Visual avoidance in phobia: particularities in neural activity, autonomic responding, and cognitive risk evaluations.

We investigated the neural mechanisms and the autonomic and cognitive responses associated with visual avoidance behavior in spider phobia. Spider phobic and control participants imagined visiting different forest locations with the possibility of encountering spiders, snakes, or birds (neutral reference category). In each experimental trial, participants saw a picture of a forest location followed by a picture of a spider, snake, or bird, and then rated their personal risk of encountering these animals in this context, as well as their fear. The greater the visual avoidance of spiders that a phobic participant demonstrated (as measured by eye tracking), the higher were her autonomic arousal and neural activity in the amygdala, orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and precuneus at picture onset. Visual avoidance of spiders in phobics also went hand in hand with subsequently reduced cognitive risk of encounters. Control participants, in contrast, displayed a positive relationship between gaze duration toward spiders, on the one hand, and autonomic responding, as well as OFC, ACC, and precuneus activity, on the other hand. In addition, they showed reduced encounter risk estimates when they looked longer at the animal pictures. Our data are consistent with the idea that one reason for phobics to avoid phobic information may be grounded in heightened activity in the fear circuit, which signals potential threat. Because of the absence of alternative efficient regulation strategies, visual avoidance may then function to down-regulate cognitive risk evaluations for threatening information about the phobic stimuli. Control participants, in contrast, may be characterized by a different coping style, whereby paying visual attention to potentially threatening information may help them to actively down-regulate cognitive evaluations of risk.

Altered directed functional connectivity in temporal lobe epilepsy in the absence of interictal spikes: A high density EEG study.

OBJECTIVE In patients with epilepsy, seizure relapse and behavioral impairments can be observed despite the absence of interictal epileptiform discharges (IEDs). Therefore, the characterization of pathologic networks when IEDs are not present could have an important clinical value. Using Granger-causal modeling, we investigated whether directed functional connectivity was altered in electroencephalography (EEG) epochs free of IED in left and right temporal lobe epilepsy (LTLE and RTLE) compared to healthy controls. METHODS Twenty LTLE, 20 RTLE, and 20 healthy controls underwent a resting-state high-density EEG recording. Source activity was obtained for 82 regions of interest (ROIs) using an individual head model and a distributed linear inverse solution. Granger-causal modeling was applied to the source signals of all ROIs. The directed functional connectivity results were compared between groups and correlated with clinical parameters (duration of the disease, age of onset, age, and learning and mood impairments). RESULTS We found that: (1) patients had significantly reduced connectivity from regions concordant with the default-mode network; (2) there was a different network pattern in patients versus controls: the strongest connections arose from the ipsilateral hippocampus in patients and from the posterior cingulate cortex in controls; (3) longer disease duration was associated with lower driving from contralateral and ipsilateral mediolimbic regions in RTLE; (4) aging was associated with a lower driving from regions in or close to the piriform cortex only in patients; and (5) outflow from the anterior cingulate cortex was lower in patients with learning deficits or depression compared to patients without impairments and to controls. SIGNIFICANCE Resting-state network reorganization in the absence of IEDs strengthens the view of chronic and progressive network changes in TLE. These resting-state connectivity alterations could constitute an important biomarker of TLE, and hold promise for using EEG recordings without IEDs for diagnosis or prognosis of this disorder.

Structural brain correlates of defective gesture performance in schizophrenia

INTRODUCTION The neural correlates of impaired performance of gestures are currently unclear. Lesion studies showed variable involvement of the ventro-dorsal stream particularly left inferior frontal gyrus (IFG) in gesture performance on command. However, findings cannot be easily generalized as lesions may be biased by the architecture of vascular supply and involve brain areas beyond the critical region. The neuropsychiatric syndrome of schizophrenia shares apraxic-like errors and altered brain structure without macroanatomic lesions. Schizophrenia may therefore qualify as a model disorder to test neural correlates of gesture impairments. METHODS We included 45 schizophrenia patients and 44 healthy controls in the study to investigate the structural brain correlates of defective gesturing in schizophrenia using voxel based morphometry. Gestures were tested in two domains: meaningful gestures (transitive and intransitive) on verbal command and imitation of meaningless gestures. Cut-off scores were used to separate patients with deficits, patients without deficits and controls. Group differences in gray matter (GM) volume were explored in an ANCOVA. RESULTS Patients performed poorer than controls in each gesture category (p < .001). Patients with deficits in producing meaningful gestures on command had reduced GM predominantly in left IFG, with additional involvement of right insula and anterior cingulate cortex. Patients with deficits differed from patients without deficits in right insula, inferior parietal lobe (IPL) and superior temporal gyrus. CONCLUSIONS Impaired performance of meaningful gestures on command was linked to volume loss predominantly in the praxis network in schizophrenia. Thus, the behavioral similarities between apraxia and schizophrenia are paralleled by structural alterations. However, few associations between behavioral impairment and structural brain alterations appear specific to schizophrenia.

Neural systems underlying learning and representation of global motion

We demonstrate performance-related changes in cortical and cerebellar activity. The largest learning-dependent changes were observed in the anterior lateral cerebellum, where the extent and intensity of activation correlated inversely with psychophysical performance. After learning had occurred (a few minutes), the cerebellar activation almost disappeared; however, it was restored when the subjects were presented with a novel, untrained direction of motion for which psychophysical performance also reverted to chance level. Similar reductions in the extent and intensity of brain activations in relation to learning occurred in the superior colliculus, anterior cingulate, and parts of the extrastriate cortex. The motion direction-sensitive middle temporal visual complex was a notable exception, where there was an expansion of the cortical territory activated by the trained stimulus. Together, these results indicate that the learning and representation of visual motion discrimination are mediated by different, but probably interacting, neuronal subsystems.

A neuronal model of a global workspace in effortful cognitive tasks

A minimal hypothesis is proposed concerning the brain processes underlying effortful tasks. It distinguishes two main computational spaces: a unique global workspace composed of distributed and heavily interconnected neurons with long-range axons, and a set of specialized and modular perceptual, motor, memory, evaluative, and attentional processors. Workspace neurons are mobilized in effortful tasks for which the specialized processors do not suffice. They selectively mobilize or suppress, through descending connections, the contribution of specific processor neurons. In the course of task performance, workspace neurons become spontaneously coactivated, forming discrete though variable spatio-temporal patterns subject to modulation by vigilance signals and to selection by reward signals. A computer simulation of the Stroop task shows workspace activation to increase during acquisition of a novel task, effortful execution, and after errors. We outline predictions for spatio-temporal activation patterns during brain imaging, particularly about the contribution of dorsolateral prefrontal cortex and anterior cingulate to the workspace.

Prefrontal cortex and episodic memory retrieval mode

A multistudy analysis of positron emission tomography data identified three right prefrontal and two left prefrontal cortical sites, as well as a region in the anterior cingulate gyrus, where neuronal activity is correlated with the maintenance of episodic memory retrieval mode (REMO), a basic and necessary condition of remembering past experiences. The right prefrontal sites were near the frontal pole [Brodmann's area (BA) 10], frontal operculum (BA 47/45), and lateral dorsal area (BA 8/9). The two left prefrontal sites were homotopical with the right frontal pole and opercular sites. The same kinds of REMO sites were not observed in any other cerebral region. Many previous functional neuroimaging studies of episodic memory retrieval have reported activations near the frontal REMO sites identified here, although their function has not been clear. Many of these, too, probably have signaled their involvement in REMO. We propose that REMO activations largely if not entirely account for the frontal hemispheric asymmetry of retrieval as described by the original hemispheric encoding retrieval asymmetry model.

Correlation of regional cerebral blood flow and change of plasma sodium concentration during genesis and satiation of thirst

Positron emission tomography studies were conducted during genesis of moderate thirst by rapid i.v. infusion of hypertonic saline (0.51 M) and after satiation of thirst by drinking water. The correlation of regional cerebral blood flow with the change in the plasma Na concentration showed a significant group of cerebral activations in the anterior cingulate region and also a site in the middle temporal gyrus and in the periaqueductal gray. Strongest deactivations occurred in the parahippocampal and frontal gyri. The data are consistent with an important role of the anterior cingulate in the genesis of thirst.

Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease

The central nervous system (CNS) effects of mental stress in patients with coronary artery disease (CAD) are unexplored. The present study used positron emission tomography (PET) to measure brain correlates of mental stress induced by an arithmetic serial subtraction task in CAD and healthy subjects. Mental stress resulted in hyperactivation in CAD patients compared with healthy subjects in several brain areas including the left parietal cortex [angular gyrus/parallel sulcus (area 39)], left anterior cingulate (area 32), right visual association cortex (area 18), left fusiform gyrus, and cerebellum. These same regions were activated within the CAD patient group during mental stress versus control conditions. In the group of healthy subjects, activation was significant only in the left inferior frontal gyrus during mental stress compared with counting control. Decreases in blood flow also were produced by mental stress in CAD versus healthy subjects in right thalamus (lateral dorsal, lateral posterior), right superior frontal gyrus (areas 32, 24, and 10), and right middle temporal gyrus (area 21) (in the region of the auditory association cortex). Of particular interest, a subgroup of CAD patients that developed painless myocardial ischemia during mental stress had hyperactivation in the left hippocampus and inferior parietal lobule (area 40), left middle (area 10) and superior frontal gyrus (area 8), temporal pole, and visual association cortex (area 18), and a concomitant decrease in activation observed in the anterior cingulate bilaterally, right middle and superior frontal gyri, and right visual association cortex (area 18) compared with CAD patients without myocardial ischemia. These findings demonstrate an exaggerated cerebral cortical response and exaggerated asymmetry to mental stress in individuals with CAD.

Forebrain mechanisms of nociception and pain: Analysis through imaging

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

Pain perception: Is there a role for primary somatosensory cortex?

Anatomical, physiological, and lesion data implicate multiple cortical regions in the complex experience of pain. These regions include primary and secondary somatosensory cortices, anterior cingulate cortex, insular cortex, and regions of the frontal cortex. Nevertheless, the role of different cortical areas in pain processing is controversial, particularly that of primary somatosensory cortex (S1). Human brain-imaging studies do not consistently reveal pain-related activation of S1, and older studies of cortical lesions and cortical stimulation in humans did not uncover a clear role of S1 in the pain experience. Whereas studies from a number of laboratories show that S1 is activated during the presentation of noxious stimuli as well as in association with some pathological pain states, others do not report such activation. Several factors may contribute to the different results among studies. First, we have evidence demonstrating that S1 activation is highly modulated by cognitive factors that alter pain perception, including attention and previous experience. Second, the precise somatotopic organization of S1 may lead to small focal activations, which are degraded by sulcal anatomical variability when averaging data across subjects. Third, the probable mixed excitatory and inhibitory effects of nociceptive input to S1 could be disparately represented in different experimental paradigms. Finally, statistical considerations are important in interpreting negative findings in S1. We conclude that, when these factors are taken into account, the bulk of the evidence now strongly supports a prominent and highly modulated role for S1 cortex in the sensory aspects of pain, including localization and discrimination of pain intensity.

The effects of practice on the functional anatomy of task performance

The effects of practice on the functional anatomy observed in two different tasks, a verbal and a motor task, are reviewed in this paper. In the first, people practiced a verbal production task, generating an appropriate verb in response to a visually presented noun. Both practiced and unpracticed conditions utilized common regions such as visual and motor cortex. However, there was a set of regions that was affected by practice. Practice produced a shift in activity from left frontal, anterior cingulate, and right cerebellar hemisphere to activity in Sylvian-insular cortex. Similar changes were also observed in the second task, a task in a very different domain, namely the tracing of a maze. Some areas were significantly more activated during initial unskilled performance (right premotor and parietal cortex and left cerebellar hemisphere); a different region (medial frontal cortex, “supplementary motor area”) showed greater activity during skilled performance conditions. Activations were also found in regions that most likely control movement execution irrespective of skill level (e.g., primary motor cortex was related to velocity of movement). One way of interpreting these results is in a “scaffolding-storage” framework. For unskilled, effortful performance, a scaffolding set of regions is used to cope with novel task demands. Following practice, a different set of regions is used, possibly representing storage of particular associations or capabilities that allow for skilled performance. The specific regions used for scaffolding and storage appear to be task dependent.

Neuroimaging studies of word reading

This review discusses how neuroimaging can contribute to our understanding of a fundamental aspect of skilled reading: the ability to pronounce a visually presented word. One contribution of neuroimaging is that it provides a tool for localizing brain regions that are active during word reading. To assess the extent to which similar results are obtained across studies, a quantitative review of nine neuroimaging investigations of word reading was conducted. Across these studies, the results converge to reveal a set of areas active during word reading, including left-lateralized regions in occipital and occipitotemporal cortex, the left frontal operculum, bilateral regions within the cerebellum, primary motor cortex, and the superior and middle temporal cortex, and medial regions in the supplementary motor area and anterior cingulate. Beyond localization, the challenge is to use neuroimaging as a tool for understanding how reading is accomplished. Central to this challenge will be the integration of neuroimaging results with information from other methodologies. To illustrate this point, this review will highlight the importance of spelling-to-sound consistency in the transformation from orthographic (word form) to phonological (word sound) representations, and then explore results from three neuroimaging studies in which the spelling-to-sound consistency of the stimuli was deliberately varied. Emphasis is placed on the pattern of activation observed within the left frontal cortex, because the results provide an example of the issues and benefits involved in relating neuroimaging results to behavioral results in normal and brain damaged subjects, and to theoretical models of reading.

General and specific brain regions involved in encoding and retrieval of events: what, where, and when.

Remembering an event involves not only what happened, but also where and when it occurred. We measured regional cerebral blood flow by positron emission tomography during initial encoding and subsequent retrieval of item, location, and time information. Multivariate image analysis showed that left frontal brain regions were always activated during encoding, and right superior frontal regions were always activated at retrieval. Pairwise image subtraction analyses revealed information-specific activations at (i) encoding, item information in left hippocampal, location information in right parietal, and time information in left fusiform regions; and (ii) retrieval, item in right inferior frontal and temporal, location in left frontal, and time in anterior cingulate cortices. These results point to the existence of general encoding and retrieval networks of episodic memory whose operations are augmented by unique brain areas recruited for processing specific aspects of remembered events.

Estudo de alterações estruturais cerebrais em pacientes com esquizofrenia crônica e de primeiro episódio através de imagens por ressonância magnética com morfometria baseada no voxel

Introdução: Embora alterações estruturais cerebrais na esquizofrenia venham sendo repetidamente demonstradas em estudos de ressonância magnética (RM), ainda permanece incerto se tais alterações são estáticas ou progressivas. Enquanto estudos longitudinais são tradicionalmente utilizados na avaliação da questão da progressão, estudos transversais de neuroimagem comparando diretamente pacientes com esquizofrenia crônica e de primeiro episódio a controles saudáveis têm sido bastante raros até o presente. Com o recente interesse em meganálises combinando dados multicêntricos de RM visando-se a maior poder estatístico, o presente estudo multicêntrico de morfometria baseada no voxel (VBM) foi realizado para avaliar os padrões de alterações estruturais cerebrais segundo os diferentes estágios da doença, bem como para avaliar quais (se alguma) dessas alterações se correlacionariam especificamente a moderadores clínicos potenciais, tais como exposição cumulativa a antipsicóticos, tempo de doença e gravidade da doença. Métodos: Selecionou-se uma ampla amostra de pacientes com esquizofrenia (161, sendo 99 crônicos e 62 de primeiro episódio) e controles (151) a partir de quatro estudos prévios de RM (1,5T) realizados na mesma região do Brasil. O processamento e análise das imagens foi realizado usando-se o software Statistical Parametric Mapping (SPM8) com emprego do algoritmo DARTEL (diffeomorphic anatomical registration through exponentiated Lie algebra). Os efeitos de grupo sobre os volumes regionais de substância cinzenta (SC) foram analisados através de comparações voxel-a-voxel por análises de covariância em modelos lineares gerais, inserindo-se, em todas as análises, o volume total de SC, protocolo do scanner, idade e sexo como variáveis de confusão. Por fim, foram realizadas análises de correlação entre os aludidos moderadores clínicos potenciais e os volumes cerebrais globais e regionais. Resultados: Os pacientes com esquizofrenia de primeiro episódio apresentaram reduções volumétricas sutis em comparação aos controles, em um circuito neural circunscrito e identificável apenas em análises SVC (small volume correction) [p < 0.05, com correção family-wise error (FWE)], incluindo a ínsula, estruturas têmporo-límbicas e corpo estriado. Os pacientes crônicos, por outro lado, apresentaram um padrão de alterações extensas comparativamente aos controles, envolvendo os córtices frontais orbitais, superiores e inferiores bilateralmente, córtex frontal médio direito, ambos os córtices cingulados anteriores, ambas as ínsulas, e os córtices temporais superior e médio direitos (p < 0.05, análises whole-brain com correção FWE). Foram encontradas correlações negativas significantes entre exposição cumulativa a antipsicóticos e volumes globais de SC e substância branca nos pacientes com esquizofrenia, embora as correlações com reduções regionais não tenham sido significantes. Detectaram-se, ainda, correlações negativas significantes entre tempo de doença e volumes regionais relativos da ínsula esquerda, córtex cingulado anterior direito e córtices pré-frontais dorsolaterais nas análises SVC para os grupos conjuntos (esquizofrenia crônica e de primeiro episódio). Conclusão: Os achados supracitados indicam que: a) as alterações estruturais associadas com o diagnóstico de esquizofrenia são mais disseminadas na forma crônica em comparação à de primeiro episódio; b) reduções volumétricas regionais em áreas específicas do cérebro podem variar em função do tempo de doença; c) a exposição cumulativa a antipsicóticos associou-se a alterações volumétricas globais, e não regionais

A pain neuromatrix approach to patients with chronic pain

This paper presents an approach to rehabilitation of pain patients. The fundamental principles of the approach are (i) pain is an output of the brain that is produced whenever the brain concludes that body tissue is in danger and action is required, and (ii) pain is a multisystem output that is produced when an individual-specific cortical pain neuromatrix is activated. When pain becomes chronic, the efficacy of the pain neuromatrix is strengthened via nociceptive and non-nociceptive mechanisms, which means that less input, both nociceptive and non-nociceptive, is required to produce pain. The clinical approach focuses on decreasing all inputs that imply that body tissue is in danger and then on activating components of the pain neuromatrix without activating its output. Rehabilitation progresses to increase exposure to threatening input across sensory and non-sensory domains. (C) 2003 Elsevier Ltd. All rights reserved.