Weight loss during chronic, cervical vagus nerve stimulation in depressed patients with obesity: an observation.

Fourteen patients were treated over 2 years with cervical vagus nerve stimulation (VNS) for adjunctive therapy of severe, treatment-resistant depression. Here, we report the serendipitous observation that this treatment was associated with highly significant, gradual weight loss despite the patients' report of not dieting or exercising. The weight loss was proportional to the initial BMI, that is, the more severe the obesity, the greater the weight loss. Weight loss did not correlate with changes in mood symptoms. The vagus nerve carries visceral information to and from the brain; modulation of its activity may alter eating behavior. Chronic cervical VNS may merit controlled study for the treatment of severe obesity.

Sex-related differences in amygdala functional connectivity during resting conditions.

Recent neuroimaging studies have established a sex-related hemispheric lateralization of amygdala involvement in memory for emotionally arousing material. Here, we examine the possibility that sex-related differences in amygdala involvement in memory for emotional material develop from differential patterns of amygdala functional connectivity evident in the resting brain. Seed voxel partial least square analyses of regional cerebral blood flow data revealed significant sex-related differences in amygdala functional connectivity during resting conditions. The right amygdala was associated with greater functional connectivity in men than in women. In contrast, the left amygdala was associated with greater functional connectivity in women than in men. Furthermore, the regions displaying stronger functional connectivity with the right amygdala in males (sensorimotor cortex, striatum, pulvinar) differed from those displaying stronger functional connectivity with the left amygdala in females (subgenual cortex, hypothalamus). These differences in functional connectivity at rest may link to sex-related differences in medical and psychiatric disorders.

Object and spatial alternation tasks with minimal delays activate the right anterior hippocampus proper in humans.

Substantial evidence indicates that the hippocampus plays a critical role in long-term declarative memory. In contrast, the role of the human hippocampus in working memory, particularly when information needs to be maintained only for a few seconds, remains controversial. Using PET, we show robust activation of the right anterior hippocampus proper during the performance of both object and spatial alternation tasks. Hippocampal activation emerged even though subjects only had to remember a single, simple stimulus over a minimum delay of 1 s. No hippocampal activation occurred when the delay was increased to 5 s. This suggests that the role of the hippocampus in working memory is not to maintain information across a delay interval. Instead, its activity reflects a more transient function during encoding and/or retrieval. These data are among the first observations to demonstrate human hippocampal involvement in working memory.

Organization of working memory within the human prefrontal cortex: a PET study of self-ordered object working memory.

The prefrontal cortex plays a critical role in working memory, the active maintenance of information for brief periods of time for guiding future motor and cognitive processes. Two competing models have emerged to account for the growing human and non-human primate literature examining the functional neuroanatomy of working memory. One theory holds that the lateral frontal cortex plays a domain-specific role in working memory with the dorsolateral and ventrolateral cortical regions supporting working memory for spatial and non-spatial material, respectively. Alternatively, the lateral frontal cortex may play a process-specific role with the more dorsal regions becoming recruited whenever active manipulation or monitoring of information in working memory becomes necessary. Many working memory tasks do not allow for direct tests of these competing models. The present study used a novel self-ordered working memory task and positron emission tomography to identify whether dorsal or ventral lateral cortical areas are recruited during a working memory task that required extensive monitoring of non-spatial information held within working memory. We observed increased blood flow in the right dorsolateral, but not ventrolateral, prefrontal cortex. Increases in blood flow in the dorsolateral region correlated strongly with task performance. Thus, the results support the process-specific hypothesis.

Genetic and state variables of neurocognitive dysfunction in schizophrenia: a twin study.

To characterize the familiality of cognitive dysfunction in schizophrenia, we studied performance on three tasks (visuospatial attention; visuolinguistic conflict, arrow-word; and Wisconsin Card Sorting Test [WCST]) by monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia. The subject sample consisted of six MZ twin pairs, nine DZ twin pairs, and one MZ and one DZ nonschizophrenia cotwin of a patient with schizophrenia. There were two sources of cognitive dysfunction: a nonheritable, state component and a heritable, trait component. Deficits surfaced during the WCST in nonschizophrenia MZ cotwins; this impairment resolved following training in nonschizophrenia MZ cotwins, but not in the probands with schizophrenia, who performed abnormally in all tasks. The results suggest that nonheritable protective factors modulate the specific, plastic, and sometimes subtle neurocognitive deficits related to the schizophrenia genotype.

Cortical activation induced by intraoral stimulation with water in humans.

Studies of gustatory processing frequently utilize water as a control stimulus. However, the neural representations of intraoral stimulation with water have received little attention. We report a series of positron emission tomography studies involving intraoral stimulation with deionized distilled water. Attempting to taste water produced large, bilateral activations in insular, opercular, Rolandic and cerebellar cortices relative to resting with eyes closed or 'smelling' odorless air. The magnitude and volume of activation was substantially reduced when tasting water was contrasted with voluntary swallowing. This indicates that much of the activity induced by water reflects intraoral somatosensory or motor processing. Nevertheless, portions of the insula, operculum, post-central gyrus and cerebellum remained significantly activated in the contrast between 'tasting' water and swallowing. This activity appears to represent a specific neural correlate of fluid stimulation, and may reflect aspects of trigeminal, gustatory or thermal coding. These findings emphasize the large volume of cortex dedicated to intraoral processing, and highlight the importance of controlling for nongustatory factors in studies of gustation.

Functional neuroimaging of the olfactory system in humans.

Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have begun to provide unique information regarding the neural underpinnings of olfactory functioning in humans. We review the relative strengths and weaknesses of PET and fMRI techniques for studying olfaction. We then review PET and fMRI studies relating to the olfactory functions of the pyriform cortex, orbitofrontal cortex, amygdala and the entorhinal/hippocampal region. A pixelwise correlational analysis of PET data is also presented in order to clarify the relationship between blood flow in the medial temporal lobes and psychoperceptual variables.

Neuroanatomical correlates of the near response: voluntary modulation of accommodation/vergence in the human visual system.

This study identifies brain regions participating in the execution of eye movements for voluntary positive accommodation (VPA) during open-loop vergence conditions. Neuronal activity was estimated by measurement of changes in regional cerebral blood flow (rCBF) with positron emission tomography and 15O-water. Thirteen naive volunteers viewed a checkerboard pattern with their dominant right eye, while a lens interrupted the line of gaze during alternate 1.5 s intervals. Three counterbalanced tasks required central fixation and viewing of a stationary checkerboard pattern: (i) through a 0.0 diopter (D) lens; (ii) through a -5.0-D lens while avoiding volitional accommodation and permitting blur; and (iii) through a -5. 0-D lens while maintaining maximal focus. The latter required large-amplitude, high-frequency VPA. As an additional control, seven of the subjects viewed passively a digitally blurred checkerboard through a 0.0-D lens as above. Optometric measurements confirmed normal visual acuity and ability to perform the focusing task (VPA). Large-amplitude saccadic eye movements, verified absent by electro-oculography, were inhibited by central fixation. Image averaging across subjects demonstrated multifocal changes in rCBF during VPA: striate and extrastriate visual cortices; superior temporal cortices; and cerebellar cortex and vermis. Decreases in rCBF occurred in the lateral intraparietal area, prefrontal and frontal and/or supplementary eye fields. Analysis of regions of interest in the visual cortex showed systematic and appropriate task dependence of rCBF. Activations may reflect sensorimotor processing along the reflex arc of the accommodation system, while deactivations may indicate inhibition of systems participating in visual search.

A computer-controlled olfactometer for fMRI and electrophysiological studies of olfaction.

A design for an inexpensive and reliable olfactometer is presented. The design has several advantages for fMRI and electrophysiology investigators. These advantages include relatively rapid odorant rise times, computer control, multiple odor administration, and no ferrous materials near the subjects. In addition, the device is contamination resistant, and, because the air is neither warmed nor humidified, it is unlikely to become an incubator for bacteria. The olfactometer is constructed of off-the-shelf chromatography parts that require little modification.

The functional neuroanatomy of voluntary swallowing.

Swallowing is a complex physiological process involving voluntary and reflexive motor activity, sensorimotor integration, salivation, and visceral regulation. Despite the numerous processes required for normal deglutition, traditional models of the central control of swallowing only emphasize the involvement of the brainstem and the inferior precentral gyrus (IPCG). However a number of neurological disorders involving other brain regions also cause dysphagia. To determine the brain regions participating in voluntary swallowing, we assayed regional cerebral blood flow (rCBF) with positron emission tomography (PET) while healthy human subjects swallowed, performed lateral tongue movements, or rested with their eyes closed. Voluntary swallowing produced strong rCBF increases within the IPCG bilaterally, the right anterior insula/claustrum, and the left cerebellum. The maxima in these regions differed from those induced by lateral tongue movements. Swallowing also produced rCBF increases in the putamen, thalamus, and several additional cortical areas, but these foci were not as clearly distinguishable from activity arising during tongue movements. These findings indicate that swallowing involves the recruitment of a large-scale distributed neural network that includes the anterior insula and cerebellum. The distributed nature of this network helps to explain why so many neurological conditions produce dysphagia.

The role of the fusiform gyrus in successful encoding of face stimuli.

PET was used to measure regional cerebral blood flow (rCBF) while memorizing pictures of unfamiliar human faces presented one at a time (FaceMemory). Other conditions included: (1) FaceRepeat-memorization of four individual faces presented repeatedly; (2) FaceWatching-viewing passively single faces without overt memory demands; and (3) Scrambled-counting dots superimposed on pictures of scrambled faces. After each FaceMemory condition and after the final FaceWatching condition scan, recall was tested by measuring face recognition. Contrasting FaceMemory and Scrambled conditions revealed several temporal activations: right midfusiform and bilateral anterior fusiform gyri. Contrasting FaceWatching and Scrambled conditions showed bilateral activation in the temporal poles and in the anterior fusiform gyri. No hippocampal activation arose from any contrast. Region of interest analyses on the above areas showed correlations with performance: (1) only rCBF in the right midfusiform correlated positively with encoding during the FaceMemory and FaceWatching conditions; (2) in the right temporal polar cortex rCBF decreased during FaceMemory and correlated positively with performance, whereas rCBF increased during FaceWatching and correlated negatively with incidental performance; and (3) activity in the anterior fusiform gyri remained constant across the conditions of FaceMemory, FaceRepeat, FaceWatching, and Scrambled and was uncorrelated with performance. These data suggest an expanded mnemonic role for the right midfusiform in depth of processing/encoding of face information, temporal polar cortex in face perception and recognition, and anterior fusiform activity in featural visual feature processing.

Human cortical gustatory areas: a review of functional neuroimaging data.

In an effort to define human cortical gustatory areas we reviewed functional neuroimaging data for which coordinates standardized in Talairach proportional space were available. We observed a wide distribution of peaks within the insula and parietal and frontal opercula, suggesting multiple gustatory regions within this cortical area. Multiple peaks also emerged in the orbitofrontal cortex. However, only two peaks, both in the right hemisphere, were observed in the caudolateral orbitofrontal cortex, the region likely homologous to the secondary taste area described in monkeys. Overall significantly more peaks originated from the right hemisphere suggesting asymmetrical cortical representation of taste favoring the right hemisphere.

Elucidating dynamic brain interactions with across-subjects correlational analyses of positron emission tomographic data: the functional connectivity of the amygdala and orbitofrontal cortex during olfactory tasks.

Covariance analyses of positron emission tomography (PET) data are used increasingly to elucidate the functional connectivity between brain regions during different cognitive tasks. Functional connectivity may be estimated by examining the covariance between regions over time or across subjects. In functional brain-mapping studies, across-subjects covariance matrices derived from within-task (nonsubtracted) and between-task (subtracted) data characterize different, complementary aspects of functional interactions. The authors study amygdala-orbitofrontal interactions during three task conditions (aversive olfaction, odor detection, and resting with eyes closed) to illustrate the strengths and limitations of across-subjects covariance analyses based on subtracted and nonsubtracted data. This example underscores the dynamic nature of connectivity between the amygdalae and orbitofrontal cortices and highlights the importance of including data from resting conditions in covariance analyses.

Aversive gustatory stimulation activates limbic circuits in humans.

Animal studies implicate the amygdala and its connections in the recognition of aversive stimuli. A recent PET study demonstrated that the human amygdala and left orbitofrontal cortex show substantial increases in regional cerebral blood flow (rCBF) during exposure to aversive odourants. To examine if aversive gustatory stimuli similarly activate these regions, nine healthy women tasted an aversive saline solution, pure water and chocolate while rCBF was measured with PET. The aversive saline condition, when contrasted with the water condition, increased activity in the right amygdala, left anterior orbitofrontal cortex, medial thalamus, pregenual and dorsal anterior cingulate, and the right hippocampus. The right amygdala, left orbitofrontal cortex and pregenual cingulate remained significantly activated when saline was compared with chocolate. The present results indicate that the amygdala and orbitofrontal cortex respond to aversive stimuli in both the olfactory and gustatory modalities, and highlight the role of the pregenual cingulate in negative emotional processing.

4 T-fMRI study of nonspatial shifting of selective attention: cerebellar and parietal contributions.

Regional blood oxygenation in the cerebellum and posterior cerebral cortices was monitored with functional magnetic resonance imaging (fMRI) at four Tesla while 16 normal subjects performed three tasks with identical visual stimulation: fixation; attention focused upon either stimulus shape or color and sustained during blocks of trials (sustained attention); and rapid, serial shifts in attention between stimulus shape or color within blocks of trials (shifting attention). The stimuli were displayed centrally for 100 ms followed by a central fixation mark for 900 ms. Each stimulus was either a circle or a square displayed in either red or green. Attention shifting required switching between color and shape information after each target detection and occurred on average once every three seconds. Subjects pressed a response key upon detecting the target; reaction time and response accuracy were recorded. Two protocols for T2*-weighted echo-planar imaging were optimized, one with a surface coil for the cerebellum alone and the other with a volume coil for imaging both cerebellum and posterior brain structures (parietal, occipital, and part of temporal cortices). Because fMRI of the cerebellum is particularly susceptible to cardiac and respiratory fluctuations, novel techniques were applied to isolate brain activation signals from physiological noise. Functional activation maps were generated for contrasts of 1) sustained attention to color minus fixation; 2) sustained attention to shape minus fixation; and 3) shifting attention minus sustained attention (to color and shape; i.e., summed across blocks of trials). Consistent with the ease of these tasks, subjects performed with >80% accuracy during both sustained attention and shifting attention. Analysis of variance did not show significant differences in false alarms or true hits across either attentional condition. A subgroup of subjects whose performance data were recorded during ten minutes of continuous practice did not show significant changes over time. Both contrasts between the conditions of sustained attention to color or to shape as compared with the fixation condition showed significant bilateral activation in occipital and inferior temporal regions (Brodmann areas 18, 19, and 37). The anterior medial cerebellum was also significantly activated ipsilateral to the finger used for responding. The principal comparison of interest, the contrast between the condition of shifting attention and the condition of sustained attention produced significant and reproducible activation: lateral cerebellar hemisphere (ansiform lobule: Crus I Anterior and Crus I Posterior; left Crus I Posterior); cerebellar folium; posterior superior parietal lobule (R and L); and cuneus and precuneus (R and L).

PET study of the localization and laterality of lingual somatosensory processing in humans.

Regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) during four tasks in right-handed volunteers with eyes closed: resting, protruding the tongue, stroking the left side of the protruding tongue, and stroking the right side of the protruding tongue. The primary somatosensory tongue representation (S1) mapped to the contralateral central sulcus (Brodmann (BA) 3/4) at approximately 28 mm above the intercommissural plane. Of note, stimulation of the left side of the tongue produced also an ipsilateral S1 response. Analysis of variance (ANOVA) of rCBF at S1 across all four conditions yielded only a significant effect for tongue stimulation, with no effect of laterality; the usually large asymmetries (contralateral >> ipsilateral) in S1 did not surface. We hypothesize that this atypical activation pattern arises from the tongue's specialization for language.

Emotion, olfaction, and the human amygdala: amygdala activation during aversive olfactory stimulation.

Electrophysiologic and lesion studies of animals increasingly implicate the amygdala in aspects of emotional processing. Yet, the functions of the human amygdala remain poorly understood. To examine the contributions of the amygdala and other limbic and paralimbic regions to emotional processing, we exposed healthy subjects to aversive olfactory stimuli while measuring regional cerebral blood flow (rCBF) with positron emission tomography. Exposure to a highly aversive odorant produced strong rCBF increases in both amygdalae and in the left orbitofrontal cortex. Exposure to less aversive odorants produced rCBF increases in the orbitofrontal cortex but not in the amygdala. Change of rCBF within the left amygdala and the left OFC was highly intercorrelated, indicating a strong functional interaction between these brain regions. Furthermore, the activity within the left amygdala was associated significantly with subjective ratings of perceived aversiveness. These findings provide evidence that the human amygdala participates in the hedonic or emotional processing of olfactory stimuli.

Practice-related changes in human brain functional anatomy during nonmotor learning.

Practice of a novel task leads to improved performance. The brain mechanisms associated with practice-induced improvement in performance are largely unknown. To address this question we have examined the functional anatomy of the human brain with positron emission tomography (PET) during the naive and practiced performance of a simple verbal response selection task (saying an appropriate verb for a visually presented noun). As a control state, subjects were asked to repeat the visually presented nouns. Areas of the brain most active during naive performance (anterior cingulate, left prefrontal and left posterior temporal cortices, and the right cerebellar hemisphere), compared to repeating the visually presented nouns, were all significantly less active during practiced performance. These changes were accompanied by changes in the opposite direction in sylvian-insular cortex bilaterally and left medial extrastriate cortex. In effect, brief practice made the cortical circuitry used for verbal response selection indistinguishable from simple word repetition. Introduction of a novel list of words reversed the learning-related effects. These results indicate that two distinct circuits can be used for verbal response selection and normal subjects can change the brain circuits used during task performance following less than 15 min of practice. One critical factor in determining the circuitry used appears to be the degree to which a task is learned or automatic.

Neural correlates of self-induced dysphoria.

OBJECTIVE: The authors explored the question of whether acute, transient changes in mood are reflected in activation of discrete neuronal systems in the human brain. METHOD: Using positron emission tomography, they measured the regional cerebral blood flow (CBF) of seven psychiatrically healthy subjects under two conditions. During the control condition the subjects were resting with their eyes closed. During the active condition, with their eyes still closed, they were asked to imagine or recall a situation that would make them feel very sad. They were explicitly asked to experience sadness and to avoid any feelings of anger or anxiety. RESULTS: There were significant differences in regional CBF measured during the control condition and during the active condition, particularly in the inferior and orbitofrontal cortices. Women showed bilateral inferior and orbitofrontal activation, but men displayed predominantly left-sided activation in these areas. CONCLUSIONS: The authors conclude that the inferior and orbitofrontal cortices play an important role in normal emotional cognitive processes.

Does inter-subject variability in cortical functional organization increase with neural 'distance' from the periphery?

In mapping the functional anatomy of the human brain, anatomical variability is a recurring concern. The degree to which the functional organization of any one subject or group of subjects is more generally predictive is largely unknown. We have previously reported that the inter-subject variability of primary visual, somatosensory and motor cortices is small (4-8 mm). Many have suggested, however, that higher-order brain areas will be considerably more variable. For this reason we assessed the anatomical variability of several brain areas participating in language perception and production. In 10 anatomically normal subjects undergoing evaluation for partial complex epilepsy we applied a previously described battery of lexical tasks; intra-subject image averaging was used to minimize the effects of variations in response magnitude. We found inter-subject anatomical variability to be uniformly consistent, with no appreciable effect of distance from the neural periphery.