Although neuroimaging research has made substantial progress in identifying the large-scale neural substrate of anxiety disorders, its value for clinical application lags behind expectations. Machine-learning approaches have predictive potential for individual-patient prognostic purposes and might thus aid translational efforts in psychiatric research.
Associative memory is essential to everyday activities, such as the binding of faces and corresponding names to form single bits of information. However, this ability often becomes impaired with increasing age. The most important neural substrate of associative memory is the hippocampus, a structure crucially implicated in the pathogenesis of Alzheimer's disease (AD). The main aim of this study was to compare neural correlates of associative memory in healthy aging and mild cognitive impairment (MCI), an at-risk state for AD. We used fMRI to investigate differences in brain activation and connectivity between young controls (n?=?20), elderly controls (n?=?32) and MCI patients (n?=?21) during associative memory retrieval. We observed lower hippocampal activation in MCI patients than control groups during a face-name recognition task, and the magnitude of this decrement was correlated with lower associative memory performance. Further, increased activation in precentral regions in all older adults indicated a stronger involvement of the task positive network (TPN) with age. Finally, functional connectivity analysis revealed a stronger link of hippocampal and striatal components in older adults in comparison to young controls, regardless of memory impairment. In elderly controls, this went hand-in-hand with a stronger activation of striatal areas. Increased TPN activation may be linked to greater reliance on cognitive control in both older groups, while increased functional connectivity between the hippocampus and the striatum may suggest dedifferentiation, especially in elderly controls.
Cognitive behavioral therapy (CBT) is an evidence-based treatment for mental disorders. Several meta-analytical reviews supported its efficacy and effectiveness in the treatment of panic disorder with agoraphobia (PD/AG). Recently, it has been shown that neurobiological changes are associated with the process and outcome of CBT. However, the general and specific neurobiological effects of CBT are still widely unknown. Therefore, the potential of applying neuroscience to clinical practice and optimizing CBT is still limited. The current review summarizes recent findings about the neural correlates of CBT in PD/AG measured with fMRI. Furthermore, the current review will focus on neural activation patterns predicting and moderating therapeutic success of CBT, due to its potential application in personalized treatment in the future. Finally, we will discuss some future perspectives of the neurosciences in CBT research.
Variation in the 5'-flanking promoter region of the serotonin transporter gene SLC6A4, the 5-HTT-linked polymorphic region (5-HTTLPR) has been inconclusively associated with response to cognitive-behavioural therapy (CBT). As genomic functions are stronger related to neural than to behavioural markers, we investigated the association of treatment response, 5-HTTLPR and functional brain connectivity in patients with panic disorder with agoraphobia (PD/AG). Within the national research network PANIC-NET 231 PD/AG patients who provided genetic information underwent a manualized exposure-based CBT. A subset of 41 patients participated in a functional magnetic resonance imaging (fMRI) add-on study prior to treatment applying a differential fear conditioning task. Neither the treatment nor the reduced fMRI sample showed a direct effect of 5-HTTLPR on treatment response as defined by a reduction in the Hamilton Anxiety Scale score ?50 % from baseline to post assessment. On a neural level, inhibitory anterior cingulate cortex (ACC)-amygdala coupling during fear conditioning that had previously been shown to characterize treatment response in this sample was driven by responders with the L/L genotype. Building upon conclusive evidence from basic and preclinical findings on the association of the 5-HTTLPR polymorphism with emotion regulation and related brain connectivity patterns, present findings translate these to a clinical sample of PD/AG patients and point towards a potential intermediate connectivity phenotype modulating response to exposure-based CBT.
The purpose of the study was to contrast first panic attacks (PAs) of patients with panic disorder (PD) with vs. without agoraphobia and to explore differences between first PAs leading to the development of PD and those that remain isolated. Data were drawn from a community survey (N=2259 including 88 isolated PAs and 75 PD cases). An additional sample of 234 PD patients was recruited in a clinical setting. A standardized interview assessed the symptoms of the first PA, context of its occurrence and subsequent coping attempts. Persons who developed PD reported more severe first PAs, more medical service utilization and exposure-limiting coping attempts than those with isolated PAs. The context of the first PA did not differ between PD and isolated PAs. PD with agoraphobia was specifically associated with greater symptom severity and occurrence of first attacks in public. Future research should validate these findings using a longitudinal approach.
Ego disturbances in schizophrenia might be caused by a failure of the efference copy mechanism, which compares efferent with reafferent signals and attenuates the sensory consequences of self-produced movements. We carried out a functional magnetic resonance imaging study in which 16 patients with schizophrenia and 16 healthy matched controls were studied while performing both intentional and unintentional continuous hand movements in two consecutive experiments. We periodically varied the delay of visual feedback to create a sensory-motor discrepancy. Exclusively for intentional movements the activation pattern of the inferior frontal gyrus (IFG) in patients was opposite to that of controls: less attenuated during time-congruent feedback and less activated during time-incongruent feedback. Additionally, several functional connections within the mismatch detection network (IFG with insula, putamen, medial orbitofrontal cortex) were affected. Also, activity of the dysconnected orbitofrontal cortex was correlated with ego disturbance in patients. We discuss that in healthy individuals the IFG might enable a distinction between self and non-self using time-characteristics of feedback, whereas in patients this sensory mismatch detection appears to be altered. Moreover, due to the dysconnectivity of the IFG, the efferent and reafferent signal exchange between perceptual and motor areas seems to be affected. This might cause self-monitoring deficits in patients, phenomena that contribute to the emergence of ego disturbances.
Theoretical models postulate an important role of attributional style (AS) in the formation and maintenance of persecutory delusions and other positive symptoms of schizophrenia. However, current research has gathered conflicting findings. In a cross-sectional design, patients with persistent positive symptoms of schizophrenia (n = 258) and healthy controls (n = 51) completed a revised version of the Internal, Personal and Situational Attributions Questionnaire (IPSAQ-R) and assessments of psychopathology. In comparison to controls, neither patients with schizophrenia in general nor patients with persecutory delusions (n = 142) in particular presented an externalizing and personalizing AS. Rather, both groups showed a "self-blaming" AS and attributed negative events more toward themselves. Persecutory delusions were independently predicted by a personalizing bias for negative events (beta = 0.197, P = .001) and by depression (beta = 0.152, P = .013), but only 5% of the variance in persecutory delusions could be explained. Cluster analysis of IPSAQ-R scores identified a "personalizing" (n = 70) and a "self-blaming" subgroup (n = 188), with the former showing slightly more pronounced persecutory delusions (P = .021). Results indicate that patients with schizophrenia and patients with persecutory delusions both mostly blamed themselves for negative events. Nevertheless, still a subgroup of patients could be identified who presented a more pronounced personalizing bias and more severe persecutory delusions. Thus, AS in patients with schizophrenia might be less stable but more determined by individual and situational characteristics that need further elucidation.
Speech-associated gesturing leads to memory advantages for spoken sentences. However, unexpected or surprising events are also likely to be remembered. With this study we test the hypothesis that different neural mechanisms (semantic elaboration and surprise) lead to memory advantages for iconic and unrelated gestures. During fMRI-data acquisition participants were presented with video clips of an actor verbalising concrete sentences accompanied by iconic gestures (IG; e.g., circular gesture; sentence: "The man is sitting at the round table"), unrelated free gestures (FG; e.g., unrelated up down movements; same sentence) and no gestures (NG; same sentence). After scanning, recognition performance for the three conditions was tested. Videos were evaluated regarding semantic relation and surprise by a different group of participants. The semantic relationship between speech and gesture was rated higher for IG (IG>FG), whereas surprise was rated higher for FG (FG>IG). Activation of the hippocampus correlated with subsequent memory performance of both gesture conditions (IG+FG>NG). For the IG condition we found activation in the left temporal pole and middle cingulate cortex (MCC; IG>FG). In contrast, for the FG condition posterior thalamic structures (FG>IG) as well as anterior and posterior cingulate cortices were activated (FG>NG). Our behavioral and fMRI-data suggest different mechanisms for processing related and unrelated co-verbal gestures, both of them leading to enhanced memory performance. Whereas activation in MCC and left temporal pole for iconic co-verbal gestures may reflect semantic memory processes, memory enhancement for unrelated gestures relies on the surprise response, mediated by anterior/posterior cingulate cortex and thalamico-hippocampal structures.
G72 (syn. DAOA, D-amino acid oxidase activator) is a susceptibility gene for both schizophrenia and bipolar disorder. Diffusion tensor imaging studies hint at changes in fiber tract integrity in both disorders. We aimed to investigate whether a G72 susceptibility haplotype causes changes in fiber tract integrity in young healthy subjects. We compared fractional anisotropy in 47 subjects that were either homozygous for the M23/M24 risk haplotype (n = 20) or homozygous for M23(rs3918342)/M24(rs1421292) wild type (n = 27) using diffusion tensor imaging with 3 T. Tract-based spatial statistics, a method especially developed for diffusion data analysis, was used to delineate the major fiber tracts. We found clusters of increased FA values in homozygous risk haplotype carriers in the right periinsular region and in the right inferior parietal lobe (IPL). We did not find clusters indicating decreased FA values. The insula and the IPL have been implicated in both schizophrenia and bipolar pathophysiology. Increased FA values might reflect changes in dendritic morphology as previously described by in vitro studies. These findings further corroborate the hypothesis that a shared gene pool between schizophrenia and bipolar disorder might lead to neuroanatomic changes that confer an unspecific vulnerability for both disorders.
Depression often involves anxiety symptoms and shows a strong comorbidity with panic disorder. However, the neural basis is unclear. The aim of the current study was to use semantic priming to investigate the neural correlates of panic and anxiety-related information processing in depression. In a lexical decision task, panic/agoraphobia-disorder-related and neutral word-pairs were presented during functional magnetic resonance imaging. Participants comprised 19 patients with major depression but without comorbid anxiety and 19 demographically matched controls. On a behavioral level, comparable significant priming effects were found for the neutral condition, while only patients showed a significant inhibition effect (slower reaction time for panic-related stimuli) for the panic condition. On a neural level, significant group differences emerged in left fronto-parietal (enhanced activation for patients) and left temporo-occipital regions (reduced activation for patients). The results showed that depressed patients recruit not only areas related to the interaction of emotion and semantic processing but also regions that are related to fear circuitry to process panic-related information. Hence, in the context of depression, there seems to be a pathological processing of panic-related information that could play an important role during the disorder and should be considered.
Major depression is associated with impairments in semantic verbal fluency (VF). However, the neural correlates underlying dysfunctional cognitive processing in depressed subjects during the production of semantic category members still remain unclear. In the current study, an overt and continuous semantic VF paradigm was used to examine these mechanisms in a representative sample of 33 patients diagnosed with a current episode of unipolar depression and 33 statistically matched healthy controls. Subjects articulated words in response to semantic category cues while brain activity was measured with functional magnetic resonance imaging (fMRI). Compared to controls, patients showed poorer task performance. On the neural level, a group by condition interaction analysis, corrected for task performance, revealed a reduced task-related deactivation in patients in the right parahippocampal gyrus, the right fusiform gyrus, and the right supplementary motor area. An additional and an increased task-related activation in patients were observed in the right precentral gyrus and the left cerebellum, respectively. These results indicate that a failure to suppress potentially interfering activity from inferior temporal regions involved in default-mode network functions and visual imagery, accompanied by an enhanced recruitment of areas implicated in speech initiation and higher-order language processes, may underlie dysfunctional cognitive processing during semantic VF in depression. The finding that patients with depression demonstrated both decreased performance and aberrant brain activation during the current semantic VF task demonstrates that this paradigm is a sensitive tool for assessing brain dysfunctions in clinical populations.
Genetic studies found the A allele of the single nucleotide polymorphism rs1006737 in the CACNA1C gene, which encodes for the alpha 1C subunit of the voltage-dependent, L-type calcium ion channel Cav1.2, to be overrepresented in patients with major depressive disorder (MDD). Altered prefrontal brain functioning and impaired semantic verbal fluency (SVF) are robust findings in these patients. A recent functional magnetic resonance imaging (fMRI) study found the A allele to be associated with poorer performance and increased left inferior frontal gyrus (IFG) activation during SVF tasks in healthy subjects. In the present study, we investigated the effects of rs1006737 on neural processing during SVF in MDD. In response to semantic category cues, 40 patients with MDD and 40 matched controls overtly generated words while brain activity was measured with fMRI. As revealed by whole brain analyses, genotype significantly affected brain activity in patients. Compared to patients with GG genotype, patients with A allele demonstrated increased task-related activation in the left middle/inferior frontal gyrus and the bilateral cerebellum. Patients with A allele also showed enhanced functional coupling between left middle/inferior and right superior/middle frontal gyri. No differential effects of genotype on SVF performance or brain activation were found between diagnostic groups. The current data provide further evidence for an impact of rs1006737 on the left IFG and demonstrate that genetic variation in CACNA1C modulates neural responses in patients with MDD. The observed functional alterations in prefrontal and cerebellar areas might represent a mechanism by which rs1006737 influences susceptibility to MDD.
Cognitive behavioral therapy (CBT) is an effective treatment for panic disorder with agoraphobia (PD/AG). It is unknown, how variants of CBT differentially modulate brain networks involved in PD/AG. This study was aimed to evaluate the effects of therapist-guided (T+) versus self-guided (T-) exposure on the neural correlates of fear conditioning in PD/AG.
Changes in fiber tract architecture have gained attention as a potentially important aspect of schizophrenia neuropathology. Although the exact pathogenesis of these abnormalities yet remains to be elucidated, a genetic component is highly likely. Neuregulin-1 (NRG1) is one of the best-validated schizophrenia susceptibility genes. We here report the impact of the Neuregulin-1 rs35753505 variant on white matter structure in healthy young individuals with no family history of psychosis.
Memory impairments are common in major depression. Neural processing during non-emotional episodic memory in depressed patients has only sparsely been investigated, since the majority of studies have focused on emotional stimuli. The aim of this study was to explore neural correlates of episodic memory in depressive patients and to assess brain regions related to subsequent memory performance. Forty-six participants (23 depressed patients) performed a non-emotional episodic memory encoding and retrieval task while brain activation was measured with functional magnetic resonance imaging. Patients with depression showed decreased activation in the right prefrontal cortex and right cingulate cortex during memory encoding, but increased activation in the right inferior frontal gyrus (IFG) during recognition memory. While a strong association between hippocampal and parahippocampal activation during memory encoding with subsequent memory performance became evident in healthy controls, this relationship was absent in patients with depression. Taken together, these findings demonstrate that memory related brain regions are affected in their appropriate functioning during memory encoding in depressed patients. Therefore, patients with depression may rely to a greater degree on other brain regions such as the IFG during episodic memory retrieval.
Neurosteroids are synthesized both in brain and peripheral steroidogenic tissue from cholesterol or steroidal precursors. Neurosteroids have been shown to be implicated in neural proliferation, differentiation, and activity. Preclinical and clinical studies also suggest a modulatory role of neurosteroids in anxiety-related phenotypes. However, little is known about the contribution of genetic variants in genes relevant for the neurosteroidogenesis to anxiety disorders.
Major depressive disorder is a serious psychiatric illness with a highly variable and heterogeneous clinical course. Due to the lack of consistent data from previous studies, the study of morphometric changes in major depressive disorder is still a major point of research requiring additional studies. The aim of the study presented here was to characterize and quantify regional gray matter abnormalities in a large sample of clinically well-characterized patients with major depressive disorder.
Self-concept is deeply affected in schizophrenia. Positive symptoms in particular are related to disturbed self/other distinctions. The neural networks underlying self-evaluation in schizophrenia have barely been investigated. The study reported here involved 13 patients with schizophrenia and 13 matched controls. During functional MRI, participants decided in three conditions whether the presented positive and negative personality traits characterized themselves, an intimate person, or included a certain letter. Based on the responses, each experimental condition was designed using a flexible factorial model. Controls and patients showed a similar behavioral pattern during self-evaluation, with group comparison revealing decreased activation in patients in the left inferior temporal gyrus and both temporal poles during self-ascription of traits, and in the anterior medial prefrontal cortex during evaluation of an intimate person. In patients, positive symptoms correlated positively with brain activation in the left parahippocampus during trait self-ascription. Hence, while evaluating themselves, schizophrenia patients revealed decreased activation in areas related to self-awareness overlapping with networks involved in theory of mind, empathy and social knowledge. Moreover, patients brain activation during self-reflection was affected by the current positive symptomatology. The close interaction between self and other highlights the clinical and social relevance of self-processing deficits in schizophrenia.
Objective: The mechanisms of action underlying treatment are inadequately understood. This study examined 5 variables implicated in the treatment of panic disorder with agoraphobia (PD/AG): catastrophic agoraphobic cognitions, anxiety about bodily sensations, agoraphobic avoidance, anxiety sensitivity, and psychological flexibility. The relative importance of these process variables was examined across treatment phases: (a) psychoeducation/interoceptive exposure, (b) in situ exposure, and (c) generalization/follow-up. Method: Data came from a randomized controlled trial of cognitive behavioral therapy for PD/AG (n = 301). Outcomes were the Panic and Agoraphobia Scale (Bandelow, 1995) and functioning as measured in the Clinical Global Impression scale (Guy, 1976). The effect of process variables on subsequent change in outcome variables was calculated using bivariate latent difference score modeling. Results: Change in panic symptomatology was preceded by catastrophic appraisal and agoraphobic avoidance across all phases of treatment, by anxiety sensitivity during generalization/follow-up, and by psychological flexibility during exposure in situ. Change in functioning was preceded by agoraphobic avoidance and psychological flexibility across all phases of treatment, by fear of bodily symptoms during generalization/follow-up, and by anxiety sensitivity during exposure. Conclusions: The effects of process variables on outcomes differ across treatment phases and outcomes (i.e., symptomatology vs. functioning). Agoraphobic avoidance and psychological flexibility should be investigated and therapeutically targeted in addition to cognitive variables. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
Although exposure-based cognitive-behavioral therapy (CBT) is an effective treatment option for panic disorder with agoraphobia, the neural substrates of treatment response remain unknown. Evidence suggests that panic disorder with agoraphobia is characterized by dysfunctional safety signal processing. Using fear conditioning as a neurofunctional probe, the authors investigated neural baseline characteristics and neuroplastic changes after CBT that were associated with treatment outcome in patients with panic disorder with agoraphobia.
The left superior temporal sulcus (STS) plays an important role in integrating audiovisual information and is functionally connected to disparate regions of the brain. For the integration of gesture information in an abstract sentence context (metaphoric gestures), intact connectivity between the left STS and the inferior frontal gyrus (IFG) should be important. Patients with schizophrenia have problems with the processing of metaphors (concretism) and show aberrant structural connectivity of long fiber bundles. Thus, we tested the hypothesis that patients with schizophrenia differ in the functional connectivity of the left STS to the IFG for the processing of metaphoric gestures. During functional magnetic resonance imaging data acquisition, 16 patients with schizophrenia (P) and a healthy control group (C) were shown videos of an actor performing gestures in a concrete (iconic, IC) and abstract (metaphoric, MP) sentence context. A psychophysiological interaction analysis based on the seed region from a previous analysis in the left STS was performed. In both groups we found common positive connectivity for IC and MP of the STS seed region to the left middle temporal gyrus (MTG) and left ventral IFG. The interaction of group (C>P) and gesture condition (MP>IC) revealed effects in the connectivity to the bilateral IFG and the left MTG with patients exhibiting lower connectivity for the MP condition. In schizophrenia the left STS is misconnected to the IFG, particularly during the processing of MP gestures. Dysfunctional integration of gestures in an abstract sentence context might be the basis of certain interpersonal communication problems in the patients.
Genome-wide association studies have identified the CACNA1C single nucleotide polymorphism (SNP) rs1006737 as one of the most consistent genetic findings as susceptibility locus for major psychiatric disorders. Furthermore, animal and genetic imaging studies have reported strong functional evidence for the association of CACNA1C with learning, memory, neural plasticity, and its association with the hippocampal formation. In the present study we investigated the impact of the CACNA1C SNP rs1006737 on the fractional anisotropy (FA) in the hippocampal formation as well as on verbal learning and memory in healthy individuals.
Social cognition and the corresponding functionality of involved brain networks are essential for effortless social interaction. Patients with schizophrenia exhibit impaired social functioning. In this study, we focused on the neural networks involved in the automatic perception of cooperative behavior and their alterations in schizophrenia. We performed a functional magnetic resonance imaging study of 19 schizophrenia patients and 19 healthy matched controls. Participants watched a set of short videos with two actors manipulating objects, either with (C+) or without cooperation (C-). Additionally, we assessed delusional symptoms in patients using the Scales for the Assessment of Positive Symptoms and psychosis proneness in healthy controls using the brief schizotypal personality questionnaire. The observed group-by-condition interaction revealed a contrasting activation pattern for patients versus healthy controls in the medial and lateral prefrontal cortex, the middle cingulate cortex, and the left angular gyrus. Furthermore, increased activation of the middle prefrontal areas, left angular gyrus, and the posterior sulcus temporalis superior in response to the noncooperative condition (C-) was positively correlated with delusional symptoms in patients. Our findings suggest an overactivated "theory of mind" network in patients for the processing of noncooperative behavior. Thus, "overmentalizing" might be based on delusions and altered processing of cooperative behavior in patients with schizophrenia.
Understanding cause and effect is a fundamental aspect of human cognition. When shown videos of simple two-dimensional shapes colliding, humans experience one object causing the other to move, e.g., one billiard-like ball seeming to hit and move the other. The impression of causality can also occur when people attribute social interactions to moving objects. Whether the judgment of social and physical causality engages distinct or shared neural networks is not known. In a functional magnetic imaging (fMRI) study, participants were presented with two types of dynamic videos: a blue ball colliding with a red ball (P; physical condition) and a blue ball ("Mr. Blue") passing a red ball ("Mrs. Red") without making contact (S; social condition). Participants judged causal relationships (C) or movement direction (D; control task) in both video types, resulting in four conditions (PC; SC; PD; SD). We found common neural activations for physical and social causality judgments (SC > SD)?(PC > PD) in the right middle/inferior frontal gyrus, right inferior parietal lobule, the right supplementary motor area, and bilateral insulae. For social causal judgments (SC > PC), we found distinct neural activity in the right temporo-parietal junction (rTPJ). These results provide evidence for a common neural network underlying judgments of causality that apply to both physical and social situations. The results also indicate that social causality judgments recruit additional neural resources in an area critical for determining animacy and intentionality.
The alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene is one of the best replicated susceptibility loci for bipolar disorder, schizophrenia and major depression. It is involved in learning, memory and brain plasticity. Genetic studies using functional magnetic resonance imaging (fMRI) reported evidence of association with the CACNA1C single nucleotide polymorphism rs1006737 with functional correlates of episodic memory encoding and retrieval, especially activations in the hippocampus. These results, however, are inconsistent with regard to the magnitude and directionality of effect. In the present study, brain activation was measured with fMRI during an episodic memory encoding and retrieval task using neutral faces in two independent samples of 94 and 111 healthy subjects, respectively. Within whole brain analyses, a main effect of genotype emerged mainly in the right hippocampus during encoding as well as retrieval within the first sample: Carriers of the minor allele (A) exhibited lower activations compared to G/G allele carriers. This effect could be replicated within the second sample, however, only for the retrieval condition. The results strengthen findings that rs1006737 is associated with neural systems related to memory processes in hippocampal regions which are detectable in healthy subjects.
Although homework assignments are an integral component of cognitive-behavioral therapy (CBT) and relate to positive therapy outcomes, it is unclear whether specific homework types and their completion have specific effects on outcome.
Patients with schizophrenia have semantic processing disturbances leading to expressive language deficits (formal thought disorder). The underlying pathology has been related to alterations in the semantic network and its neural correlates. Moreover, crossmodal processing, an important aspect of communication, is impaired in schizophrenia. Here we investigated specific processing abnormalities in patients with schizophrenia with regard to modality and semantic distance in a semantic priming paradigm. Fourteen patients with schizophrenia and fourteen demographically matched controls made visual lexical decisions on successively presented word-pairs (SOA = 350 ms) with direct or indirect relations, unrelated word-pairs, and pseudoword-target stimuli during fMRI measurement. Stimuli were presented in a unimodal (visual) or crossmodal (auditory-visual) fashion. On the neural level, the effect of semantic relation indicated differences (patients > controls) within the right angular gyrus and precuneus. The effect of modality revealed differences (controls > patients) within the left superior frontal, middle temporal, inferior occipital, right angular gyri, and anterior cingulate cortex. Semantic distance (direct vs. indirect) induced distinct activations within the left middle temporal, fusiform gyrus, right precuneus, and thalamus with patients showing fewer differences between direct and indirect word-pairs. The results highlight aberrant priming-related brain responses in patients with schizophrenia. Enhanced activation for patients possibly reflects deficits in semantic processes that might be caused by a delayed and enhanced spread of activation within the semantic network. Modality-specific decreases of activation in patients might be related to impaired perceptual integration. Those deficits could induce and increase the prominent symptoms of schizophrenia like impaired speech processing.
The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.
The Scale for the Assessment of Thought, Language and Communication (TLC) represents an instrument for the assessment of formal thought disorder (FTD). The factorial dimensionality of the TLC has yielded ambiguous results for a distinction between positive (e.g. circumstantiality) and negative (e.g. poverty of speech) FTD. The purpose of the current study was to first translate and validate the TLC scale in German. Second, the internal structure was explored in order to identify different FTD dimensions. Two hundred and ten participants (146 patients with ICD-10 diagnoses: depression n = 63, schizophrenia n = 63, mania n = 20; 64 healthy subjects) were interviewed and FTD was rated with the TLC. The principal component analysis of the German TLC version revealed a 3-factor solution, reflecting a disorganized factor, an emptiness factor and a linguistic control factor. The current investigation yielded similar results to those originally reported for the TLC. Thus, a distinction between a positive disorganized, a negative and a semantic word level factor can be supported for the German translation.
Attributions are constantly assigned in everyday life. A well-known phenomenon is the self-serving bias: that is, peoples tendency to attribute positive events to internal causes (themselves) and negative events to external causes (other persons/circumstances). Here, we investigated the neural correlates of the cognitive processes implicated in self-serving attributions using social situations that differed in their emotional saliences. We administered an attributional bias task during fMRI scanning in a large sample of healthy subjects (n = 71). Eighty sentences describing positive or negative social situations were presented, and subjects decided via buttonpress whether the situation had been caused by themselves or by the other person involved. Comparing positive with negative sentences revealed activations of the bilateral posterior cingulate cortex (PCC). Self-attribution correlated with activation of the posterior portion of the precuneus. However, self-attributed positive versus negative sentences showed activation of the anterior portion of the precuneus, and self-attributed negative versus positive sentences demonstrated activation of the bilateral insular cortex. All significant activations were reported with a statistical threshold of p ? .001, uncorrected. In addition, a comparison of our fMRI task with data from the Internal, Personal and Situational Attributions Questionnaire, Revised German Version, demonstrated convergent validity. Our findings suggest that the precuneus and the PCC are involved in the evaluation of social events with particular regional specificities: The PCC is activated during emotional evaluation, the posterior precuneus during attributional evaluation, and the anterior precuneus during self-serving processes. Furthermore, we assume that insula activation is a correlate of awareness of personal agency in negative situations.
The mechanisms underlying hemispheric specialization of memory are not completely understood. Functional magnetic resonance imaging (fMRI) can be used to develop and test models of hemispheric specialization. In particular for memory tasks however, the interpretation of fMRI results is often hampered by the low reliability of the data. In the present study we therefore analyzed the test-retest reliability of fMRI brain activation related to an implicit memory encoding task, with a particular focus on brain activity of the medial temporal lobe (MTL). Fifteen healthy subjects were scanned with fMRI on two sessions (average retest interval 35?days) using a commonly applied novelty encoding paradigm contrasting known and unknown stimuli. To assess brain lateralization, we used three different stimuli classes that differed in their verbalizability (words, scenes, fractals). Test-retest reliability of fMRI brain activation was assessed by an intraclass-correlation coefficient (ICC), describing the stability of inter-individual differences in the brain activation magnitude over time. We found as expected a left-lateralized brain activation network for the words paradigm, a bilateral network for the scenes paradigm, and predominantly right-hemispheric brain activation for the fractals paradigm. Although these networks were consistently activated in both sessions on the group level, across-subject reliabilities were only poor to fair (ICCs???0.45). Overall, the highest ICC values were obtained for the scenes paradigm, but only in strongly activated brain regions. In particular the reliability of brain activity of the MTL was poor for all paradigms. In conclusion, for novelty encoding paradigms the interpretation of fMRI results on a single subject level is hampered by its low reliability. More studies are needed to optimize the retest reliability of fMRI activation for memory tasks.
Background: Pauses during speech may reflect the planning and monitoring of discourse, two processes putatively impaired in patients with schizophrenia, particularly those with formal thought disorder (FTD). We used functional MRI to examine the neural correlates of between-clause and of filled pauses, which are respectively associated with speech planning and speech monitoring. Methods: BOLD contrast was measured while six schizophrenia patients with FTD and six healthy subjects spoke about Rorshach inkblots. In an event-related design, we examined activity associated with pauses that occurred between clauses and with pauses that were filled. Results: There was no significant group difference in the frequency of between-clause pauses but patients with FTD made strikingly fewer filled pauses than controls. Between-clause pauses were associated with activation in the anterior part of the left superior temporal gyrus (STG) and the left insula in controls and the engagement of these regions was significantly attenuated in patients. Conclusion: The anterior part of the left STG and the left insula are normally involved in both the planning and monitoring of discourse. The attenuated engagement of these regions with between-clause pauses and the striking infrequency of filled pauses in the patients are consistent with cognitive models implicating defective speech planning and speech monitoring in schizophrenia, especially in relation to FTD.
Many figurative expressions are fully conventionalized in everyday speech. Regarding the neural basis of figurative language processing, research has predominantly focused on metaphoric expressions in minimal semantic context. It remains unclear in how far metaphoric expressions during continuous text comprehension activate similar neural networks as isolated metaphors. We therefore investigated the processing of similes (figurative language, e.g., "He smokes like a chimney!") occurring in a short story. Sixteen healthy, male, native German speakers listened to similes that came about naturally in a short story, while blood-oxygenation-level-dependent (BOLD) responses were measured with functional magnetic resonance imaging (fMRI). For the event-related analysis, similes were contrasted with non-figurative control sentences (CS). The stimuli differed with respect to figurativeness, while they were matched for frequency of words, number of syllables, plausibility, and comprehensibility. Similes contrasted with CS resulted in enhanced BOLD responses in the left inferior (IFG) and adjacent middle frontal gyrus. Concrete CS as compared to similes activated the bilateral middle temporal gyri as well as the right precuneus and the left middle frontal gyrus (LMFG). Activation of the left IFG for similes in a short story is consistent with results on single sentence metaphor processing. The findings strengthen the importance of the left inferior frontal region in the processing of abstract figurative speech during continuous, ecologically-valid speech comprehension; the processing of concrete semantic contents goes along with a down-regulation of bilateral temporal regions.
ness and modality of interpersonal communication have a considerable impact on comprehension. They are relevant for determining thoughts and constituting internal models of the environment. Whereas concrete object-related information can be represented in mind irrespective of language, abstract concepts require a representation in speech. Consequently, modality-independent processing of abstract information can be expected. Here we investigated the neural correlates of abstractness (abstract vs. concrete) and modality (speech vs. gestures), to identify an abstractness-specific supramodal neural network. During fMRI data acquisition 20 participants were presented with videos of an actor either speaking sentences with an abstract-social [AS] or concrete-object-related content [CS], or performing meaningful abstract-social emblematic [AG] or concrete-object-related tool-use gestures [CG]. Gestures were accompanied by a foreign language to increase the comparability between conditions and to frame the communication context of the gesture videos. Participants performed a content judgment task referring to the person vs. object-relatedness of the utterances. The behavioral data suggest a comparable comprehension of contents communicated by speech or gesture. Furthermore, we found common neural processing for abstract information independent of modality (AS > CS ? AG > CG) in a left hemispheric network including the left inferior frontal gyrus (IFG), temporal pole, and medial frontal cortex. Modality specific activations were found in bilateral occipital, parietal, and temporal as well as right inferior frontal brain regions for gesture (G > S) and in left anterior temporal regions and the left angular gyrus for the processing of speech semantics (S > G). These data support the idea that abstract concepts are represented in a supramodal manner. Consequently, gestures referring to abstract concepts are processed in a predominantly left hemispheric language related neural network.
Imitation of facial expressions engages the putative human mirror neuron system as well as the insula and the amygdala as part of the limbic system. The specific function of the latter two regions during emotional actions is still under debate. The current study investigated brain responses during imitation of positive in comparison to non-emotional facial expressions. Differences in brain activation of the amygdala and insula were additionally examined during observation and execution of facial expressions. Participants imitated, executed and observed happy and non-emotional facial expressions, as well as neutral faces. During imitation, higher right hemispheric activation emerged in the happy compared to the non-emotional condition in the right anterior insula and the right amygdala, in addition to the pre-supplementary motor area, middle temporal gyrus and the inferior frontal gyrus. Region-of-interest analyses revealed that the right insula was more strongly recruited by (i) imitation and execution than by observation of facial expressions, that (ii) the insula was significantly stronger activated by happy than by non-emotional facial expressions during observation and imitation and that (iii) the activation differences in the right amygdala between happy and non-emotional facial expressions were increased during imitation and execution, in comparison to sole observation. We suggest that the insula and the amygdala contribute specifically to the happy emotional connotation of the facial expressions depending on the task. The pattern of the insula activity might reflect increased bodily awareness during active execution compared to passive observation and during visual processing of the happy compared to non-emotional facial expressions. The activation specific for the happy facial expression of the amygdala during motor tasks, but not in the observation condition, might reflect increased autonomic activity or feedback from facial muscles to the amygdala.
Supramodal representation of emotion and its neural substrates have recently attracted attention as a marker of social cognition. However, the question whether perceptual integration of facial and vocal emotions takes place in primary sensory areas, multimodal cortices, or in affective structures remains unanswered yet. Using novel computer-generated stimuli, we combined emotional faces and voices in congruent and incongruent ways and assessed functional brain data (fMRI) during an emotional classification task. Both congruent and incongruent audiovisual stimuli evoked larger responses in thalamus and superior temporal regions compared with unimodal conditions. Congruent emotions were characterized by activation in amygdala, insula, ventral posterior cingulate (vPCC), temporo-occipital, and auditory cortices; incongruent emotions activated a frontoparietal network and bilateral caudate nucleus, indicating a greater processing load in working memory and emotion-encoding areas. The vPCC alone exhibited differential reactions to congruency and incongruency for all emotion categories and can thus be considered a central structure for supramodal representation of complex emotional information. Moreover, the left amygdala reflected supramodal representation of happy stimuli. These findings document that emotional information does not merge at the perceptual audiovisual integration level in unimodal or multimodal areas, but in vPCC and amygdala.
The N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. Administered to healthy individuals, a subanesthetic dose of the noncompetitive NMDAR antagonist ketamine reproduces several psychopathological symptoms commonly observed in patients with schizophrenia. In a counterbalanced, placebo-controlled, double-blind, within-participants study, fifteen healthy subjects were administered a continuous subanesthetic S-ketamine infusion while cortical activation was measured using functional magnetic resonance imaging. While being scanned, subjects performed an overt word generation task. Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Ketamine administration elicited effects on psychopathology, including difficulties in abstract thinking, lack of spontaneity and flow of conversation as well as formal thought disorder. On a behavioral level, verbal fluency performance was unaffected. The PANSS score for formal thought disorder positively correlated with activation measures encompassing the left superior temporal gyrus, the right middle and inferior frontal gyrus and the precuneus. Difficulty in abstract thinking was correlated with pronounced activations in prefrontal as well as in anterior cingulate regions, whereas hyperactivations in the left superior temporal gyrus were found in association with a lack of spontaneity and flow of conversation. In the absence of behavioral impairments during verbal fluency, NMDAR blocking evoked psychopathological symptoms and cortical activations in regions previously reported in schizophrenia patients. The results provide further support for the hypothesis of an NMDAR dysfunction in the pathophysiology of schizophrenia.
Neurogranin (NRGN) is the main postsynaptic protein regulating the availability of calmodulin-Ca(2+) in neurons. NRGN is expressed exclusively in the brain, particularly in dendritic spines and has been implicated in spatial learning and hippocampal plasticity. Genetic variation in rs12807809 in the NRGN gene has recently been confirmed to be associated with schizophrenia in a meta-analysis of genome-wide association studies: the T-allele was found to be genome-wide significantly associated with schizophrenia. Cognitive tests and personality questionnaires were administered in a large sample of healthy subjects. Brain activation was measured with functional magnetic resonance imaging (fMRI) during an episodic memory encoding and retrieval task in a subsample. All subjects were genotyped for NRGN rs12807809. There was no effect of genotype on personality or cognitive measures in the large sample. Homozygote carriers of the T-allele showed better performance in the retrieval task during fMRI. After controlling for memory performance, differential brain activation was evident in the anterior cingulate cortex for the encoding and posterior cingulate regions during retrieval. We could demonstrate that rs12807809 of NRGN is associated with differential neural functioning in the anterior and posterior cingulate. These areas are involved in episodic memory processes and have been implicated in the pathophysiology of schizophrenia in structural and functional imaging as well as postmortem studies.
Functional magnetic resonance imaging (fMRI) can be combined with genotype assessment to identify brain systems that mediate genetic vulnerability to mental disorders ("imaging genetics"). A data analysis approach that is widely applied is "functional connectivity". In this approach, the temporal correlation between the fMRI signal from a pre-defined brain region (the so-called "seed point") and other brain voxels is determined. In this technical note, we show how the choice of freely selectable data analysis parameters strongly influences the assessment of the genetic modulation of connectivity features. In our data analysis we exemplarily focus on three methodological parameters: (i) seed voxel selection, (ii) noise reduction algorithms, and (iii) use of additional second level covariates. Our results show that even small variations in the implementation of a functional connectivity analysis can have an impact on the connectivity pattern that is as strong as the potential modulation by genetic allele variants. Some effects of genetic variation can only be found for one specific implementation of the connectivity analysis. A reoccurring difficulty in the field of psychiatric genetics is the non-replication of initially promising findings, partly caused by the small effects of single genes. The replication of imaging genetic results is therefore crucial for the long-term assessment of genetic effects on neural connectivity parameters. For a meaningful comparison of imaging genetics studies however, it is therefore necessary to provide more details on specific methodological parameters (e.g., seed voxel distribution) and to give information how robust effects are across the choice of methodological parameters.
Schizophrenia is a severe neuropsychiatric disorder with high heritability, though its exact etiopathogenesis is yet unknown. An increasing number of studies point to the importance of white matter anomalies in the pathophysiology of schizophrenia. While several studies have identified the impact of schizophrenia susceptibility gene variants on gray matter anatomy in both schizophrenia patients and healthy risk variant carriers, studies dealing with the impact of these gene variants on white matter integrity are still scarce. We here present a study on the effects of a Dysbindin schizophrenia susceptibility gene variant on fiber tract integrity in healthy young subjects. 101 subjects genotyped for Dysbindin-gene variant rs1018381, though without personal or first degree relative history of psychiatric disorders underwent diffusion tensor imaging (DTI), 83 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) analysis to delineate the major fiber tracts. Carriers of the minor allele T of the rs1018381 in the Dysbindin gene showed two clusters of reduced fractional anisotropy (FA) values in the perihippocampal region of the right temporal lobe compared to homozygote carriers of the major allele C. Clusters of increased FA values in T-allele carriers were found in the left prefrontal white matter, the right fornix, the right midbrain area, the left callosal body, the left cerebellum and in proximity of the right superior medial gyrus. Dysbindin has been implicated in neurite outgrowth and morphology. Impairments in anatomic connectivity as found associated with the minor Dysbindin allele in our study may result in increased risk for schizophrenia due to altered fiber tracts.
The connection between cholinergic transmission and cognitive performance has been established in behavioural studies. The specific contribution of the muscarinic receptor system on cognitive performance and brain activation, however, has not been evaluated satisfyingly. To investigate the specific contribution of the muscarinic transmission on neural correlates of working memory, we examined the effects of scopolamine, an antagonist of the muscarinic receptors, using functional magnetic resonance imaging (fMRI). Fifteen healthy male, non-smoking subjects performed a fMRI scanning session following the application of scopolamine (0.4 mg, i.v.) or saline in a placebo-controlled, repeated measure, pseudo-randomized, single-blind design. Working memory was probed using an n-back task. Compared to placebo, challenging the cholinergic transmission with scopolamine resulted in hypoactivations in parietal, occipital and cerebellar areas and hyperactivations in frontal and prefrontal areas. These alterations are interpreted as compensatory strategies used to account for downregulation due to muscarinic acetylcholine blockade in parietal and cerebral storage systems by increased activation in frontal and prefrontal areas related to working memory rehearsal. Our results further underline the importance of cholinergic transmission to working memory performance and determine the specific contribution of muscarinic transmission on cerebral activation associated with executive functioning.
Video games are an exciting part of new media. Although game play has been intensively studied, the underlying neurobiology is still poorly understood. Flow theory is a well-established model developed to describe subjective game experience. In 13 healthy male subjects, we acquired fMRI data during free play of a video game and analyzed brain activity based on the game content. In accordance with flow theory, we extracted the following factors from the game content: (i) balance between ability and challenge; (ii) concentration and focus; (iii) direct feedback of action results; (iv) clear goals; and (v) control over the situation/activity. We suggest that flow is characterized by specific neural activation patterns and that the latter can be assessed-at least partially-by content factors contributing to the emergence of flow. Each of the content factors was characterized by specific and distinguishable brain activation patterns, encompassing reward-related midbrain structures, as well as cognitive and sensorimotor networks. The activation of sensory and motor networks in the conjunction analyses underpinned the central role of simulation for flow experience. Flow factors can be validated with functional brain imaging which can improve the understanding of human emotions and motivational processes during media entertainment.
Genome-wide association studies identified the single nucleotide polymorphism rs1344706 in ZNF804A as a common risk-variant for schizophrenia and bipolar disorder. Whereas the molecular function of ZNF804A is yet unclear, recent imaging genetics studies have started to characterize the neural systems architecture linking rs1344706 genotype to psychosis. Carring rs1344706 risk-alleles was associated with a decrease in functional connectivity within the dorsolateral prefrontal cortices (DLPFCs) as well as an increase in connectivity between the DLPFC and the hippocampal formation (HF) in the context of a working memory task. The present study aimed at replicating these findings in an independent sample of 94 healthy subjects. Subjects were genotyped for rs1344706 and performed a working memory task during functional magnetic resonance imaging. Results indicate no support for a decrease of functional coupling between the bilateral DLPFCs at higher ZNF804A risk status. However, the current data show the previously described alteration in functional coupling between the right DLPFC and the HFs, albeit with weaker effects. Decoupled by default, the functional connectivity between the right DLPFC and anterior HFs increased with the number of rs1344706 risk alleles. The present data support fronto-hippocampal dysconnectivity as intermediate phenotype linking rs1344706 genotype to psychosis. We discuss the issues in replicating the interhemispheric DLPFC coupling in light of the effect sizes rs1344706 genotype has on brain function, concluding that further independent replication studies are fundamentally needed to ascertain the role of rs1344706 in the functional integration of neural systems.
Cognitive-behavioral therapy (CBT) is a first-line treatment for panic disorder with agoraphobia (PD/AG). Nevertheless, an understanding of its mechanisms and particularly the role of therapist-guided exposure is lacking. This study was aimed to evaluate whether therapist-guided exposure in situ is associated with more pervasive and long-lasting effects than therapist-prescribed exposure in situ.
Emotions influence our everyday life in several ways. With the present study, we wanted to examine the impact of emotional information on neural correlates of semantic priming, a well-established technique to investigate semantic processing. Stimuli were presented with a short SOA of 200 ms as subjects performed a lexical decision task during fMRI measurement. Seven experimental conditions were compared: positive/negative/neutral related, positive/negative/neutral unrelated, nonwords (all words were nouns). Behavioral data revealed a valence specific semantic priming effect (i.e., unrelated > related) only for neutral and positive related word pairs. On a neural level, the comparison of emotional over neutral relations showed activation in left anterior medial frontal cortex, superior frontal gyrus, and posterior cingulate. Interactions for the different relations were located in left anterior part of the medial frontal cortex, cingulate regions, and right hippocampus (positive > neutral + negative) and left posterior part of medial frontal cortex (negative > neutral + positive). The results showed that emotional information have an influence on semantic association processes. While positive and neutral information seem to share a semantic network, negative relations might induce compensatory mechanisms that inhibit the spread of activation between related concepts. The neural correlates highlighted a distributed neural network, primarily involving attention, memory and emotion related processing areas in medial fronto-parietal cortices. The differentiation between anterior (positive) and posterior part (negative) of the medial frontal cortex was linked to the type of affective manipulation with more cognitive demands being involved in the automatic processing of negative information.
The aim of our study was to examine brain networks involved with sustaining memory encoding performance in healthy aging and in Alzheimers disease (AD). Since different brain regions are affected by degradation in these two conditions, it might be conceivable that different compensation mechanisms occur to keep up memory performance in aging and in AD. Using an event-related functional magnetic resonance imaging (FMRI) design and a correlation analysis, 8 patients suffering from AD and 29 elderly control subjects were scanned while they studied a list of words for a subsequent memory test. Individual performance was assessed on the basis of a subsequent recognition test, and brain regions were identified where functional activations during study correlated with memory performance. In both groups, successful memory encoding performance was significantly correlated with the activation of the right frontal cortex. Furthermore, in healthy controls, there was a significant correlation of memory performance and the activation of the left medial and lateral temporal lobe. In contrast, in AD patients, increasing memory performance goes along with increasing activation of the hippocampus and a bilateral brain network including the frontal and temporal cortices. Our data show that in healthy aging and in AD, common and distinct compensatory mechanisms are employed to keep up a certain level of memory performance. Both in healthy aging and in patients with AD, an increased level of monitoring and control processes mediated by the (right) frontal lobe seems to be necessary to maintain a certain level of memory performance. In addition, memory performance in healthy older subjects seems to rely on an increased effort in encoding item-specific semantic and contextual information in lateral areas of the (left) temporal lobe. In AD patients, on the other hand, the maintenance of memory performance is related to an increase of activation of the (left) hippocampus in conjunction with a bilateral network of cortical areas that might be involved with phonological and visual rehearsal of the incoming information.
Real-time functional magnetic resonance imaging (rtfMRI) is a novel technique that has allowed subjects to achieve self-regulation of circumscribed brain regions. Despite its anticipated therapeutic benefits, there is no report on successful application of this technique in psychiatric populations. The objectives of the present study were to train schizophrenia patients to achieve volitional control of bilateral anterior insula cortex on multiple days, and to explore the effect of learned self-regulation on face emotion recognition (an extensively studied deficit in schizophrenia) and on brain network connectivity. Nine patients with schizophrenia were trained to regulate the hemodynamic response in bilateral anterior insula with contingent rtfMRI neurofeedback, through a 2-weeks training. At the end of the training stage, patients performed a face emotion recognition task to explore behavioral effects of learned self-regulation. A learning effect in self-regulation was found for bilateral anterior insula, which persisted through the training. Following successful self-regulation, patients recognized disgust faces more accurately and happy faces less accurately. Improvements in disgust recognition were correlated with levels of self-activation of right insula. RtfMRI training led to an increase in the number of the incoming and outgoing effective connections of the anterior insula. This study shows for the first time that patients with schizophrenia can learn volitional brain regulation by rtfMRI feedback training leading to changes in the perception of emotions and modulations of the brain network connectivity. These findings open the door for further studies of rtfMRI in severely ill psychiatric populations, and possible therapeutic applications.
Rhyming words, as in songs or poems, is a universal feature of human language across all ages. In the present fMRI study a novel overt rhyming task was applied to determine the neural correlates of rhyme production. Fifteen right-handed healthy male volunteers participated in this verbal fluency study. Participants were instructed to overtly articulate as many words as possible either to a given initial letter (LVF) or to a semantic category (SVF). During the rhyming verbal fluency task (RVF), participants had to generate words that rhymed with pseudoword stimuli. On-line overt verbal responses were audiotaped in order to correct the imaging results for the number of generated words. Fewer words were generated in the rhyming compared to both the lexical and the semantic condition. On a neural level, all language tasks activated a language network encompassing the left inferior frontal gyrus, the middle and superior temporal gyri as well as the contralateral right cerebellum. Rhyming verbal fluency compared to both lexical and semantic verbal fluency demonstrated significantly stronger activation of left inferior parietal region. Generating novel rhyme words seems to be mainly mediated by the left inferior parietal lobe, a region previously found to be associated with meta-phonological as well as sub-lexical linguistic processes.
People vicariously experience embarrassment when observing others public pratfalls or etiquette violations. In two consecutive studies we investigated the subjective experience and the neural correlates of vicarious embarrassment for others in a broad range of situations. We demonstrated, first, that vicarious embarrassment was experienced regardless of whether the observed protagonist acted accidentally or intentionally and was aware or unaware that he/she was in an embarrassing situation. Second, using functional magnetic resonance imaging (fMRI), we showed that the anterior cingulate cortex and the left anterior insula, two cortical structures typically involved in vicarious feelings of others pain, are also strongly implicated in experiencing the social pain for others flaws and pratfalls. This holds true even for situations that engage protagonists not aware of their current predicament. Importantly, the activity in the anterior cingulate cortex and the left anterior insula positively correlated with individual differences in trait empathy. The present findings establish the empathic process as a fundamental prerequisite for vicarious embarrassment experiences, thus connecting affect and cognition to interpersonal processes."When we are living with people who have a delicate sense of propriety, we are in misery on their account when anything unbecoming is committed. So I always feel for and with Charlotte when a person is tipping his chair. She cannot endure it." [Elective Affinities, J. W. Goethe].
Recent research on the neural integration of speech and gesture has examined either gesture in the context of concrete [iconic (IC) gestures] or abstract sentence content [metaphoric (MP) gestures]. However, there has not yet been a direct comparison of the processing of both gesture types. This study tested the theory that left posterior temporal and inferior frontal brain regions are each uniquely involved in the integration of IC and MP gestures. During fMRI-data acquisition, participants were shown videos of an actor performing IC and MP gestures and associated sentences. An isolated gesture (G) and isolated sentence condition (S) were included to separate unimodal from bimodal effects at the neural level. During IC conditions, we found increased activity in the left posterior middle temporal gyrus and its right hemispheric homologue. The same regions in addition to the left inferior frontal gyrus (IFG) were activated during MP conditions in contrast to the isolated conditions (G&S). These findings support the hypothesis that there are distinct integration processes for IC and MP gestures. In line with recent claims of the semantic unification theory, there seems to be a division between perceptual-matching processes within the posterior temporal lobe and higher-order relational processes within the IFG.
Although functional magnetic resonance imaging (fMRI) has gained increasing importance in investigating neural substrates of anxiety disorders, less is known about the stress eliciting properties of the scanner environment itself. The aim of the study was to investigate feasibility, self-reported distress and anxiety management strategies during an fMRI experiment in a comprehensive sample of patients with panic disorder and agoraphobia (PD/AG). Within the national research network PANIC-NET, n=89 patients and n=90 controls participated in a multicenter fMRI study. Subjects completed a retrospective questionnaire on self-reported distress, including a habituation profile and exploratory questions about helpful strategies. Drop-out rates and fMRI quality parameters were employed as markers of study feasibility. Different anxiety measures were used to identify patients particularly vulnerable to increased scanner anxiety and impaired data quality. Three (3.5%) patients terminated the session prematurely. While drop-out rates were comparable for patients and controls, data quality was moderately impaired in patients. Distress was significantly elevated in patients compared to controls; claustrophobic anxiety was furthermore associated with pronounced distress and lower fMRI data quality in patients. Patients reported helpful strategies, including motivational factors and cognitive coping strategies. The feasibility of large-scale fMRI studies on PD/AG patients could be proved. Study designs should nevertheless acknowledge that the MRI setting may enhance stress reactions. Future studies are needed to investigate the relationship between self-reported distress and fMRI data in patient groups that are subject to neuroimaging research.
Behavioral and electrophysiological data indicate compromised stimulus suppression in schizophrenia. The physiological basis of this effect and its contributions to the etiology of the disease are poorly understood. We examined neural and metabolic measures of P50 suppression in 12 patients with schizophrenia and controls. First, whole-head magnetoencephalography (MEG) assessed amplitudes of left- and right-hemispheric evoked responses and induced oscillations. Secondly, functional magnetic resonance imaging (fMRI) measured the hemodynamic responses to pairs of beeps with a short interval (500ms) as compared with those with a long interval (1500ms). The suppression of alpha power (8-13Hz) time-locked to the stimuli was negatively correlated with the suppression of evoked components and the hemodynamic measures. Remarkably, the suppression of alpha power was reduced in the patients already prior to stimulus onset. Conceivably, alpha oscillations play a central role in stimulus adaptation of neuronal networks and reflect an active mechanism for sensory suppression. The reduced stimulus suppression in schizophrenia seems to be in part due to impaired generation of alpha oscillations in the auditory cortex, resulting in higher metabolic demand as detected by fMRI. Delayed recovery of alpha rhythm may reflect an impaired gating function and contribute to sensory and cognitive deficits in schizophrenia.
Plant extracts such as Hypericum perforatum and Pycnogenol have been tested as alternatives to the classical ADHD drugs. It has been possible to describe neuroprotective effects of such plant extracts. A reduction of ADHD symptoms could be shown in clinical studies after the application of Pycnogenol, which is a pine bark extract. The impacts of the standardized herbal extracts Hypericum perforatum, Pycnogenol and Enzogenol up to a concentration of 5000 ng/mL on cell survival and energy metabolism in human SH-SY5Y neuroblastoma cells has been investigated in the present examination. Hypericum perforatum significantly decreased the survival of cells after treatment with a concentration of 5000 ng/mL, whereas lower concentrations exerted no significant effects. Pycnogenol( induced a significant increase of cell survival after incubation with a concentration of 32.25?ng/mL and a concentration of 250 ng/mL. Other applied concentrations of Pycnogenol failed to exert significant effects. Treatment with Enzogenol did not lead to significant changes in cell survival.Concerning energy metabolism, the treatment of cells with a concentration of 5000 ng/mL Hypericum perforatum led to a significant increase of ATP levels, whereas treatment with a concentration of 500 ng/mL had no significant effect. Incubation of cells with Pycnogenol and Enzogenol exerted no significant effects.None of the tested substances caused any cytotoxic effect when used in therapeutically relevant concentrations.
It has been demonstrated that cognitive behavioural therapy (CBT) has a moderate effect on symptom reduction and on general well being of patients suffering from psychosis. However, questions regarding the specific efficacy of CBT, the treatment safety, the cost-effectiveness, and the moderators and mediators of treatment effects are still a major issue. The major objective of this trial is to investigate whether CBT is specifically efficacious in reducing positive symptoms when compared with non-specific supportive therapy (ST) which does not implement CBT-techniques but provides comparable therapeutic attention.
The production of language is one of the most complex and amazing skills in humans. Increasing evidence demonstrated that associative relations (e.g., car - garage) play an important role during concept formation but during speech production the effects and processing of associations are highly debated. Hence, the present study investigated the impact of associations and different SOAs on the production of sentences (Experiment 1) and on naming objects (Experiment 2). In an adapted version of the picture-word interference task, participants were asked to name two pictures using a standardized sentence (e.g., "The car is to the left of the trousers"). Thereby, a simultaneous (SOA is 0 ms) or slightly preceding (SOA is -150 ms) auditory or visual distractor had to be ignored. Distractors were related to the first noun (for example: "The car is to the left to the trousers", distractor: "garage") or to the second noun (distractor: "belt") or unrelated to both nouns (distractor: "bottle") of the sentence. At simultaneous presentation, visual and auditory distractors related to the first noun of the sentence prolonged naming responses (i.e., interference). For slightly preceding distractors, only visual presentation induced interference for the first noun of the sentence. During no condition, longer naming responses were found for the second noun of the sentence. These effects suggest that associatively related concepts are active during speech production and can be competitors, i.e., they lead to semantic interference. In Experiment 2, subjects had to name an object (e.g., car) while ignoring a visually presented distractor (e.g., motor). The stimulus set was the same as in Experiment 1. The results showed a facilitation effect if the distractor and the target were associatively related. Overall, the current results provide new insight in the models of speech production: while during single word production, associations facilitate naming, they interfere during sentence production. Hence, associations have an important influence on producing speech but the impact is varied by the context, i.e., single word or sentential.
The cholinergic system is essential in mediating cognitive processes. Although there has been extensive research regarding cholinergic receptor subsystems, the specific contribution of the muscarinic and nicotinic receptor system to cognitive processes still has not been sufficiently explored. In the present study, we examined the selective contribution of muscarinic and nicotinic antagonism to cognitive performance in healthy human subjects. A single-blind, double-dummy, time-elapsed, repeated measures cross-over design was used on 15 healthy males. Subjects completed a neuropsychological test battery assessing a wide range of cognitive domains after 0.4 mg scopolamine (intravenous), 0.2 mg/kg mecamylamine (max. 15 mg; oral) or placebo. Subjects were tested under three conditions: placebo/placebo (PP), scopolamine/placebo (SP) and mecamylamine/placebo (MP). Results show that scopolamine significantly impaired the free recall and recognition performance in the verbal learning test. No other cognitive domain was affected, neither by scopolamine nor by mecamylamine. In line with the existing literature, antagonism of muscarinic receptors resulted in specific cognitive impairments, predominantly memory performance.
Semantic judgments involve both representations of meaning plus executive mechanisms that guide knowledge retrieval in a task-appropriate way. These 2 components of semantic cognition-representation and control-are commonly linked to left temporal and prefrontal cortex, respectively. This simple proposal, however, remains contentious because in most functional neuroimaging studies to date, the number of concepts being activated and the involvement of executive processes during retrieval are confounded. Using functional magnetic resonance imaging, we examined a task in which semantic representation and control demands were dissociable. Words with multiple meanings like "bank" served as targets in a double-prime paradigm, in which multiple meaning activation and maximal executive demands loaded onto different priming conditions. Anterior inferior temporal gyrus (ITG) was sensitive to the number of meanings that were retrieved, suggesting a role for this region in semantic representation, while posterior middle temporal gyrus (pMTG) and inferior frontal cortex showed greater activation in conditions that maximized executive demands. These results support a functional dissociation between left ITG and pMTG, consistent with a revised neural organization in which left prefrontal and posterior temporal areas work together to underpin aspects of semantic control.
The glutamatergic N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Administered to healthy volunteers, a subanesthetic dose of the non-competitive NMDA receptor antagonist ketamine leads to psychopathological symptoms similar to those observed in schizophrenia. In patients with schizophrenia, ketamine exacerbates the core symptoms of illness, supporting the hypothesis of a glutamatergic dysfunction. In a counterbalanced, placebo-controlled, double-blind study design, healthy subjects were administered a continuous subanesthetic S-ketamine infusion while differences in BOLD responses measured with fMRI were detected. During the scanning period, subjects performed continuous overt verbal fluency tasks (phonological, lexical and semantic). Ketamine-induced psychopathological symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Ketamine elicited psychosis like psychopathology. Post-hoc t-tests revealed significant differences between placebo and ketamine for the amounts of words generated during lexical and semantic verbal fluency, while the phonological domain remained unaffected. Ketamine led to enhanced cortical activations in supramarginal and frontal brain regions for phonological and lexical verbal fluency, but not for semantic verbal fluency. Ketamine induces activation changes in healthy subjects similar to those observed in patients with schizophrenia, particularly in frontal and temporal brain regions. Our results provide further support for the hypothesis of an NMDA receptor dysfunction in the pathophysiology of schizophrenia.
Tourettes syndrome is characterised by motor and vocal tics as well as a high level of impulsivity and emotional dysregulation. Neuroimaging studies point to structural changes of the basal ganglia, prefrontal cortex and parts of the limbic system. However, there is no link between behavioural symptoms and the structural changes in the amygdala. One aspect of daily social interaction is the perception of emotional facial expressions, closely linked to amgydala function.
In social situations, we encounter information transferred in firsthand (egocentric) and secondhand (allocentric) communication contexts. However, the mechanism by which an individual distinguishes whether a past interaction occurred in an egocentric versus allocentric situation is poorly understood. This study examined the neural bases for encoding memories of social interactions through experimentally manipulating the communication context. During fMRI data acquisition, participants watched video clips of an actor speaking and gesturing directly toward them (egocentric context) or toward an unseen third person (allocentric context). After scanning, a recognition task gauged participants ability to recognize the sentences they had just seen and to recall the context in which the sentences had been spoken. We found no differences between the recognition of sentences spoken in egocentric and allocentric contexts. However, when asked about the communication context ("Had the actor directly spoken to you?"), participants tended to believe falsely that the actor had directly spoken to them during allocentric conditions. Greater activity in the hippocampus was related to correct context memory, whereas the ventral ACC was activated for subsequent inaccurate context memory. For the interaction between encoding context and context memory, we observed increased activation for egocentric remembered items in the bilateral and medial frontal cortex, the BG, and the left parietal and temporal lobe. Our data indicate that memories of social interactions are biased to be remembered egocentrically. Self-referential encoding processes reflected in increased frontal activation and decreased hippocampal activation might be the basis of correct item but false context memory of social interactions.
The objective of this short review is to highlight rewarding aspects of social interactions for humans and discuss their neural basis. Thereby we report recent research findings to illustrate how social stimuli in general are processed in the reward system and highlight the role of Theory of Mind as one mediating process for experiencing social reward during social interactions. In conclusion we discuss clinical implications for psychiatry and psychotherapy.
Oxidative stress (OS), is defined as an imbalance of pro- and antioxidants, leading to increased production of free radicals, which can lead to cell damage and death, has been postulated as important factors in the pathogenesis of neurodegenerative disorders such as Alzheimers disease (AD). Most research has concentrated on the antioxidant system, for the first time, this proof of concept study examines the prooxidant system by investigating kinetic parameters of the free radical producing enzyme xanthine oxidase directly in post mortem brain tissue.
The "self-reference effect" describes better memory for material someone has related to ones self previously. Schizophrenia can affect aspects of the inner self such as own thoughts or actions. Schizophrenia symptoms, therefore, might not only have an influence on the self-concept, including the self-attribution of positive or negative personality traits, but also reduce the self-reference effect. 15 schizophrenia patients and 15 matched healthy controls were asked to decide on positive and negative personality traits across three separate conditions: self-evaluation, other evaluation (of an intimate person), and during a lexical control task, respectively. An unannounced recognition task followed. Patients revealed a negative bias in the evaluation of themselves and of the well-known other person. The reference to a person (oneself, close other) increased later recognition performance. However, patients with schizophrenia revealed an overall decreased recognition performance. The amount of patients passivity symptoms, i.e., an increase in the permeability of their "self-other boundary", correlated negatively with their recognition performance for previously self-referred characteristics and traits referred to the intimate other. This was not the case for lexically processed stimuli or an increase of negative symptoms. Our data underline the necessity of taking into account symptom subgroups when dealing with specific cognitive dysfunctions in schizophrenia.
Attention deficits belong to the main cognitive symptoms of schizophrenia and come along with altered neural activity in previously described cerebral networks. Given the high heritability of schizophrenia the question arises if impaired function of these networks is modulated by susceptibility genes and detectable in healthy risk allele carriers.
Semantic priming, a well-established technique to study conceptual representation, has thus far produced variable fMRI results, both regarding the type of priming effects and their correlation with brain activation. The aims of the current study were (a) to investigate two types of semantic relations--categorical versus associative--under controlled processing conditions and (b) to investigate whether categorical and associative relations between words are correlated with response enhancement or response suppression. We used fMRI to examine neural correlates of semantic priming as subjects performed a lexical decision task with a long SOA (800 msec). Four experimental conditions were compared: categorically related trials (couch-bed), associatively related trials (couch-pillow), unrelated trials (couch-bridge), and nonword trials (couch-sibor). We found similar behavioral priming effects for both categorically and associatively related pairs. However, the neural priming effects differed: Categorically related pairs resulted in a neural suppression effect in the right MFG, whereas associatively related pairs resulted in response enhancement in the left IFG. A direct contrast between them revealed activation for categorically related trials in the right insular lobe. We conclude that perceptual and functional similarity of categorically related words may lead to response suppression within right-lateralized frontal regions that represent more retrieval effort and the recruitment of a broader semantic field. Associatively related pairs that require a different processing of the related target compared to the prime may lead to the response enhancement within left inferior frontal regions. Nevertheless, the differences between associative and categorical relations might be parametrical rather than absolutely distinct as both relationships recruit similar regions to a different degree.
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