Metabolic mapping of functional activity in human subjects with the [18F]fluorodeoxyglucose technique.

The 2-[18F]fluoro-2-deoxy-D-glucose technique was used to measure regional cerebral glucose utilization by human subjects during functional activation. Normal male volunteers subjected to one or more sensory stimuli (tactile, visual, or auditory) exhibited focal increases in glucose metabolism in response to the stimulus. Unilateral visual hemifield stimulation caused the contralateral striate cortex to become more metabolically active than the striate cortex ipsilateral to the stimulated hemifield. Similarly, stroking the fingers and hand of one arm with brush produced an increase in metabolism in the contralateral postcentral gyrus, compared with the homologous ipsilateral region. The auditory stimulus, which consisted of a monaurally presented factual story caused an increase in glucose metabolism in the auditory cortex in the hemisphere contralateral to the stimulated ear. These results demonstrate that the technique is capable of providing functional maps in vivo related to both body region and submodality of sensory information in the human brain.

Corticocortical connections among visual areas in the cat.

The cortical interconnections of 17 visual areas in the cat were studied by making single injections through recording micropipettes of the neuroanatomical tracers 3H-leucine and horseradish peroxidase (HRP) into the visual cortex of 40 adult animals. Coronal sections from each of the brains were analyzed for location of silver grains and HRP-filled neurons. There are five main results: (1) all corticocortical connections among visual areas are reciprocal. (2) Each cortical visual area has a unique set of cortical connections; the cortical targets of no two cortical visual areas are identical. (3) There is a vast and complicated pattern of connections among the visual areas which implies that there are numerous parallel circuits which run through any one visual area. (4) The connections among the cortical visual areas link retinotopically similar loci and are consistent with the visuotopic maps which microelectrode recording experiments have provided. (5) The connections among visual cortical areas often originate from, or terminate in, discontinuous patches within each area; this result obtains not only for areas 17, 18, 19, and posteromedial lateral suprasylvian area (PMLS), but for at least 13 other areas as well. The data reveal many parallel pathways and suggest multiple functional circuits interconnecting visual cortical areas. Since each visual area has multiple inputs and outputs it may have multiple functions, a different one for each of the circuits of which it is a part.

Laminar origins of visual corticocortical connections in the cat.

The interconnections among visual areas in cat cortex were studied with respect to the specific laminae in which the cortically projecting neurons are located. Single injections of HRP were made through recording micropipettes into nine different visual areas. In 15 cortical areas the laminar distribution of neurons which were retrogradely filled with HRP was plotted. In this way we determined the laminar origins of the cortical projections to the nine separate cortical visual areas which were injected. There are three major observations. First, areas 17 and 18 are the only two visual areas in which layers II and III are the primary site of cortically projecting cells; in the other 13 areas the deeper layers of cortex provide a large percentage of such neurons. Second, within any one cortical area, cortically projecting neurons may be distributed among different layers; the specific layer depends upon the cortical target of those neurons. Third, any one cortical area receives projections from several different cortical layers, the specific layers being dependent upon the area from which the projection originates. An individual cortical area, therefore, contributes to several different cortical visual circuits, with each of these circuits defined by the laminar connections of its neurons.

The retinotopic organization of lateral suprasylvian visual areas in the cat.

This is the second in a series of papers in which we describe our continuing efforts to define functional units of visual cortex based upon electro-physiological mapping of single and multiple unit activity in both awake and the nitrous oxide anesthetized cats. In the first paper (Tusa, Palmer and Rosenquist, '78), the extent and retinotopic organization of area 17 were described. In this paper, we describe the somewhat more complex organization of the visual cortex lying on the banks of the middle and posterior suprasylvian sulci. This region of cortex consists of six retinotopically organized units. These areas are arranged as three roughly mirror symmetrical pairs separated in each case by the fundus of the middle or posterior suprasylvian sulci. Some thalamo-cortical autoradiographic material is presented which supports this parcellation of the cortex.

Ibotenic acid lesions of the lateral substantia nigra restore visual orientation behavior in the hemianopic cat.

Transection of non-tectotectal fibers in the caudal one-half of the commissure of the superior colliculus restores visual orienting to a cat previously rendered hemianopic by a large unilateral visual cortical lesion. Other observations related to this recovery phenomenon (i.e., the Sprague effect) have suggested that the caudal commissural fibers whose destruction produces the recovery 1) are contralateral afferents to the superior colliculus on the side of the cortical lesion, and 2) profoundly influence visuo-motor processing in this superior colliculus. We performed anatomical and behavioral experiments to determine which of the more than 40 contralateral collicular afferents are directly involved in the Sprague effect. To guide subsequent behavioral studies, we performed a pilot anatomical experiment in which we injected WGA-HRP unilaterally into one superior colliculus at identical retinotopic loci in each of a pair of cats. One cat was normal (control), and the other (experimental) had previously received a caudal transection of the collicular commissure. Quantitative comparison of the retrograde labeling in collicular afferents revealed that a number of mesencephalic regions contain neurons that project to the colliculus via the caudal collicular commissure. Additional collicular injections of WGA-HRP demonstrated the exact location and distribution of collicular afferent neurons within these nuclei. In the behavioral experiments, we attempted to replicate the Sprague effect by destroying the neurons giving rise to the axons in the caudal collicular commissure. Ibotenic acid lesions of these neurons were performed in cats that were hemianopic following the removal of the contralateral visual cortex. Small lesions of a "critical zone" in the rostro-lateral substantia nigra pars reticulata and possibly the overlying ventral zona incerta consistently produced a visual recovery whereas lesions of the other collicular afferents did not. Paradoxically, large nigral lesions that also included the critical zone did not result in a recovery. A conceptual framework for these findings involving striato-nigro-tecto-preoculomotor interactions is presented.

Ibotenic acid lesions of the substantia nigra pars reticulata ipsilateral to a visual cortical lesion fail to restore visual orienting responses in the cat.

Unilateral removal of all known visual cortical areas in the cat renders the animal hemianopic in the contralateral visual field as measured by visual perimetry and other behavioral tests. We have shown that visual orientation behavior can be restored to the previously blind hemifield by destruction of a critical zone in the substantia nigra pars reticulata contralateral to a cortical lesion (Wallace et al., J. Comp. Neurol. 296:222-252, 1990). The model proposed to explain this recovery postulates that damage to the crossed nigrotectal projection disinhibits the superior colliculus ipsilateral to the cortical lesion and this leads to recovery. If disinhibition can account for recovery, then destruction of the uncrossed nigrotectal projection, which is known to exert a tonic inhibition on the superior colliculus, should also result in recovery. We made unilateral visual cortical ablations and ipsilateral ibotenic acid lesions of the substantia nigra pars reticulata. Visual orienting behavior was assessed in animals for a period of 4 to 31 weeks. Contrary to the prediction of the model, we failed to observe a recovery of visual orienting behavior in the blind hemifield in any of 23 animals.

Retinotopic organization of areas 18 and 19 in the cat.

The location and retinotopic organization of areas 18 and 19 in cat cortex were determined using electrophysiological mapping techniques. These two areas each contain a single representation of the visual hemifield and each has a distinctive cytoarchitecture. The visual hemifield representations in these two areas are nearly mirror images of each other. Compared to area 17, areas 18 and 19 have less cortical surface area, have a lower cortical magnification factor, contain less of the visual field and contain second order instead of first order transformations of the visual hemifield. An unusual asymmetry was found between the representations of the upper and lower visual quadrants not seen before in maps of other areas of cat or other species. A considerable amount of variability in the retinotopic organization of these two areas was found among cats.

The retinotopic organization of area 17 (striate cortex) in the cat.

The location and retinotopic organization of visual areas in the cat cortex were determined by systematically mapping visual cortex in over 100 cats. The positions of the receptive fields of single neurons or small clusters of neurons were related to the locations of the corresponding recording sites in the cortex to determine the representations of the visual field in these cortical areas. In this report, the first of a series, we describe the organization of area 17. A single representation of the cat's entire visual field corresponds closely to the cytoarchitectonically defined area 17. This area has the largest cortical surface area (380 mm2) and the highest cortical magnification factor (3.6 mm2/degree2 at area centralis) of all the cortical areas we have studied. There was perfect agreement between the borders of area 17 determined electrophysiologically and cytoarchitecturally. This area contains a first order transformation of the visual hemifield in which every adjacent point in the visual field is represented as an adjacent point in the cortex. Some variability exists among cats in the extent and retinotopic representation of the visual field in area 17.

Disinhibition of the superior colliculus restores orienting to visual stimuli in the hemianopic field of the cat.

Following unilateral removal of all known visual cortical areas, a cat is rendered hemianopic in the contralateral visual field. Visual orientation can be restored to the blind hemifield by transection of the commissure of the superior colliculus or by destruction of the superior colliculus (SC) or the substantia nigra pars reticulata (SNpr) contralateral to the cortical lesion. It is hypothesized that a mechanism mediating recovery is disinhibition of the SC ipsilateral to the cortical lesion. The ipsilateral nigrotectal projection exerts a robust inhibitory tone onto cells in the SC. However, ibotenic acid destruction of SNpr neurons, which should decrease inhibition onto the SC, does not result in recovery. The failure of ipsilateral SNpr lesions to produce recovery puts into question the validity of SC disinhibition as a mechanism of recovery. We directly tested the disinhibition hypothesis by reversibly disinhibiting the SC ipsilateral to a visual cortical lesion with a gamma-aminobutyric acid (GABA)A antagonist, bicuculline methiodide. In accordance with the hypothesis, transient disinhibition of the SC restored visual orienting for several hours in three of eight animals. Recovery was not a volume or pH effect and was distinct from the release of irrepressible motor effects (i.e., approach and avoidance behaviors) seen within the first hour after injection. Thus, in the absence of all visual cortical areas unilaterally, disinhibition of the SC can transiently restore the ability of the cat to orient to visual stimuli in the previously "blind" hemifield.

Recovery from cortical blindness mediated by destruction of nontectotectal fibers in the commissure of the superior colliculus in the cat.

Transection of the commissure of the superior colliculus restores visual orientation behavior to a cat previously rendered hemianopic by a unilateral visual cortical lesion (the Sprague effect). Using two methods, we asked whether this recovery resulted from the severing of the tectotectal component of the commissure or whether the destruction of some other connection was responsible. First, we transected either the rostral or the caudal one-half of the tectal commissure in hemianopic cats. If destruction of tectotectal fibers is responsible for the Sprague effect, then only rostral transections should produce the recovery since nearly all tectotectal connections lie in the rostral one-half of the commissure. However, rostral cuts failed to produce a recovery, whereas caudal commisurotomies did. Second, ibotenic acid was used to destroy the cells in the superior colliculus contralateral to the cortical lesion. This lesion eliminated the contralateral tectotectal pathway from the contralateral colliculus but left other fibers (originating elsewhere but coursing through the commissure) largely intact. These ibotenic acid lesions failed to produce the recovery; but when the caudal portion of the tectal commissure was subsequently transected in the same animals, the recovery was observed. The results of both experiments support the conclusion that the transection of a nontectotectal component of the commissure of the superior colliculus is responsible for the recovery of visual orientation behavior in a cortically blind cat.

Ischemic lesions of the occipital cortex and optic radiations: positron emission tomography.

We used 18-F-fluoro-2-deoxyglucose positron emission tomography (PET) and computed tomography (CT) to study eight patients with homonymous hemianopias or quadrantanopias due to ischemic lesions of the visual pathways. Four patients with ischemic damage to all or part of the occipital lobe had decreased glucose metabolism in the affected region. Three patients with ischemic damage limited to the optic radiations had decreased glucose metabolism in the portion of striate cortex appropriate for the visual field defect. Changes in glucose metabolism frequently occurred in the undamaged ipsilateral thalamus and visual association areas.

Cerebral metabolism and patterned visual stimulation: a positron emission tomographic study of the human visual cortex.

We studied the impact of visual stimulation upon cerebral metabolism in normal young men using FDG-PET. Results obtained from subjects receiving patterned visual stimulation while performing an ocular fixation task were compared with results from ocular fixation alone. Visual stimulation in the macular region of either hemifield produced significant increases in metabolism of the contralateral posterior striate cortex. Visual stimulation induced highly significant asymmetries in metabolism of the prefrontal and inferior parietal cortices. Metabolic activation in extrastriate areas tended to be right-sided. These findings support the classic notion of retinotopic organization within the primary visual sensory cortex. They also indicate that the patterns of cerebral metabolism are not equivalent between the two cerebral hemispheres. This latter finding suggests that in humans the right cerebral hemisphere may be specialized for visual processing.

Compounds that activate the mouse melanocortin-1 receptor identified by screening a small molecule library based upon the beta-turn.

A library of 951 compounds based upon the beta-turn motif were examined for their ability to stimulate the melanocortin-1 receptor. From this screening process, we have identified two compounds possessing low micromolar agonist activity at the mMC1R. The compound EL1 with racemic Nal(2') in the i + 1 position, DPro in the i + 2 position, and Trp in the i + 3 position possesses an EC(50) of 42.5 +/- 6.9 microM. Compound EL2 with Trp in the i + 1 position, DLys in the i + 2 position, and Phe in the i + 3 position possesses an EC(50) value of 63.4 +/- 26.9 microM. The results of the library screening process are consistent with a hypothesis dating back to the 1980s proposing that a beta-turn conformation involving the melanocortin "Phe-Arg-Trp" core amino acids provides the key recognition element. Additionally, these compounds represent the first nonpeptidic heterocyclic molecules reported to date that are able to activate the MC1R, a melanocyte receptor involved in skin pigmentation and animal coat coloration.

Ibotenic acid lesions in the pedunculopontine region result in recovery of visual orienting in the hemianopic cat.

Cats rendered hemianopic by a unilateral visual cortical ablation can recover the visual orienting response in the hemianopic visual field following disruption of the caudal non-tectotectal containing half of the commissure of the superior colliculus. Ibotenic acid lesions of a small 'critical zone' in the contralateral substantia nigra result in a similar recovery effect. A conceptual framework developed by Wallace et al. (1990) [J. Comp. Neurol. 296, 222-252] proposed that elimination of contralateral substantia nigra 'critical zone' inhibition on the superior colliculus ipsilateral to a visual cortical lesion is responsible for the recovery. This model is insufficient, however, to explain the observation that hemi-decorticate cats with contralateral substantia nigra 'critical zone' lesions which include but extend beyond the 'critical zone' do not demonstrate the recovery. In these cats, subsequent transection of the commissure of the superior colliculus does lead to the recovery. We hypothesize that another projection through the caudal commissure of the superior colliculus, from the pedunculopontine nucleus, is involved in the recovery effect. Visual orienting behavior was recorded before and after ibotenic acid lesions made in the pedunculopontine nucleus region contralateral to a visual cortical ablation in 16 cats. Four cats with lesions in a small rostral region of the contralateral pedunculopontine nucleus recovered the visual orienting response in the previously hemianopic visual field. Contralateral tectal projections from the pedunculopontine nucleus are thought to be cholinergic and terminate as distinct patches in the intermediate gray layers of the superior colliculus. Since this region of the pedunculopontine nucleus also receives GABA-ergic afferents from the substantia nigra, we propose that a subcortical neural circuit including the substantia nigra, pedunculopontine nucleus, and superior colliculus is involved in the recovery of visual orienting.

Mapping of functional activity in brain with 18F-fluoro-deoxyglucose.

The efficacy of using the 18F-fluoro-deoxyglucose (18F-DG) for measuring regional cerebral glucose utilization in man during functional activation is demonstrated. Normal male volunteers subjected to sensory stimuli (visual, auditory, tactile) exhibited focal increases in glucose metabolism in response to the stimulus. Unilateral visual hemifield stimulation caused the contralateral striate cortex to become more active metabolically than the striate cortex ipsilateral to the stimulated hemifield. Similarly, stroking of the fingers and hand of one arm with a brush produced an increase in metabolism in the contralateral postcentral gyrus compared to the homologous ipsilateral region. The auditory stimulus, which consisted of monaural listening to either a meaningful or nonmeaningful story, caused an increase in glucose metabolism in the right temporal cortex independent of which ear was stimulated. These results demonstrate that the 18F-DG technique is capable of providing functional maps in vivo in the human brain.

Ibotenic acid lesions of the superior colliculus produce longer lasting deficits in visual orienting behavior than aspiration lesions in the cat.

We compared the effects of unilateral surgical aspiration and ibotenic acid produced lesions of the superior colliculus (SC) on visual orienting behavior in 20 cats. Four animals with aspiration lesions initially showed an hemianopia in the contralateral hemifield which recovered fully in 4.5 weeks or less. These lesions also destroyed axons in the commissure of the superior colliculus (CS). In 9 animals we produced complete loss of cells in one SC, with preservation of axons in the CSC, by injections of ibotenic acid. In these animals the contralateral hemianopia persisted for an average of 16.6 weeks, but may have persisted longer had we not intervened by either sacrificing the animal or ablating the visual cortex contralateral to the SC lesion. The cortical lesion produced an immediate hemianopia in the contralateral hemifield and a recovery in the previously hemianopic ('collicular') hemifield. In the remaining 7 animals with attempted ibotenic acid lesions, 5 had incomplete lesions and 2 others sustained major damage to the SC as well as the CSC. These 7 animals recovered visual orienting on an average of 3.0 weeks postoperatively. We conclude that unilateral loss of collicular cell function and the presence of fibers coursing through the commissure of the superior colliculus are both necessary for the prolonged deficit in visual orienting behavior. We suggest that competition between the two hemifields may play a role in the hemianopia caused by collicular manipulations and that the cholinergic pathway from the pedunculopontine nucleus to the contralateral SC via the CSC may be involved.

The spatial relationship between the cerebral cortex and fiber trajectory through the corpus callosum of the cat.

We related fiber trajectory through the feline corpus callosum to the site of fiber origin in the cortical mantle and to functional modality. The cortical fields which contribute axons to the different portions of the corpus callosum were revealed by applying horseradish peroxidase (HRP) to the cut ends of selected groups of callosal axons in twelve adult cats. Overall, the application of HRP at progressively more caudal positions in the corpus callosum labels fields of neurons at successively more caudal positions in the cerebral cortex. Comparison of these data to functionally distinct cortical zones shows that the callosal body conveys a mixture of fibers arising from functionally diverse regions of the cerebrum, whereas portions of the rostral and caudal ends appear to be essentially unimodal, conveying motor and visual signals, respectively.

Efferent projections of the thalamic intralaminar nuclei in the cat.

Efferent projections of the central lateral (CL), paracentral (PC) and central medial (CE) intralaminar nuclei (ILN) to cortical and subcortical sites were studied in the cat. The combined methods of electrophysiologically guided cortical injections of tritiated leucine and stereotaxic injections of horseradish peroxidase (HRP) into the CL and PC nuclei were utilized. Additionally, fluorescent double-labeling techniques demonstrated patterns of intralaminar axon collateralization. We found that the ILN project ipsilaterally to all visual cortical areas except area 17. Projections to visual cortex are not arranged topographically or retinotopically. The ILN also project to the frontal eye fields (areas 6 and 8), anterior cingulate gyrus, suprasylvian fringe of the auditory cortex, insular cortex, parietal areas 5 and 7, caudate nucleus and claustrum. We noted especially heavy projections to the frontal eye fields and parietal areas 5 and 7. Fibers from the ILN terminate in cortical layers I and VI, and at the layer III-IV border. The demonstration of collateralization of ILN axons to two separate cortical areas implies that the same neuronal message may pass from the ILN to multiple cortical areas. It is concluded that the ILN may mediate a general cortical activation and may play a role in attention to visual, auditory and somatosensory (especially nociceptive) stimuli.

Afferent connections of the thalamic intralaminar nuclei in the cat.

Afferents to the central lateral (CL), paracentral (PC) and central medial (CE) intralaminar nuclei (ILN) from cortical and subcortical sites were studied in the cat. We utilized stereotaxically guided injections of HRP into the CL and PC nuclei and tritiated leucine injections into various visual, parietal and limbic areas of cortex to demonstrate these connections. In studying the relatively weak visual cortical projections to the ILN, we demonstrated projections from areas 19, 20a, 21a, 21b, AMLS, PMLS and PLLS. However, our HRP injections into the ILN often revealed only a few labeled cells in any of the above areas; therefore conclusions regarding the absence of projections to ILN from remaining visual cortical areas should be made cautiously. The ILN receive heavier projections from the frontal eye fields, cingulate cortex, splenial cortex, insular cortex, somatosensory areas SI and SII, auditory areas SF, AII, and Ep, and parietal areas 5 and 7. The most robust projections appear to be from from frontal eye fields, cingulate and parietal areas. No topography was apparent in the projections to the ILN. All cortical projections originate ipsilaterally from layers V and VI. Heavy subcortical projections to the ILN originate in the pretectum, superior colliculus, reticular formation, and periaqueductal grey. Fewer afferents arise from several other brainstem and thalamic nuclei.

The projections of single thalamic neurons onto multiple visual cortical areas in the cat.

Fluorescent dyes Fast Blue and Nuclear Yellow injected into pairs of visual cortical and parietal 'association' cortical areas in the cat revealed the presence of retrogradely double-labeled cells in the intralaminar nuclei and lateral posterior-pulvinar complex of the thalamus. These results demonstrate the projection of individual thalamic neurons onto multiple cortical areas.