Orbitofrontal involvement in the processing of unpleasant auditory information

Although little is known about the contribution of the orbitofrontal cortex to the processing of new information in man, lesion studies in monkeys have suggested that it plays a critical role. The present study investigated changes in cerebral blood flow with positron emission tomography in normal human subjects during exposure to unpleasant auditory stimuli. The results indicated that the caudal orbitofrontal cortex, area 13, which is powerfully linked to the medial temporal limbic region and is involved in the regulation of autonomic responses, is a key part of the frontal cortex responding in the face of unpleasant incoming information.     

fMRI of neuronal activation with symptom provocation in unmedicated patients with obsessive compulsive disorder

BACKGROUND: Previous studies suggest that a neural circuit involving over-activation of cortical, paralimbic, limbic, and striatal structures may underlie OCD symptomatology, but results may have been limited by medication use in those studies. To address this, we examined the effects of symptom induction on fMRI neural activation in medication-free patients with OCD. METHODS: Seven outpatients with OCD were exposed to individually tailored provocative and innocuous stimuli during fMRI scans. Self-ratings of OCD symptoms were performed prior to each scan and after exposure to stimuli. Images were analyzed as composite data sets and individually. RESULTS: Stimulus presentation was associated with significant increases in OCD self-ratings. Significant activation was demonstrated in several regions of the frontal cortex (orbitofrontal, superior frontal, and the dorsolateral prefrontal); the anterior, medial and lateral temporal cortex; and the right anterior cingulate. Right superior frontal activation inversely correlated with baseline compulsion symptomatology and left orbitofrontal cortical activation was inversely associated with changes in OCD self-ratings following provocative stimuli. CONCLUSIONS: These results in unmedicated patients are consistent with those from previous studies with medicated patients and suggest that OCD symptomatology is mediated by multiple brain regions including the anterior cingulate as well as frontal and temporal brain regions.     

Separate brain regions code for salience vs. valence during reward prediction in humans

Predicting rewards and avoiding aversive conditions is essential for survival. Recent studies using computational models of reward prediction implicate the ventral striatum in appetitive rewards. Whether the same system mediates an organism's response to aversive conditions is unclear. We examined the question using fMRI blood oxygen level-dependent measurements while healthy volunteers were conditioned using appetitive and aversive stimuli. The temporal difference learning algorithm was used to estimate reward prediction error. Activations in the ventral striatum were robustly correlated with prediction error, regardless of the valence of the stimuli, suggesting that the ventral striatum processes salience prediction error. In contrast, the orbitofrontal cortex and anterior insula coded for the differential valence of appetitive/aversive stimuli. Given its location at the interface of limbic and motor regions, the ventral striatum may be critical in learning about motivationally salient stimuli, regardless of valence, and using that information to bias selection of actions.     

The effect of graded aversive stimuli on limbic and visual activation

Activation studies have shown that in response to evocative visual stimuli, brain activity increases in the visual cortex and limbic areas. However, non-affective characteristics of these images, such as color composition and visual complexity, confound the interpretation of these results. To address this issue, we had subjects rate over 100 images on aversive intensity (facial mutilation, dead bodies) and semantic complexity (number of objects subjects could name). From these images, we assembled digitized image sets of non-aversive, mild and strong intensity, balanced on semantic complexity and content (human faces and figures), and adjusted for color composition. A fourth condition consisted of a fixation cross on a blank screen. Thirteen subjects underwent eight positron emission tomography scans using the [(15)O] water methodology. Measurement of skin conductance was recorded simultaneously. All picture conditions, relative to the blank screen, activated the amygdalae and bilateral orbitofrontal cortex, while we found activation trends associated with increasing aversive content in the sub-lenticular region. Skin conductance increased during all picture conditions. Relative to the non-aversive pictures, aversive image content caused modulation of occipital and occipital-temporal cortex. These results demonstrated activation of the amygdala to salient, arousing stimuli, and not just aversive stimuli. In addition, they suggest that pictorial complexity, as indexed by our semantic measure, does not account for the modulation of visual cortex by aversive, emotional stimuli.     

Greater orbitofrontal activity predicts better memory for faces

Having demonstrated recently that the orbitofrontal cortex is selectively involved when novel abstract visual information is encoded, we investigated whether the same orbitofrontal area would be activated during the encoding of novel human faces. The present positron emission tomography study demonstrated that area 11 in the right orbitofrontal region, which is directly linked to the medial temporal lobe, is a critical frontal area selectively activated when normal human subjects are engaged in encoding visually presented faces. Furthermore, better face recognition performance correlated with greater cerebral blood flow specifically in this orbitofrontal area.     

Brain activation in PTSD in response to trauma-related stimuli.

BACKGROUND: Repetitive recall of traumatic memories and chronic intermittent hyperarousal are characteristic of posttraumatic stress disorder (PTSD). Hyperarousal and memory dysfunction implicates "limbic" brain regions, including the amygdaloid complex, hippocampal formation, and limbic cortex, such as the orbitofrontal and anterior cingulate areas. To investigate the neurobiologic role of these brain regions in PTSD, we measured regional cerebral blood flow in PTSD with single photon emission computerized tomography (SPECT) during a symptom provocation paradigm. METHODS: Fourteen Vietnam veterans with PTSD, 11 combat control subjects, and 14 normal control subjects were studied with [99mTc]HMPAO in two sessions 48 hours apart: one session after exposure to white noise and the other following exposure to combat sounds. Skin conductance, heart rate, and subjective experience were recorded at the time of the studies. RESULTS: Activation for all three groups occurred in the anterior cingulate/middle prefrontal gyrus. Activation in the region of the left amygdala/nucleus accumbens was found in PTSD patients only. Deactivation was found in all three groups in the left retrosplenial region. CONCLUSIONS: These findings implicate regions of the "limbic" brain, which may mediate the response to aversive stimuli in healthy individuals and in patients suffering from PTSD.     

Medial temporal and prefrontal contributions to working memory tasks with novel and familiar stimuli.

Lesions of parahippocampal structures impair performance of delayed matching tasks in nonhuman primates, suggesting a role for these structures in the maintenance of items in working memory and short-term stimulus matching. However, most human functional imaging studies have not shown medial temporal activation during working memory tasks and have primarily focused on functional magnetic resonance imaging (fMRI) signal intensity changes in the prefrontal and posterior parietal cortex. The goal of this study was to test the hypothesis that the difference between the human and nonhuman primate data results from the use of highly familiar stimuli in human working memory studies and trial-unique stimuli in nonhuman primate studies. We used fMRI to examine prefrontal and temporal lobe activation during performance of a working memory (two-back) task, using blocks of novel and highly familiar complex pictures. Performance of the working memory task with novel complex pictures resulted in greater signal change within medial temporal lobe structures than performance of the task with familiar complex pictures. In contrast, the working memory task with highly familiar stimuli resulted in greater prefrontal activation. These results are consistent without hypothesis that the medial temporal lobe is recruited for the short-term maintenance of information that has no prior representation in the brain, whereas the prefrontal cortex is important for monitoring familiar stimuli that have a high degree of interference. A second set of tasks examined stimulus matching. Subjects performed a target-matching task, during which they identified a single target presented in blocks of novel or familiar stimuli. The results provide evidence of hippocampal and parahippocampal recruitment in the target-matching task with familiar stimuli. These results are consistent with prior animal studies and suggest that prefrontal regions may be important for the monitoring and matching of familiar stimuli which have a high potential for interference, whereas medial temporal regions may become proportionally more important for matching and maintenance of novel stimuli.     

Neural inputs into the temporopolar cortex of the rhesus monkey

Temporopolar cortex (TP) can be subdivided into agranular, dysgranular, and granular components. The telencephalic input into the temporopolar cortex arises from the orbitofrontal and medial frontal regions, modality-specific visual and auditory association areas, paralimbic regions, the piriform olfactory cortex, the hippocampus, the amygdala, the claustrum, and the basal forebrain. Afferents from limbic and paralimbic regions are directed mostly to the agranular and dysgranular sectors of the temporal pole, whereas afferents from isocortical association areas are distributed predominantly within the granular sector. The temporopolar cortex provides a site for the potential convergence of sensory and limbic inputs. Auditory inputs predominate in the dorsolateral part of the temporopolar cortex whereas visual inputs become prominent only in the ventral portions of this region. Olfactory inputs are directed mostly to the medial parts of the temporal pole. These medial parts also receive more extensive projections from the amygdaloid nuclei.     

Attending to and remembering tactile stimuli: a review of brain imaging data and single-neuron responses.

Clinical and neuroimaging observations of the cortical network implicated in tactile attention have identified foci in parietal somatosensory, posterior parietal, and superior frontal locations. Tasks involving intentional hand-arm movements activate similar or nearby parietal and frontal foci. Visual spatial attention tasks and deliberate visuomotor behavior also activate overlapping posterior parietal and frontal foci. Studies in the visual and somatosensory systems thus support a proposal that attention to the spatial location of an object engages cortical regions responsible for the same coordinate referents used for guiding purposeful motor behavior. Tactile attention also biases processing in the somatosensory cortex through amplification of responses to relevant features of selected stimuli. Psychophysical studies demonstrate retention gradients for tactile stimuli like those reported for visual and auditory stimuli, and suggest analogous neural mechanisms for working memory across modalities. Neuroimaging studies in humans using memory tasks, and anatomic studies in monkeys support the idea that tactile information relayed from the somatosensory cortex is directed ventrally through the insula to the frontal cortex for short-term retention and to structures of the medial temporal lobe for long-term encoding. At the level of single neurons, tactile (such as visual and auditory) short-term memory appears as a persistent response during delay intervals between sampled stimuli.     

Neural correlates of memory for items and for associations: an event-related functional magnetic resonance imaging study

Although results from cognitive psychology, neuropsychology, and behavioral neuroscience clearly suggest that item and associative information in memory rely on partly different brain regions, little is known concerning the differences and similarities that exist between these two types of information as a function of memory stage (i.e., encoding and retrieval). We used event-related functional magnetic resonance imaging to assess neural correlates of item and associative encoding and retrieval of simple images in 18 healthy subjects. During encoding, subjects memorized items and pairs. During retrieval, subjects made item recognition judgments (old vs. new) and associative recognition judgments (intact vs. rearranged). Relative to baseline, item and associative trials activated bilateral medial temporal and prefrontal regions during both encoding and retrieval. Direct contrasts were then performed between item and associative trials for each memory stage. During en- coding, greater prefrontal, hippocampal, and parietal activation was observed for associations, but no significant activation was observed for items at the selected threshold. During recognition, greater activation was observed for associative trials in the left dorsolateral prefrontal cortex and superior parietal lobules bilaterally, whereas item recognition trials showed greater activation of bilateral frontal regions, bilateral anterior medial temporal areas, and the right temporo-parietal junction. Post hoc analyses suggested that the anterior medial temporal activation observed during item recognition was driven mainly by new items, confirming a role for this structure in novelty detection. These results suggest that although some structures such as the medial temporal and prefrontal cortex play a general role in memory, the pattern of activation in these regions can be modulated by the type of information (items or associations) interacting with memory stages.     

Real-time fMRI of cortico-limbic brain activity during emotional processing

The ability to detect dynamic changes in brain activity during affective processing within individual subjects in real-time can advance our understanding of the neural mechanisms of emotion, psychiatric illness, and therapeutic intervention. We investigated whether activity in limbic and paralimbic regions elicited by blocks of aversive (AV) and neutral (NEU) pictures can be detected by real-time fMRI. Real-time analysis of signal change during each block revealed that activations in insula and medial frontal cortex were more frequent during AV than NEU epochs. Single subject and group analysis off-line with conventional statistical parametric mapping methods matched the results obtained in real-time. Detecting cortico-limbic brain activation during perception and experience of emotionally salient visual stimuli with real-time fMRI technology is feasible.     

Frontotemporal interactions in face encoding and recognition.

Cognition may result from different patterns of neural interactions distributed across the brain. If this is true then across different cognitive tasks different functional interactions should be observed within an anatomical network. To investigate this hypothesis, a network analysis of PET data obtained from a face memory study was conducted. PET scans were obtained while subjects performed face perception, face encoding and face recognition tasks. Partial least squares (PLS) analysis of rCBF was used to identify brain regions that were engaged during these tasks, and anatomically based structural equation modeling (SEM) was used to construct functional models for matching, encoding and recognition. There was some overlap in the functional interactions observed across the three cognitive tasks. In all three tasks, there were positive interactions involving the left occipitotemporal regions. These interactions may represent the perceptual component of the three tasks. Task-specific functional interactions were also observed. During face encoding, there was a bilateral positive influence of occipitotemporal regions on medial temporal regions. In addition, there were positive interhemispheric interactions between middle temporal regions and between limbic regions during encoding. These patterns may reflect the participation of medial temporal cortex in the formation of new memories. In the face recognition task, there was a positive loop in the right hemisphere from occipital cortex to frontal cortex and back from frontal cortex to occipitotemporal cortex. In addition, there was a strong positive input into the right hippocampal region from right occipitotemporal cortex. This pattern of interaction was specific to the recognition task and might represent the process whereby the input faces are compared to the internal representation laid down during encoding, thus enabling recognition.     

A functional anatomic study of emotion in schizophrenia

Using salient pictures with aversive (AV) and non-aversive (NA) content, we probed limbic-emotional function in schizophrenia, testing specific hypotheses that the amygdala would exhibit abnormal activity and a relationship with positive symptoms. Fourteen schizophrenic patients and 13 healthy comparison subjects viewed pictures during [15O] water positron emission tomography (PET). Both groups reported identical subjective experience of the aversive stimuli and both activated right insula (AV-NA). The schizophrenic group showed greater activation of the medial prefrontal cortex (MPFC) for the AV-NA comparison. Control subjects activated bilateral amygdaloid and orbitofrontal regions for NA relative to a blank condition (simple visual fixation, BL), whereas schizophrenic subjects only activated left orbitofrontal cortex. Activity in the left amygdala correlated with positive symptoms in the patients. Both groups activated visual cortex, and the schizophrenic subjects exhibited less modulation throughout visual cortex for NA-BL, as well as more focused deficits in the left fusiform and left mid-occipital gyrus for AV-NA, possibly related to decreased eye movements in the schizophrenic patients. Overall, the data are consistent with a general failure to process salient stimuli in schizophrenia, and the findings support the involvement of the amygdala in the positive symptoms of schizophrenia.     

Neurobiologic processes in drug reward and addiction

Neurophysiologic processes underlie the uncontrolled, compulsive behaviors defining the addicted state. These"hard-wired"changes in the brain are considered critical for the transition from casual to addictive drug use. This review of preclinical and clinical (primarily neuroimaging) studies will describe how the delineation between pleasure, reward, and addiction has evolved as our understanding of the biologic mechanisms underlying these processes has progressed. Although the mesolimbic dopaminergic efflux associated with drug reward was previously considered the biologic equivalent of pleasure, dopaminergic activation occurs in the presence of unexpected and novel stimuli (either pleasurable or aversive) and appears to determine the motivational state of wanting or expectation. The persistent release of dopamine during chronic drug use progressively recruits limbic brain regions and the prefrontal cortex, embedding drug cues into the amygdala (through glutaminergic mechanisms) and involving the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex in the obsessive craving for drugs. The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug, contextual drug cues, craving, or stress, with each process defined by a relatively distinct brain region or neural pathway. The compulsive drive toward drug use is complemented by deficits in impulse control and decision making, which are also mediated by the orbitofrontal cortex and anterior cingulate. Within this framework, future targets for pharmacologic treatment are suggested.     

Parametric fMRI analysis of visual encoding in the human medial temporal lobe

A number of functional brain imaging studies indicate that the medial temporal lobe system is crucially involved in encoding new information into memory. However, most studies were based on differences in brain activity between encoding of familiar vs. novel stimuli. To further study the underlying cognitive processes, we applied a parametric design of encoding. Seven healthy subjects were instructed to encode complex color pictures into memory. Stimuli were presented in a parametric fashion at different rates, thus representing different loads of encoding. Functional magnetic resonance imaging (fMRI) was used to assess changes in brain activation. To determine the number of pictures successfully stored into memory, recognition scores were determined afterwards. During encoding, brain activation occurred in the medial temporal lobe, comparable to the results obtained by others. Increasing the encoding load resulted in an increase in the number of successfully stored items. This was reflected in a significant increase in brain activation in the left lingual gyrus, in the left and right parahippocampal gyrus, and in the right inferior frontal gyrus. This study shows that fMRI can detect changes in brain activation during variation of one aspect of higher cognitive tasks. Further, it strongly supports the notion that the human medial temporal lobe is involved in encoding novel visual information into memory.     

Taste-olfactory convergence, and the representation of the pleasantness of flavour, in the human brain

The functional architecture of the central taste and olfactory systems in primates provides evidence that the convergence of taste and smell information onto single neurons is realized in the caudal orbitofrontal cortex (and immediately adjacent agranular insula). These higher-order association cortical areas thus support flavour processing. Much less is known, however, about homologous regions in the human cortex, or how taste-odour interactions, and thus flavour perception, are implemented in the human brain. We performed an event-related fMRI study to investigate where in the human brain these interactions between taste and odour stimuli (administered retronasally) may be realized. The brain regions that were activated by both taste and smell included parts of the caudal orbitofrontal cortex, amygdala, insular cortex and adjoining areas, and anterior cingulate cortex. It was shown that a small part of the anterior (putatively agranular) insula responds to unimodal taste and to unimodal olfactory stimuli, and that a part of the anterior frontal operculum is a unimodal taste area (putatively primary taste cortex) not activated by olfactory stimuli. Activations to combined olfactory and taste stimuli where there was little or no activation to either alone (providing positive evidence for interactions between the olfactory and taste inputs) were found in a lateral anterior part of the orbitofrontal cortex. Correlations with consonance ratings for the smell and taste combinations, and for their pleasantness, were found in a medial anterior part of the orbitofrontal cortex. These results provide evidence on the neural substrate for the convergence of taste and olfactory stimuli to produce flavour in humans, and where the pleasantness of flavour is represented in the human brain.     

Functional connectivity with the hippocampus during successful memory formation

Although it is well established that the hippocampus is critical for episodic memory, little is known about how the hippocampus interacts with cortical regions during successful memory formation. Here, we used event-related functional magnetic resonance imaging (fMRI) to identify areas that exhibited differential functional connectivity with the hippocampus during processing of novel objects that were subsequently remembered or forgotten on a postscan test. Functional connectivity with the hippocampus was enhanced during successful, as compared with unsuccessful, memory formation, in a distributed network of limbic cortical areas-including perirhinal, orbitofrontal, and retrosplenial/posterior cingulate cortex-that are anatomically connected with the hippocampal formation. Increased connectivity was also observed in lateral temporal, medial parietal, and medial occipital cortex. These findings demonstrate that successful memory formation is associated with transient increases in cortico-hippocampal interaction.     

Brain areas activated by uncertain reward-based decision-making in healthy volunteers

Reward-based decision-making has been found to activate several brain areas, including the ven- trolateral prefronta~ lobe, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and mesolimbic dopaminergic system. In this study, we observed brain areas activated under three de- grees of uncertainty in a reward-based decision-making task （certain, risky, and ambiguous）. The tasks were presented using a brain function audiovisual stimulation system. We conducted brain scans of 15 healthy volunteers using a 3.0T magnetic resonance scanner. We used SPM8 to ana- lyze the location and intensity of activation during the reward-based decision-making task, with re- spect to the three conditions. We found that the orbitofrontal cortex was activated in the certain reward condition, while the prefrontal cortex, precentral gyrus, occipital visual cortex, inferior parietal lobe, cerebellar posterior lobe, middle temporal gyrus, inferior temporal gyrus, limbic lobe, and midbrain were activated during the ＇risk＇ condition. The prefrontal cortex, temporal pole, inferior temporal gyrus, occipital visual cortex, and cerebellar posterior lobe were activated during am- biguous decision-making. The ventrolateral prefrontal lobe, frontal pole of the prefrontal lobe, orbi- tofrontal cortex, precentral gyrus, inferior temporal gyrus, fusiform gyrus, supramarginal gyrus, infe- rior parietal Iobule, and cerebellar posterior lobe exhibited greater activation in the ＇risk＇ than in the ＇certain＇ condition （P 〈 0.05）. The frontal pole and dorsolateral region of the prefrontal lobe, as well as the cerebellar posterior lobe, showed significantly greater activation in the ＇ambiguous＇ condition compared to the ＇risk＇ condition （P 〈 0.05）. The prefrontal lobe, occipital lobe, parietal lobe, temporal lobe, limbic lobe, midbrain, and posterior lobe of the cerebellum were activated during deci- sion-making about uncertain rewards. Thus, we observed different levels and regions of activation for different types of reward processing during decision-making. Specifically, when the degree of reward uncertainty increased, the number of activated brain areas increased, including greater ac- tivation of brain areas associated with loss.     

Impact of signal-to-noise on functional MRI of the human amygdala.

The impact of signal-to-noise (SNR) on fMRI of the amygdala was investigated during a picture encoding task. The SNR value required to observe reliable activation was determined by computer simulations. Blood oxygen level-dependent (BOLD) sensitivity maps were generated to indicate brain regions with sufficient SNR to test the statistical hypotheses. The results showed that the medial aspect of the amygdala had insufficient SNR to detect a 1% peak BOLD signal change for a t-test comparison in a majority of subjects. None of these subjects showed activation in regions with unacceptable SNR values, indicating a low false positive rate. Furthermore, hemispheric asymmetries in the BOLD sensitivity maps mirrored asymmetries in the activation patterns. Impoverished SNR was also found in the basal forebrain and orbitofrontal cortex. These findings emphasize the importance of considering SNR when interpreting fMRI results in the limbic forebrain.