How the harm of drugs and their availability affect brain reactions to drug cues: a meta-analysis of 64 neuroimaging activation studies.

Visual drug cues are powerful triggers of craving in drug abusers contributing to enduring addiction. According to previous qualitative reviews, the response of the orbitofrontal cortex to such cues is sensitive to whether subjects are seeking treatment. Here we re-evaluate this proposal and assessed whether the nature of the drug matters. To this end, we performed a quantitative meta-analysis of 64 neuroimaging studies on drug-cue reactivity across legal (nicotine, alcohol) or illegal substances (cocaine, heroin). We used the ALE algorithm and a hierarchical clustering analysis followed by a cluster composition statistical analysis to assess the association of brain clusters with the nature of the substance, treatment status, and their interaction. Visual drug cues activate the mesocorticolimbic system and more so in abusers of illegal substances, suggesting that the illegal substances considered induce a deeper sensitization of the reward circuitry. Treatment status had a different modulatory role for legal and illegal substance abusers in anterior cingulate and orbitofrontal areas involved in inter-temporal decision making. The class of the substance and the treatment status are crucial and interacting factors that modulate the neural reactivity to drug cues. The orbitofrontal cortex is not sensitive to the treatment status per se, rather to the interaction of these factors. We discuss that these varying effects might be mediated by internal predispositions such as the intention to quit from drugs and external contingencies such as the daily life environmental availability of the drugs, the ease of getting them and the time frame of potential reward through drug consumption.

How the effects of actions become our own.

Every day, we do things that cause effects in the outside world with little doubt about who caused what. To some, this sense of agency derives from a post hoc reconstruction of a likely causal relationship between an event and our preceding movements; others propose that the sense of agency originates from prospective comparisons of motor programs and their effects. Using functional magnetic resonance imaging, we found that the sense of agency is associated with a brain network including the pre-supplementary motor area (SMA) and dorsal parietal cortex. Transcranial magnetic stimulation affected the sense of agency only when delivered over the pre-SMA and specifically when time-locked to action planning, rather than when the physical consequences of the actions appeared. These findings make a prospective theory of the sense of agency more likely.

How Task Interactivity Shapes Action Observation.

Action observation triggers imitation, a powerful mechanism permitting interpersonal coordination. Coordination, however, also occurs when the partners' actions are nonimitative and physically incongruent. One influential theory postulates that this is achieved via top-down modulation of imitation exerted by prefrontal regions. Here, we rather argue that coordination depends on sharing a goal with the interacting partner: this shapes action observation, overriding involuntary imitation, through the predictive activity of the left ventral premotor cortex (lvPMc). During functional magnetic resonance imaging (fMRI), participants played music in turn with a virtual partner in interactive and noninteractive conditions requiring 50% of imitative/nonimitative responses. In a full-factorial design, both perceptual features and low-level motor requirements were kept constant throughout the experiment. Behaviorally, the interactive context minimized visuomotor interference due to the involuntary imitation of physically incongruent movements. This was paralleled by modulation of neural activity in the lvPMc, which was specifically recruited during the interactive task independently of the imitative/nonimitative nature of the social exchange. This lvPMc activity reflected the predictive decoding of the partner's actions, as revealed by multivariate pattern analysis. This demonstrates that, during interactions, we process our partners' behavior to prospectively infer their contribution to the shared goal achievement, generating motor predictions for cooperation beyond low-level imitation.

Hungry brains: A meta-analytical review of brain activation imaging studies on food perception and appetite in obese individuals.

The dysregulation of food intake in chronic obesity has been explained by different theories. To assess their explanatory power, we meta-analyzed 22 brain-activation imaging studies. We found that obese individuals exhibit hyper-responsivity of the brain regions involved in taste and reward for food-related stimuli. Consistent with a Reward Surfeit Hypothesis, obese individuals exhibit a ventral striatum hyper-responsivity in response to pure tastes, particularly when fasting. Furthermore, we found that obese subjects display more frequent ventral striatal activation for visual food cues when satiated: this continued processing within the reward system, together with the aforementioned evidence, is compatible with the Incentive Sensitization Theory. On the other hand, we did not find univocal evidence in favor of a Reward Deficit Hypothesis nor for a systematic deficit of inhibitory cognitive control. We conclude that the available brain activation data on the dysregulated food intake and food-related behavior in chronic obesity can be best framed within an Incentive Sensitization Theory. Implications of these findings for a brain-based therapy of obesity are briefly discussed.

Resting state brain connectivity patterns before eventual relapse into cocaine abuse.

According to recent theories, drug addicted patients suffer of an impaired response inhibition and salience attribution (I-RISA) together with a perturbed connectivity between the nuclei accumbens (NAcs) and the orbito-prefrontal (oPFC) and dorsal prefrontal (dPFC) cortices, brain regions associated with motivation and cognitive control. To empirically test these assumptions, we evaluated the (neuro)psychological trait and the functional organization of the resting state brain networks associated with the NAcs in 18 former cocaine abusers (FCAs), while being in drug abstinence since 5 months. The psychological data were grouped into three empirical variables related with emotion regulation, emotion awareness and strategic and controlled behaviour. Comparison of the resting state patterns between the entire sample of FCAs and 19 controls revealed a reduction of functional connectivity between the NAcs and the dPFC and enhanced connectivity between the NAcs and the dorsal-striatum. In the 8 FCAs who relapsed into cocaine use after 3 months, the level of functional connectivity between the NAcs and dPFC was lower than the functional connectivity estimated in the group of patients that did not relapsed. Finally, in the entire sample of FCAs, the higher the connectivity between the NAc and the oPFC the lower was the level of strategic and controlled behaviour. Taken together, these results are compatible with models of the interactions between the NAcs, the dorsal striatum and frontal cortices in the I-RISA syndrome, showing that such interactions are particularly perturbed in patients at greater risk of relapse into cocaine abuse.

Guess who's coming to dinner: Brain signatures of racially biased and politically correct behaviors.

The ability to share feelings with those of someone in pain is affected by the racial difference between the target and the onlooker. A differential empathic activation for race (DEAR effect) in favor of in-group members has been documented in the brain pain matrix. However, we are also capable of unbiased responses that manifest politically correct behaviors toward people of a different race. To address the neurofunctional signatures underlying both the DEAR effect and the manifestation of politically correct behaviors, we scanned with fMRI Caucasian participants while watching African or Caucasian actors touched by either a rubber eraser or a needle. Participants were instructed to empathize with the actors during the video presentation (stimulus phase) and to explicitly judge the pain level experienced by the actors (response phase). During the stimulus phase, we found a typical DEAR effect within the pain-matrix. This effect correlated with the level of implicit racial bias as measured by the IAT. On the other hand, during the response phase a significant out-group specific DEAR effect emerged in the prefrontal cortices. This latter effect was coupled with a revealing behavioral pattern: while the magnitude of the painful experience attributed to Caucasians and Africans was the same, our participants were significantly slower when judging the pain experience of the African actors. We propose a model that logically integrates these two contrasting forces at the neurobiological and behavioral level.

Mental images across the adult lifespan: a behavioural and fMRI investigation of motor execution and motor imagery.

Motor imagery (M.I.) is a mental state in which real movements are evoked without overt actions. There is some behavioural evidence that M.I. declines with ageing. The neurofunctional correlates of these changes have been investigated only in two studies, but none of the these studies has measured explicit correlations between behavioural variables and the brain response, nor the correlation of M.I. and motor execution (M.E.) of the same acts in ageing. In this paper, we report a behavioural and functional magnetic resonance imaging (fMRI) experiment that aimed to address this issue. Twenty-four young subjects (27 ± 5.6 years) and twenty-four elderly subjects (60 ± 4.6 years) performed two block-design fMRI tasks requiring actual movement (M.E.) or the mental rehearsal (M.I.) of finger movements. Participants also underwent a behavioural mental chronometry test in which the temporal correlations between M.I. and M.E. were measured. We found significant neurofunctional and behavioural differences between the elderly subjects and the young subjects during the M.E. and the M.I. tasks: for the M.E. task, the elderly subjects showed increased activation in frontal and prefrontal (pre-SMA) cortices as if M.E. had become more cognitively demanding; during the M.I. task, the elderly over-recruited occipito-temporo-parietal areas, suggesting that they may also use a visual imagery strategy. We also found between-group behavioural differences in the mental chronometry task: M.I. and M.E. were highly correlated in the young participants but not in the elderly participants. The temporal discrepancy between M.I. and M.E. in the elderly subjects correlated with the brain regions that showed increased activation in the occipital lobe in the fMRI. The same index was correlated with the premotor regions in the younger subjects. These observations show that healthy elderly individuals have decreased or qualitatively different M.I. compared to younger subjects.

Single domain amnestic MCI: a multiple cognitive domains fMRI investigation.

Amnestic mild cognitive impairment (a-MCI) is associated with the highest annual incidence of conversion to Alzheimer's disease (AD) (10-15%). a-MCI patients may have only a memory deficit (single domain: sd-a-MCI) or additional dysfunctions affecting other cognitive domains (multiple domain: md-a-MCI). Using functional magnetic resonance imaging (fMRI), we investigated brain activation in 16 sd-a-MCI patients and 14 controls during four different tasks assessing language, memory, attention and empathy functions. We found greater activation in sd-a-MCI compared with controls in the left inferior temporal gyrus (language), the right superior temporal gyrus (memory) and the right dorsal precentral gyrus (attention). Moreover, patients' activation correlated significantly with neuropsychological scores obtained at tests exploring the corresponding function. These findings indicate that fMRI is sensitive to detect early changes occurring in AD pathology and that individuals with sd-a-MCI show increased activation in multiple task-related brain regions. We suggest that these functional changes relate to the development of early compensatory mechanisms that reduce cognitive deficits associated with the progressive accumulation of brain damage.

With time on our side? Task-dependent compensatory processes in graceful aging.

Graceful aging has been associated with frontal hyperactivations in working- and episodic long-term memory tasks, a compensatory process, according to some, that allows the best normal elders to perform these tasks at a juvenile level, in spite of natural cortical impoverishment. In this study, 24 young and 24 healthy elderly participants were compared. Graceful aging was explored by investigating domains where most healthy elders perform like youngers (e.g. lexical-semantic knowledge) and tasks that are typically more challenging, like episodic long-term recognition memory tasks. With voxel-based morphometry, we also studied to what extent changes of fMRI activation were consistent with the pattern of brain atrophy. We found that hyperactivations and hypoactivations of the elders were not restricted to the frontal lobes, rather they presented with task-dependent patterns. Only hypoactivations and normal levels of activation systematically overlapped with regional atrophy. We conclude that compensatory processes associated with graceful aging may not necessarily be a sign of early saturation of executive resources, if this was to be represented by a systematic frontal hyperactivation, but rather they may represent the ability of recruiting new cognitive strategies. We discuss two possible approaches to further test this hypothesis.

Neural correlates of worry in generalized anxiety disorder and in normal controls: a functional MRI study.

BACKGROUND: Worry is considered a key feature of generalized anxiety disorder (GAD), whose neural correlates are poorly understood. It is not known whether the brain regions involved in pathological worry are similar to those involved in worry-like mental activity in normal subjects or whether brain areas associated with worry are the same for different triggers such as verbal stimuli or faces. This study was designed to clarify these issues. METHOD: Eight subjects with GAD and 12 normal controls underwent functional magnetic resonance imaging (fMRI) mood induction paradigms based on spoken sentences or faces. Sentences were either neutral or designed to induce worry. Faces conveyed a sad or a neutral mood and subjects were instructed to empathize with those moods. RESULTS: We found that the anterior cingulate and dorsal medial prefrontal cortex [Brodmann area (BA) 32/23 and BA 10/11] were associated with worry triggered by sentences in both subjects with GAD and normal controls. However, GAD subjects showed a persistent activation of these areas even during resting state scans that followed the worrying phase, activation that correlated with scores on the Penn State Worry Questionnaire (PSWQ). This region was activated during the empathy experiment for sad faces. CONCLUSIONS: The results show that worry in normal subjects and in subjects with GAD is based on activation of the medial prefrontal and anterior cingulate regions, known to be involved in mentalization and introspective thinking. A dysregulation of the activity of this region and its circuitry may underpin the inability of GAD patients to stop worrying.

Supercalifragilisticexpialidocious: how the brain learns words never heard before.

Vocabulary acquisition is such a major aspect of language learning in children, but also in adults when learning a foreign language, that a dedicated vocabulary learning device may exist within the language organ. To identify the relevant brain systems, we performed regional cerebral blood flow measurements in normal subjects while they were learning a list of neologisms or a list of word-nonword pairs. Structures implicated in phonological short-term memory (Broca's area, left temporo-parietal junction) were steadily activated during nonwords learning, while the left temporal lobe neocortical and paralimbic structures (parahippocampal region), associated with long-term memory, contributed to learning in a time-dependent manner, with maximal activation at the beginning of the process. The neural system specifically activated when learning new vocabulary was strongly lateralized to the left hemisphere. This evidence refines current models of memory function and supports theories which emphasise the importance of phonological competence in hemispheric dominance for language.

Anatomy of the episodic buffer: a voxel-based morphometry study in patients with dementia.

In 2000 Baddeley proposed the existence of a new component of working memory, the episodic buffer, which should contribute to the on-line maintenance of integrated memory traces. The author assumed that this component should be critical for immediate recall of a short story that exceeds the capacity of the phonological store. Accordingly, patients with Alzheimer's dementia (AD) should suffer of a deficit of the episodic buffer when immediate recall of a short story is impossible. On the other hand, the episodic buffer should be somewhat preserved in such patients when some IR can occur (Baddeley and Wilson, 2002). We adopted this logic for a voxel-based morphometry study. We compared the distribution of grey-matter density of two such groups of AD patients with and of a group of age-matched controls. We found that both AD groups had a significant atrophy of the left mid-hippocampus; on the other hand, the anterior part of the hippocampus was significantly more atrophic in patients who were also impaired on the immediate prose recall task. Six out of ten patients with no immediate recall were spared at "central executive" tasks. Taken together our findings suggest that the left anterior hippocampus contributes to the episodic buffer of the revised working memory model. We also suggest that the episodic buffer is somewhat independent from the central executive component of working memory.

Left caloric vestibular stimulation ameliorates right hemianesthesia.

BACKGROUND: Left caloric vestibular stimulation (CVS) transiently reduces impairments of right-brain-damaged patients with left unilateral neglect, including left hemianesthesia, contralateral to the side of the lesion (contralesional). Conversely, no effect on right contralesional hemianesthesia in left-brain-damaged patients is seen with right CVS. This discrepancy is unexplained. METHODS: The authors explored the effect of CVS on right- and left-brain-damaged patients with hemianesthesia. One left-brain-damaged patient had an fMRI study during tactile stimulation before and after left CVS. The same fMRI touch study, without CVS, was performed in neurologically unimpaired subjects. RESULTS: A transient remission of right hemianesthesia associated with left brain damage was observed, provided that cold CVS was administered to the left ear. In the left-brain-damaged patient studied with fMRI, left CVS modulated the neural response to right hand tactile stimuli of a portion of the secondary somatosensory area (SII) of the right hemisphere. In neurologically unimpaired subjects, fMRI scans showed that the same part of area SII in the right hemisphere was activated by ipsilateral right-sided touches and to a larger extent than area SII in the left hemisphere by left-sided touches. CONCLUSIONS: Left caloric vestibular stimulation is effective on both left and right hemianesthesia because it modulates the hemisphere that has a more complete representation of, or is capable to attend to, the whole somatosensory surface of the body. These results suggest a hardwired hemispheric asymmetry in hand representation, starting from a somatotopically organized brain region such as area SII.

Shared cortical anatomy for motor awareness and motor control.

In everyday life, the successful monitoring of behavior requires continuous updating of the effectiveness of motor acts; one crucial step is becoming aware of the movements one is performing. We studied the anatomical distribution of lesions in right-brain-damaged hemiplegic patients, who obstinately denied their motor impairment, claiming that they could move their paralyzed limbs. Denial was associated with lesions in areas related to the programming of motor acts, particularly Brodmann's premotor areas 6 and 44, motor area 4, and the somatosensory cortex. This association suggests that monitoring systems may be implemented within the same cortical network that is responsible for the primary function that has to be monitored.

Brain abnormalities underlying altered activation in dyslexia: a voxel based morphometry study.

Voxel-based morphometry was used to assess the consistency among functional imaging and brain morphometry data in developmental dyslexia. Subjects, from three different cultural contexts (UK, France and Italy), were the same as those described in a previous PET activation paper, which revealed a common pattern of reduced activation during reading tasks in the left temporal and occipital lobes. We provide evidence that altered activation observed within the reading system is associated with altered density of grey and white matter of specific brain regions, such as the left middle and inferior temporal gyri and the left arcuate fasciculus. This supports the view that dyslexia is associated with both local grey matter dysfunction and with altered connectivity among phonological/reading areas. The differences were replicable across samples confirming that the neurological disorder underlying dyslexia is the same across the cultures investigated in the study.

Brain activity during intra- and cross-modal priming: new empirical data and review of the literature.

A positron emission tomography (PET) study was conducted to investigate the neurofunctional correlate of auditory within-modality and auditory-to-visual cross-modality stem completion priming. Compared to the auditory-to-auditory priming condition, cross-modality priming was associated with a significantly larger regional cerebral blood flow (rCBF) decrease at the boundary between left inferior temporal and fusiform gyri, brain regions previously associated with modality independent lexical retrieval and reading. Instead, within-modality auditory priming was associated with a bilateral pattern of prefrontal rCBF increase. This was likely the expression of more efficient access to output lexical representations and involuntary retrieval of the recent episode during which the just generated word had been encountered.

Preserved functional competence of perilesional areas in drug-resistant epilepsy with lesion in supplementary motor cortex: fMRI and neuropsychological observations.

We report a presurgical fMRI study and a longitudinal behavioral and structural MRI study in a 26-year-old right-handed woman with drug-resistant epilepsy of the supplementary motor region with cytoarchitectural dysplasia and minimal cortico-subcortical gliotic damage. fMRI scans were acquired during a silent phonemic verbal fluency task (VF), an automatic counting task (CT), and a finger-tapping motor task (MT). These were all compared with rest. Presurgical neuropsychological assessment was substantially normal with only a minor deficit in the domain of visuo-constructive and complex motor-planning skills. Noticeably, performance on phonemic verbal fluency was normal. Presurgical fMRI results revealed a normal specialization of left SMA and pre-SMA, including a fine-grained somatotopy for mouth and hand representations despite epilepsy. Immediately after surgical removal of the epileptogenic zone (the posterior third of the superior and middle frontal gyri including pre-SMA and part of SMA, and part of the anterior cingulate region--all of which were active presurgically at the fMRI tests), the patient suffered from transcortical motor aphasia temporarily. One year after surgery, she still showed impaired performance in the verbal fluency tasks while naming and comprehension were recovered. The patient was now free from seizures. This fMRI study supports the case that repeated seizures per se may not be sufficient to alter the distribution of neural representations of cognitive function. Selective behavioral impairment after surgical removal of brain areas that were activated during presurgical fMRI permits us to establish a causal link between these activations and task performance. This link could not have been made on the basis of activation patterns or lesion data taken on their own. These findings support the case that some epileptic patients may represent a unique opportunity for cognitive neuroscience studies.

A functional-anatomical model for lipreading.

Regional cerebral blood flow (rCBF) PET scans were used to study the physiological bases of lipreading, a natural skill of extracting language from mouth movements, which contributes to speech perception in everyday life. Viewing connected mouth movements that could not be lexically identified and that evoke perception of isolated speech sounds (nonlexical lipreading) was associated with bilateral activation of the auditory association cortex around Wernicke's area, of left dorsal premotor cortex, and left opercular-premotor division of the left inferior frontal gyrus (Broca's area). The supplementary motor area was active as well. These areas have all been implicated in phonological processing, speech and mouth motor planning, and execution. In addition, nonlexical lipreading also differentially activated visual motion areas. Lexical access through lipreading was associated with a similar pattern of activation and with additional foci in ventral- and dorsolateral prefrontal cortex bilaterally and in left inferior parietal cortex. Linear regression analysis of cerebral blood flow and proficiency for lexical lipreading further clarified the role of these areas in gaining access to language through lipreading. The results suggest cortical activation circuits for lipreading from action representations that may differentiate lexical access from nonlexical processes.