Sara Palermo

Activation likelihood estimation meta-analysis of brain correlates of placebo analgesia in human experimental pain.

Placebo analgesia (PA) is one of the most studied placebo effects. Brain imaging studies published over the last decade, using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), suggest that multiple brain regions may play a pivotal role in this process. However, there continues to be much debate as to which areas consistently contribute to placebo analgesia‐related networks. In the present study, we used activation likelihood estimation (ALE) meta‐analysis, a state‐of‐the‐art approach, to search for the cortical areas involved in PA in human experimental pain models. Nine fMRI studies and two PET studies investigating cerebral hemodynamic changes were included in the analysis. During expectation of analgesia, activated foci were found in the left anterior cingulate, right precentral, and lateral prefrontal cortex and in the left periaqueductal gray (PAG). During noxious stimulation, placebo‐related activations were detected in the anterior cingulate and medial and lateral prefrontal cortices, in the left inferior parietal lobule and postcentral gyrus, anterior insula, thalamus, hypothalamus, PAG, and pons; deactivations were found in the left mid‐ and posterior cingulate cortex, superior temporal and precentral gyri, in the left anterior and right posterior insula, in the claustrum and putamen, and in the right thalamus and caudate body. Our results suggest on one hand that the modulatory cortical networks involved in PA largely overlap those involved in the regulation of emotional processes, on the other that brain nociceptive networks are downregulated in parallel with behavioral analgesia. Hum Brain Mapp, 2013.

Unawareness of deficits in Alzheimer's disease: role of the cingulate cortex

Unawareness of deficits is a symptom of Alzheimers disease that can be observed even in the early stages of the disease. The frontal hypoperfusion associated with reduced awareness of deficits has led to suggestions of the existence of a hypofunctioning prefrontal pathway involving the right dorsolateral prefrontal cortex, inferior parietal lobe, anterior cingulate gyri and limbic structures. Since this network plays an important role in response inhibition competence and patients with Alzheimers disease who are unaware of their deficits exhibit impaired performance in response inhibition tasks, we predicted a relationship between unawareness of deficits and cingulate hypofunctionality. We tested this hypothesis in a sample of 29 patients with Alzheimers disease (15 aware and 14 unaware of their disturbances), rating unawareness according to the Awareness of Deficit Questionnaire-Dementia scale. The cognitive domain was investigated by means of a wide battery including tests on executive functioning, memory and language. Neuropsychiatric aspects were investigated using batteries on behavioural mood changes, such as apathy and disinhibition. Cingulate functionality was assessed with functional magnetic resonance imaging, while patients performed a go/no-go task. In accordance with our hypotheses, unaware patients showed reduced task-sensitive activity in the right anterior cingulate area (Brodmann area 24) and in the rostral prefrontal cortex (Brodmann area 10). Unaware patients also showed reduced activity in the right post-central gyrus (Brodmann area 2), in the associative cortical areas such as the right parietotemporal-occipital junction (Brodmann area 39) and the left temporal gyrus (Brodmann areas 21 and 38), in the striatum and in the cerebellum. These findings suggest that the unawareness of deficits in early Alzheimers disease is associated with reduced functional recruitment of the cingulofrontal and parietotemporal regions. Furthermore, in line with previous findings, we also found apathy and disinhibition to be prominent features of the first behavioural changes in unaware patients.

Gray matter alterations in chronic pain: A network-oriented meta-analytic approach

Several studies have attempted to characterize morphological brain changes due to chronic pain. Although it has repeatedly been suggested that longstanding pain induces gray matter modifications, there is still some controversy surrounding the direction of the change (increase or decrease in gray matter) and the role of psychological and psychiatric comorbidities. In this study, we propose a novel, network-oriented, meta-analytic approach to characterize morphological changes in chronic pain. We used network decomposition to investigate whether different kinds of chronic pain are associated with a common or specific set of altered networks. Representational similarity techniques, network decomposition and model-based clustering were employed: i) to verify the presence of a core set of brain areas commonly modified by chronic pain; ii) to investigate the involvement of these areas in a large-scale network perspective; iii) to study the relationship between altered networks and; iv) to find out whether chronic pain targets clusters of areas. Our results showed that chronic pain causes both core and pathology-specific gray matter alterations in large-scale networks. Common alterations were observed in the prefrontal regions, in the anterior insula, cingulate cortex, basal ganglia, thalamus, periaqueductal gray, post- and pre-central gyri and inferior parietal lobule. We observed that the salience and attentional networks were targeted in a very similar way by different chronic pain pathologies. Conversely, alterations in the sensorimotor and attention circuits were differentially targeted by chronic pain pathologies. Moreover, model-based clustering revealed that chronic pain, in line with some neurodegenerative diseases, selectively targets some large-scale brain networks. Altogether these findings indicate that chronic pain can be better conceived and studied in a network perspective.

Pain anticipation: an activation likelihood estimation meta-analysis of brain imaging studies.

The anticipation of pain has been investigated in a variety of brain imaging studies. Importantly, today there is no clear overall picture of the areas that are involved in different studies and the exact role of these regions in pain expectation remains especially unexploited. To address this issue, we used activation likelihood estimation meta‐analysis to analyze pain anticipation in several neuroimaging studies. A total of 19 functional magnetic resonance imaging were included in the analysis to search for the cortical areas involved in pain anticipation in human experimental models. During anticipation, activated foci were found in the dorsolateral prefrontal, midcingulate and anterior insula cortices, medial and inferior frontal gyri, inferior parietal lobule, middle and superior temporal gyrus, thalamus, and caudate. Deactivated foci were found in the anterior cingulate, superior frontal gyrus, parahippocampal gyrus and in the claustrum. The results of the meta‐analytic connectivity analysis provide an overall view of the brain responses triggered by the anticipation of a noxious stimulus. Such a highly distributed perceptual set of self‐regulation may prime brain regions to process information where emotion, action and perception as well as their related subcategories play a central role. Not only do these findings provide important information on the neural events when anticipating pain, but also they may give a perspective into nocebo responses, whereby negative expectations may lead to pain worsening. Hum Brain Mapp 36:1648–1661, 2015.

Concordance of white matter and gray matter abnormalities in autism spectrum disorders: A voxel-based meta-analysis study

There are at least two fundamental unanswered questions in the literature on autism spectrum disorders (ASD): Are abnormalities in white (WM) and gray matter (GM) consistent with one another? Are WM morphometric alterations consistent with alterations in the GM of regions connected by these abnormal WM bundles and vice versa? The aim of this work is to bridge this gap. After selecting voxel‐based morphometry and diffusion tensor imaging studies comparing autistic and normally developing groups of subjects, we conducted an activation likelihood estimation (ALE) meta‐analysis to estimate consistent brain alterations in ASD. Multidimensional scaling was used to test the similarity of the results. The ALE results were then analyzed to identify the regions of concordance between GM and WM areas. We found statistically significant topological relationships between GM and WM abnormalities in ASD. The most numerous were negative concordances, found bilaterally but with a higher prevalence in the right hemisphere. Positive concordances were found in the left hemisphere. Discordances reflected the spatial distribution of negative concordances. Thus, a different hemispheric contribution emerged, possibly related to pathogenetic factors affecting the right hemisphere during early developmental stages. Besides, WM fiber tracts linking the brain structures involved in social cognition showed abnormalities, and most of them had a negative concordance with the connected GM regions. We interpreted the results in terms of altered brain networks and their role in the pervasive symptoms dramatically impairing communication and social skills in ASD patients. Hum Brain Mapp 35:2073–2098, 2014.

Impaired awareness of deficits in Alzheimer's disease: the role of everyday executive dysfunction.

The present study analyzed the awareness of deficits in 117 mild Alzheimers disease participants. Since few studies have examined the cognitive and behavioral domains of reduced awareness in detail, we performed a domain-specific assessment using the Awareness of deficit Questionnaire - Dementia scale with the novel aim of describing the relationship with everyday executive dysfunction. Through the use of the subtests of the Behavioral Assessment of the Dysexecutive Syndrome, we hypothesized that executive cognitive functions may play an important role in the reduced awareness of deficits. We also considered other variables of interest to provide a novel comprehensive explanation of this phenomenon. Our first approach to the study was a factor analysis considering the role of these variables in the awareness of deficits; subsequently, regression analysis models were used to define which variables were associated with a reduction of awareness in cognitive and behavioral domains. In particular, the factors retained from the factor analysis, in terms of inhibition, self-monitoring, set-shifting, and mood orientation changes, appear to be important skills for awareness of instrumental activities of daily living (R(2) = .32). We also found hypo manic mood orientation and a tendency through apathy to be prominent indications of reduced behavioral awareness (R(2) = .13).

Self-unawareness of levodopa induced dyskinesias in patients with Parkinson's disease

The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suffering from Parkinsons disease (PD). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in dyskinesias self-unawareness, we analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Special attention was given to metacognitive abilities related to action-monitoring that represent a novel explanation of the phenomenon. PD patients were assessed using different rating scales that we devised to measure movement awareness disorders. In order to ascertain whether each variable measured at a cognitive-clinical level contributes to predicting the scores of the movement-disorder-awareness-scales, we conducted multiple logistic regression models using the latter as binary dependent variables. We used the Wisconsin Card Sorting Test-metacognitive-version to assess the executive functions of the prefrontal-ventral-striatal circuitry. Data showed that a reduction of self-awareness using the Dyskinesia rating scale was associated with global monitoring (p=.04), monitoring resolution (p=.04) and control sensitivity (p=.04). Patients failed to perceive their performance, distinguish between correct and incorrect sorts, be confident in their choice and consequently decide to gamble during the task. We did not find any association with executive functions using the hypo-bradykinesia rating scale. Our findings indicate that when the comparator mechanism for monitoring attentive performance is compromised at a prefrontal striatal level, patients lose the ability to recognize their motor disturbances that do not achieve conscious awareness.

Unawareness of bipolar disorder: the role of the cingulate cortex

Reduced awareness of illness is a well-known phenomenon that has been understudied in remitted patients with bipolar disorder. In particular, the relationship between reduced awareness and executive dysfunction is an intriguing question that has yet to be resolved. The aim of the current study is to analyze the link between reduced awareness, brain dysfunction, and concomitant cognitive-behavioral disturbances from a neurocognitive perspective. In previous studies, we demonstrated the role of the anterior cingulate cortex (ACC) in the unawareness of distinct pathologies that exhibit overlapping symptoms in the context of overlapping circuit-specific dysfunction. Given the clinical importance of the results obtained, the present study considers six aware and four unaware remitted bipolar disorder patients. Cingulate functionality was assessed with functional magnetic resonance imaging while patients performed a go/no-go task. Patients were also studied on an overall cognitive task battery and with behavioral assessment of mood changes in terms of apathy and disinhibited behavior. Unaware patients showed frontoparietal hypo-perfusion, with a significant reduction of task-sensitive activity in the bilateral superior and middle frontal gyrus, putamen, insular, and ACCs.

Unawareness of deficits in ischemic injury: Role of the cingulate cortex

Reduced awareness of illness is a well-known phenomenon that has been studied in patients with vascular disease, but the precise nature of their executive dysfunction is an intriguing question that still has to be resolved. It would be particularly interesting to study patients with reduced awareness of disease possibly related to vascular lesions of the prefrontal cortex. Due to the clinical importance of the case, here we present a patient with a selective right anterior cingulate ischemic injury and impaired awareness of deficits. We suggest that the cingulo-frontal area dysfunction may represent one of the corresponding neurobiological substrates of his persistent unawareness, which has not yet been evaluated in the literature on patients with acquired brain injury (ABI).

Are schizophrenia, autistic, and obsessive spectrum disorders dissociable on the basis of neuroimaging morphological findings?: A voxel‐based meta‐analysis

Schizophrenia spectrum disorder (SCZD), autism spectrum disorder (ASD), and obsessive‐compulsive spectrum disorder (OCSD) are considered as three separate psychiatric conditions with, supposedly, different brain alterations patterns. From a neuroimaging perspective, this meta‐analytic study aimed to address whether this nosographical differentiation is actually supported by different brain patterns of gray matter (GM) or white matter (WM) morphological alterations. We explored two possibilities: (a) to find out whether GM alterations are specific for SCZD, ASD, and OCSD; and (b) to associate the identified brain alteration patterns with cognitive dysfunctions by means of an analysis of lesion decoding. Our analysis reveals that these psychiatric spectra do not present clear distinctive patterns of alterations; rather, they all tend to be distributed in two alteration clusters. Cluster 1, which is more specific for SCZD, includes the anterior insular, anterior cingulate cortex, ventromedial prefrontal cortex, and frontopolar areas, which are parts of the cognitive control system. Cluster 2, which is more specific for OCSD, presents occipital, temporal, and parietal alteration patterns with the involvement of sensorimotor, premotor, visual, and lingual areas, thus forming a network that is more associated with the auditory‐visual, auditory, premotor visual somatic functions. In turn, ASD appears to be uniformly distributed in the two clusters. The three spectra share a significant set of alterations. Our new approach promises to provide insight into the understanding of psychiatric conditions under the aspect of a common neurobiological substrate, possibly related to neuroinflammation during brain development. Autism Res 2017.