deterioration, whereas lesions of subregion OI were without effect, when compared with the behavior of a sham-operated control group. PRS-cats, furthermore, showed motor disturbances during the first postoperative week. The results obtained suggest that it is possible to subdivide the cat's prefrontal cortex functionally. In addition, it is hypothesized that behavioral changes in cats of groups PRS and PR are due to an inability to use kinesthetic information properly.