Human Lesion Studies Research Articles

Parsing cognition in schizophrenia using saccadic eye movements: a selective overview

Eye movements provide a behavioural measure of sensorimotor processing and higher cognitive functions of the brain. With the development of novel paradigms that can be used for the study of various cognitive operations, saccadic eye movements in particular, have become increasingly popular. Patients with schizophrenia have neurocognitive impairments that can be readily investigated with these paradigms. From animal, human lesion and neuroimaging studies, the cerebral centres underlying saccadic eye movements have been identified. The areas of the prefrontal cortex include the dorsolateral prefrontal cortex, the frontal eye fields, the supplementary eye fields, and the anterior cingulate cortex. Pathology of saccadic eye movements, therefore, provides information on the functional status of the underlying neural circuitry in brain disorders such as schizophrenia. In this paper, we evaluate: (i) methodological considerations that are central to the design and application of saccadic paradigms; (ii) brain activation that is associated with saccadic paradigms; (iii) recent findings in healthy subjects and schizophrenic patients; (iv) saccadic abnormalities in other psychiatric and neurological disorders and in individuals at risk for developing schizophrenia.

Lesions affecting the parahippocampal cortex yield spatial memory deficits in humans.

Anatomical studies in monkeys, and functional imaging and lesion studies in humans, suggest that, within the primate medial temporal neocortex, the parahippocampal cortex (PHC) is particularly involved in spatial tasks. However, evidence for a functional specialization of the PHC regarding its spatial memory functions has so far been lacking. Here, we investigated spatial memory functions of the human perirhinal cortex (PRC) and PHC. Patients with lesions affecting the PRC but sparing the PHC, and patients with lesions affecting both PRC and PHC, performed an oculomotor delayed response task with unpredictably varied memory delays of up to 30 s. Compared to controls, patients with PRC+PHC lesions showed a significant delay-dependent inaccuracy of memory-guided eye movements contralateral to the lesion side, whereas patients with PRC lesions showed no significant inaccuracy. Our results show that the PHC is a critical component for spatial memory in humans and suggest that (i) extrahippocampal spatial memory functions of the medial temporal lobe may not be equally distributed in the medial temporal neocortex, but may be largely confined to the PHC, and (ii) damage to connections between cortices involved in spatial cognition and rostral regions of the temporal lobe is unlikely to account for the observed spatial memory deficits with PHC lesions.

Dreams and sleep: Are new schemas revealing?

In this series of articles, several new hypotheses on sleep and dreaming are presented. In each case, we feel the data do not adequately support the hypothesis. In their lengthy discourse, Hobson et al. represent to us the familiar reciprocal interaction model dressed in new clothes, but expanded beyond reasonable testability. Vertes & Eastman have proposed that REM sleep is not involved in memory consolidation. However, we do not find their arguments persuasive in that limited differences in activity in REM and waking do not lend credence to the idea that memory consolidation occurs in one state and not the other. Solms makes an argument that dreams are generated from the dopaminergic forebrain based largely on pathological lesion studies in humans. We recognize that this argument has some intuitive appeal and agree with some of the tenets but we do not feel that the arguments are completely convincing due to the lack of anatomical controls, including symmetry and laterality. On the whole, there are interesting arguments put forward in these target articles but the evidence does not convince us that new vistas are opened. No Holy Grail of sleep here![Hobson et al.; Solms; Vertes & Eastman]

Neurophysiology and functional neuroanatomy of pain perception.

The traditional view that the cerebral cortex is not involved in pain processing has been abandoned during the past decades based on anatomic and physiologic investigations in animals, and lesion, functional neuroimaging, and neurophysiologic studies in humans. These studies have revealed an extensive central network associated with nociception that consistently includes the thalamus, the primary (SI) and secondary (SII) somatosensory cortices, the insula, and the anterior cingulate cortex (ACC). Anatomic and electrophysiologic data show that these cortical regions receive direct nociceptive thalamic input. From the results of human studies there is growing evidence that these different cortical structures contribute to different dimensions of pain experience. The SI cortex appears to be mainly involved in sensory-discriminative aspects of pain. The SII cortex seems to have an important role in recognition, learning, and memory of painful events. The insula has been proposed to be involved in autonomic reactions to noxious stimuli and in affective aspects of pain-related learning and memory. The ACC is closely related to pain unpleasantness and may subserve the integration of general affect, cognition, and response selection. The authors review the evidence on which the proposed relationship between cortical areas, pain-related neural activations, and components of pain perception is based.

Hemispheric preference in visuospatial processing: a complementary approach with fMRI and lesion studies.

Historically, the left cerebral hemisphere has been considered specialized for language, whereas the right cerebral hemisphere is aligned with spatial processes. However, studies have called into question adherence to this model and suggested that both hemispheres participate in language and spatial cognition. Using functional Magnetic Resonance Imaging (fMRI) and human brain lesion studies, we determined whether these complementary techniques could clarify issues of hemispheric dominance. Using a modified Benton Judgement of Line Orientation (JLO) test, considered a relatively pure spatial processing task, we found robust and significant (p < 0.0005) bilateral superior parietal lobe activation on fMRI in ten right-handed male adult volunteers. This was corroborated by lesion data in a cohort of 17 patients who showed significant JLO impairments after either right or left parietal lobe damage, with right parietal damage associated with somewhat more severe deficit. Detailed wavelet analysis of the fMRI time-series did, however, reveal a more dominant role of the right parietal lobe in "kick-starting" the task. To our knowledge, this is a novel way of using fMRI to address functional hemispheric differences in a cognitive task that is known to have bilateral representation.

Analysis of a distributed neural system involved in spatial information, novelty, and memory processing

Perceiving a complex visual scene and encoding it into memory involves a hierarchical distributed network of brain regions, most notably the hippocampus (HIPP), parahippocampal gyrus (PHG), lingual gyrus (LNG), and inferior frontal gyrus (IFG). Lesion and imaging studies in humans have suggested that these regions are involved in spatial information processing as well as novelty and memory encoding; however, the relative contributions of these regions of interest (ROIs) are poorly understood. This study investigated regional dissociations in spatial information and novelty processing in the context of memory encoding using a 2 x 2 factorial design with factors Novelty (novel vs. repeated) and Stimulus (viewing scenes with rich vs. poor spatial information). Greater activation was observed in the right than left hemisphere; however, hemispheric effects did not differ across regions, novelty, or stimulus type. Significant novelty effects were observed in all four regions. A significant ROI x Stimulus interaction was observed - spatial information processing effects were largest effects in the LNG, significant in the PHG and HIPP and nonsignificant in the IFG. Novelty processing was stimulus dependent in the LNG and stimulus independent in the PHG, HIPP, and IFG. Analysis of the profile of Novelty x Stimulus interaction across ROIs provided evidence for a hierarchical independence in novelty processing characterized by increased dissociation from spatial information processing. Despite these differences in spatial information processing, memory performance for novel scenes with rich and poor spatial information was not significantly different. Memory performance was inversely correlated with right IFG activation, suggesting the involvement of this region in strategically flawed encoding effort. Stepwise regression analysis revealed that memory encoding accounted for only a small fraction of the variance (< 16%) in medial temporal lobe activation. The implications of these results for spatial information, novelty, and memory processing in each stage of the distributed network are discussed.

Functional specificity in the right human auditory cortex for perceiving pitch direction.

Previous lesion and functional imaging studies in humans suggest a greater involvement of right rather than left auditory cortical areas in certain aspects of pitch processing. In the present study, adaptive psychophysical procedures were used to determine auditory perceptual thresholds in 14 neurologically normal subjects, and in 31 patients who had undergone surgical resection from either the right or left temporal lobe for the relief of intractable epilepsy. In a subset of the patients, the lesion encroached significantly upon the gyrus of Heschl or its underlying white matter as determined from MRI analysis. Subjects were asked to perform two different perceptual tasks on the same set of stimuli. In a pitch discrimination task, the subject had to decide whether two elements of a pure tone pair were the same or different. In a task requiring the judgement of direction of pitch change, subjects decided whether pitch rose or fell from the first tone to the second. Thresholds were determined by measuring the minimum pitch difference required for correct task performance. Mean thresholds in the pitch discrimination task did not differ between patient groups and control subjects. In contrast, patients with temporal lobe excisions that encroached upon the gyrus of Heschl in the right hemisphere (but not in the left) showed significantly elevated thresholds when judging the direction of pitch change. These findings support a specialization of function linked to right auditory cortical areas for the processing of pitch direction, and specifically suggest a dissociation between simple sensory discrimination and higher order perception.

Linguistic threat activates the human amygdala.

Studies in animals demonstrate a crucial role for the amygdala in emotional and social behavior, especially as related to fear and aggression. Whereas lesion and functional-imaging studies in humans indicate the amygdala's participation in assessing the significance of nonverbal as well as paralinguistic cues, direct evidence for its role in the emotional processing of linguistic cues is lacking. In this study, we use a modified Stroop task along with a high-sensitivity neuroimaging technique to target the neural substrate engaged specifically when processing linguistic threat. Healthy volunteer subjects were instructed to name the color of words of either threat or neutral valence, presented in different color fonts, while neural activity was measured by using H(2)(15)O positron-emission tomography. Bilateral amygdalar activation was significantly greater during color naming of threat words than during color naming of neutral words. Associated activations were also noted in sensory-evaluative and motor-planning areas of the brain. Thus, our results demonstrate the amygdala's role in the processing of danger elicited by language. In addition, the results reinforce the amygdala's role in the modulation of the perception of, and response to, emotionally salient stimuli. The current study further suggests conservation of phylogenetically older mechanisms of emotional evaluation in the context of more recently evolved linguistic function.

Neuropsychological assumptions and implications

Some of the assumptions underlying the arguments in Aggleton &amp; Brown's target article are reviewed; discrepancies/predictions are pointed out in relation to human lesion studies. A&amp;B's proposal is interesting, but it may require harder, confirmatory evidence before it can be considered to be all-encompassing.

The Human Amygdala and Emotion

Findings from humans and animals suggest that the amygdala helps to guide behaviors and to process knowledge about stimuli and situations that are of special importance to the survival of an organism. The amygdala makes critical contributions to many cognitive processes, including memory, attention, and deci sion-making. Lesion and functional imaging studies in humans support a role for the amygdala in recognizing emotions in facial expressions, especially fear. Although it has been known from animal studies that the amygdala is important in the acquisition of nondeclarative forms of memory, such as conditioned responses, studies in humans show that the amygdala also modulates encoding of declarative knowledge about emo tional material. Future studies will determine the amygdala's role in the conscious experience of emotion, a topic that is just beginning to be explored. Further advances are being made by high-resolution functional imaging, and by electrophysiological recordings from single neurons within the human amygdala. NEURO SCIENTIST 5:125-137, 1999

The New Neuropsychology of Sleep: Implications for Psychoanalysis

In his 1895 “Project for a Scientific Psychology,” Sigmund Freud clearly stated his goal: to integrate the workings of the mind with the workings of the brain. But in his day, too little neurobiology was known to make his goal attainable and he tried instead to understand such fascinating normal phenomena as dreaming in exclusively psychodynamic terms. A century later, Freud’s brilliant but entirely speculative dream theory is in need of radical revision, if not complete overhaul, because dreams, as well as other unusual states of consciousness, can finally be approached from the solid foundation of modern neuroscience. In other words, the goals of Freud’s Project are at last within our grasp. Ironically, an obstacle to progress is the tenacious adherence of orthodox psychoanalysis to a theory that even by the standards of its originator, is now clearly outmoded.In this paper, recent positron emission tomography (PET) imaging and brain lesion studies in humans are integrated with new basic research findings at the cellular level in animals to explain how the formal cognitive features of dreaming may be the combined product of a shift in the neuromodulator balance of the brain and a related redistribution of regional blood flow. The human PET data indicate a preferential activation in rapid eye movement (REM) sleep of the pontomesencephalic brainstem and of limbic and paralimbic cortical structures involved in the emotional and mnemonic aspects of cognition. The pontine brainstem mechanisms controlling the neuromodulator balance of the brain in rats and cats include noradrenergic and serotonergic influences which enhance waking and impede REM via anticholinergic mechanisms, and cholinergic mechanisms which are essential to REM sleep and only come into full play when the serotonergic and noradrenergic systems are inhibited. In REM, the brain thus becomes activated but processes its internally generated data in a manner quite different from that of waking.

Cortical regions associated with perceiving, naming, and knowing about colors.

Positron emission tomography (PET) was used to investigate whether retrieving information about a specific object attribute requires reactivation of brain areas that mediate perception of that attribute. During separate PET scans, subjects passively viewed colored and equiluminant gray-scale Mondrians, named colored and achromatic objects, named the color of colored objects, and generated color names associated with achromatic objects. Color perception was associated with activations in the lingual and fusiform gyri of the occipital lobes, consistent with previous neuroimaging and human lesion studies. Retrieving information about object color (generating color names for achromatic objects relative to naming achromatic objects) activated the left inferior temporal, left frontal, and left posterior parietal cortices, replicating previous findings from this laboratory. When subjects generated color names for achromatic objects relative to the low-level baseline of viewing gray-scale Mondrians, additional activations in the left fusiform/lateral occipital region were detected. However, these activations were lateral to the occipital regions associated with color perception and identical to occipital regions activated when subjects simply named achromatic objects relative to the same low-level baseline. This suggests that the occipital activations associated with retrieving color information were due to the perception of object form rather than to the top-down influence of brain areas that mediate color perception. Taken together, these results indicate that retrieving previously acquired information about an object's typical color does not require reactivation of brain regions that subserve color perception.

Abstract representations of numbers in the animal and human brain

There is evidence to suggest that animals, young infants and adult humans possess a biologically determined, domain-specific representation of number and of elementary arithmetic operations. Behavioral studies in infants and animals reveal number perception, discrimination and elementary calculation abilities in non-verbal organisms. Lesion and brain-imaging studies in humans indicate that a specific neural substrate, located in the left and right intraparietal area, is associated with knowledge of numbers and their relations (`number sense'). The number domain is a prime example where strong evidence points to an evolutionary endowment of abstract domain-specific knowledge in the brain because there are parallels between number processing in animals and humans. The numerical distance effect, which refers to the finding that the ability to discriminate between two numbers improves as the numerical distance between them increases, has been demonstrated in humans and animals, as has the number size effect, which refers to the finding that for equal numerical distance, discrimination of two numbers worsens as their numerical size increases.

Three-dimensional tomography of event-related potentials during response inhibition: evidence for phasic frontal lobe activation

Objectives: Spatial analysis of the evoked brain electrical fields during a cued revealed an extremely robust anteriorization of the positivity of a P300 microstate in the NoGo compared to the Go condition (NoGo-anteriorization in a prevailing study). To allow a neuroanatomical interpretation the NoGo-anteriorization was investigated with a new three-dimensional source tomography method (LORETA) was applied. Methods: The test contains subsets of stimuli requiring the execution (Go) or the inhibition (NoGo) of a cued motor response which can be considered as mutual control conditions for the study of inhibitory brain functions. 21-channel ERPs were obtained from 10 healthy subjects during a cued CPT, And analyzed with LORETA. Results: Topographic analyses revealed significantly different scalp distributions between the Go and the NoGo conditions in both P100 and P300 microstates, indicating that already at an early stage different neural assemblies are activated. LORETA disclosed a significant hyperactivity located in the right frontal lobe during the NoGo condition in the P300 microstate. Conclusions: The results indicate that right frontal sources are responsible for the NoGo-anteriorization of the scalp P300 which is consistent with animal and human lesion studies of inhibitory brain functions. Furthermore, it demonstrates that frontal activation is confined to a brief microstate and time-locked to phasic inhibitory motor control. This adds important functional and chronometric specificity to findings of frontal activation obtained with PET and Near-Infrared-Spectroscopy studies during the cued CPT, and suggests that these metabolic results are not due to general task demands.

The human amygdala in social judgment.

Studies in animals have implicated the amygdala in emotional and social behaviours, especially those related to fear and aggression. Although lesion and functional imaging studies in humans have demonstrated the amygdala's participation in recognizing emotional facial expressions, its role in human social behaviour has remained unclear. We report here our investigation into the hypothesis that the human amygdala is required for accurate social judgments of other individuals on the basis of their facial appearance. We asked three subjects with complete bilateral amygdala damage to judge faces of unfamiliar people with respect to two attributes important in real-life social encounters: approachability and trustworthiness. All three subjects judged unfamiliar individuals to be more approachable and more trustworthy than did control subjects. The impairment was most striking for faces to which normal subjects assign the most negative ratings: unapproachable and untrustworthy looking individuals. Additional investigations revealed that the impairment does not extend to judging verbal descriptions of people. The amygdala appears to be an important component of the neural systems that help retrieve socially relevant knowledge on the basis of facial appearance.

Functional neuroanatomical correlates of electrodermal activity: A positron emission tomographic study

To reveal areas in the central nervous system of importance for electrodermal control, regional cerebral blood flow (rCBF) was correlated to nonspecific skin conductance fluctuations (NSF) during aversive and nonaversive conditions. Participants viewed a TV screen displaying white noise or snake videotapes presented both with and without electric shocks given to the right hand. H2 15 O positron emission tomography was used to measure rCBF, and the constant voltage technique was used to measure NSF from the left hand. Electrodermal activity was positively related to rCBF in the left primary motor cortex (MI, Brodmann's Area 4) and bilaterally in the anterior (Areas 24 and 32) and posterior cingulate cortex (Area 23). Negative relations were observed bilaterally in the secondary visual cortex (Areas 18 and 19) and the right inferior parietal cortex (Area 39), with a tendency also for the right insular cortex (Areas 13, 15, and 16). Because results from lesion and stimulation studies in humans converge with the present imaging results, we conclude that the cingulum and the motor cortex, in addition to the parietal and possibly the insular cortex, form part of one or several distributed neural network(s) involved in electrodermal control. Because these areas also support anticipation, affect, and locomotion, electrodermal responses seem to reflect cognitively or emotionally mediated motor preparation.

Functional neuroanatomical correlates of electrodermal activity: A positron emission tomographic study

To reveal areas in the central nervous system of importance for electrodermal control, regional cerebral blood flow (rCBF) was correlated to nonspecific skin conductance fluctuations (NSF) during aversive and nonaversive conditions. Participants viewed a TV screen displaying white noise or snake videotapes presented both with and without electric shocks given to the right hand. H215O positron emission tomography was used to measure rCBF, and the constant voltage technique was used to measure NSF from the left hand. Electrodermal activity was positively related to rCBF in the left primary motor cortex (MI, Brodmann's Area 4) and bilaterally in the anterior (Areas 24 and 32) and posterior cingulate cortex (Area 23). Negative relations were observed bilaterally in the secondary visual cortex (Areas 18 and 19) and the right inferior parietal cortex (Area 39), with a tendency also for the right insular cortex (Areas 13, 15, and 16). Because results from lesion and stimulation studies in humans converge with the present imaging results, we conclude that the cingulum and the motor cortex, in addition to the parietal and possibly the insular cortex, form part of one or several distributed neural network(s) involved in electrodermal control. Because these areas also support anticipation, affect, and locomotion, electrodermal responses seem to reflect cognitively or emotionally mediated motor preparation.

The neuropsychology of REM sleep dreaming.

Recent PET imaging and brain lesion studies in humans are integrated with new basic research findings at the cellular level in animals to explain how the formal cognitive features of dreaming may be the combined product of a shift in neuromodulatory balance of the brain and a related redistribution of regional blood flow. The human PET data indicate a preferential activation in REM of the pontine brain stem and of limbic and paralimbic cortical structures involved in mediating emotion and a corresponding deactivation of dorsolateral prefrontal cortical structures involved in the executive and mnemonic aspects of cognition. The pontine brainstem mechanisms controlling the neuromodulatory balance of the brain in rats and cats include noradrenergic and serotonergic influences which enhance waking and impede REM via anticholinergic mechanisms and cholinergic mechanisms which are essential to REM sleep and only come into full play when the serotonergic and noradrenergic systems are inhibited. In REM, the brain thus becomes activated but processes its internally generated data in a manner quite different from that of waking.

A Developmental Functional MRI Study of Prefrontal Activation during Performance of a Go-No-Go Task

This study examines important developmental differences in patterns of activation in the prefrontal cortex during performance of a Go-No-Go paradigm using functional magnetic resonance imaging (fMRI). Eighteen subjects (9 children and 9 adults) were scanned using gradient echo, echo planar imaging during performance of a response inhibition task. The results suggest four general findings. First, the location of activation in the prefrontal cortex was not different between children and adults, which is similar to our earlier pediatric fMRI results of prefrontal activation during a working memory task (Casey et al., 1995). Second, the volume of activation was significantly greater for children relative to adults. These differences in volume of activation were observed predominantly in the dorsal and lateral prefrontal cortices. Third, although inhibitory processes have typically been associated with more ventral or orbital frontal regions, the current study revealed activation that was distributed across both dorsolateral and orbitofrontal cortices. Finally, consistent with animal and human lesion studies, activity in orbital frontal and anterior cingulate cortices correlated with behavioral performance (i.e., number of false alarms). These results further demonstrate the utility of this methodology in studying pediatric populations.

Environmental Knowledge Is Subserved by Separable Dorsal/Ventral Neural Areas

Environmental psychology models propose that knowledge of large-scale space is stored as distinct landmark (place appearance) and survey (place position) information. Studies of brain-damaged patients suffering from "topographical disorientation" tentatively support this proposal. In order to determine if the components of psychologically derived models of environmental representation are realized as distinct functional, neuroanatomical regions, a functional magnetic resonance imaging (fMRI) study of environmental knowledge was performed. During scanning, subjects made judgments regarding the appearance and position of familiar locations within a virtual reality environment. The fMRI data were analyzed in a manner that has been empirically demonstrated to rigorously control type I error and provide optimum sensitivity, allowing meaningful results in the single subject. A direct comparison of the survey position and landmark appearance conditions revealed a dorsal/ventral dissociation in three of four subjects. These results are discussed in the context of the observed forms of topographical disorientation and are found to be in good agreement with the human lesion studies. This experiment confirms that environmental knowledge is not represented by a unitary system but is instead functionally distributed across the neocortex.