Prefrontal Brain Structures Research Articles

Distress severity in perceptual anomalies moderates the relationship between prefrontal brain structure and psychosis proneness in nonclinical individuals

In the general population, psychosis risk phenotypes occur independently of attenuated prodromal syndromes. Neurobiological correlates of vulnerability could help to understand their meaningfulness. Interactions between the occurrence of psychotic-like experiences (PLE) and other psychological factors e.g., distress related to PLE, may distinguish psychosis-prone individuals from those without risk of future psychotic disorder. We aimed to investigate whether (a) correlates of total PLE and distress, and (b) symptom dimension-specific moderation effects exist at the brain structural level in non-help-seeking adults reporting PLE below and above the screening criterion for clinical high-risk (CHR). We obtained T1-weighted whole-brain MRI scans from 104 healthy adults from the community without psychosis CHR states for voxel-based morphometry (VBM). Brain structural associations with PLE and PLE distress were analysed with multiple linear regression models. Moderation of PLE by distress severity of two types of positive symptoms from the Prodromal Questionnaire (PQ-16) screening inventory was explored in regions-of-interest after VBM. Total PQ-16 score was positively associated with grey matter volume (GMV) in prefrontal regions, occipital fusiform and lingual gyri (p < 0.05, FDR peak-level corrected). Overall distress severity and GMV were not associated. Examination of distress severity on the positive symptom dimensions as moderators showed reduced strength of the association between PLE and rSFG volume with increased distress severity for perceptual PLE. In this study, brain structural variation was related to PLE level, but not distress severity, suggesting specificity. In healthy individuals, positive relationships between PLE and prefrontal volumes may indicate protective features, which supports the insufficiency of PLE for the prediction of CHR. Additional indicators of vulnerability, such as distress associated with perceptual PLE, change the positive brain structure relationship. Brain structural findings may strengthen clinical objectives through disentanglement of innocuous and risk-related PLE.

Evidence for a sex-specific contribution of polygenic load for anorexia nervosa to body weight and prefrontal brain structure in nonclinical individuals.

Genetic predisposition and brain structural abnormalities have been shown to be involved in the biological underpinnings of anorexia nervosa (AN). Prefrontal brain regions are suggested to contribute through behavioral inhibition mechanisms to body weight. However, it is unknown if and to which extent biological correlates for AN might be present in individuals without clinical AN symptomatology. We therefore investigated the contribution of polygenic load for AN on body weight and prefrontal brain structure in a sample of n = 380 nonclinical individuals. A polygenic score (PGS) reflecting the individual genetic load for the trait of anorexia nervosa was calculated. Structural MRI data were acquired and preprocessed using the cortical parcellation stream of FreeSurfer. We observed a significant PGS × sex interaction effect on body mass index (BMI), which was driven by a negative correlation between PGS and BMI in female participants. Imaging analyses revealed significant interaction effects of sex × PGS on surface area of the lateral orbitofrontal cortex (OFC), the pars orbitalis (PO), the rostral middle frontal gyrus (RMF) and the pars triangularis (PT) of the left frontal cortex. The interaction effects were driven by positive correlations between PGS and prefrontal surface areas in female participants and negative correlations in male participants. We furthermore found sex-specific associations between BMI and left RMF surface area as well as between BMI and left PO and left RMF thickness. Our findings demonstrate a sex-specific association between polygenic load for AN, BMI, and prefrontal brain structure in nonclinical individuals. Hence, this study identifies structural abnormalities associated with polygenic load for AN and BMI in brain regions deeply involved in behavioral inhibition and impulse regulation as candidate brain regions for future research.

Hippocampal metabolism and prefrontal brain structure: A combined 1H-MR spectroscopy, neuropsychological, and voxel-based morphometry (VBM) study

Hippocampal structural and functional integrity impacts on multiple remote areas of the brain, and this connectivity is central to multiple cognitive functions in healthy and disease. We studied associations of hippocampal metabolic markers N-acetyl aspartate (NAA) and glutamate (Glu and Glx; assessed with 1H magnetic resonance spectroscopy) and brain grey matter (studied with voxel-based morphometry, VBM) in 20 healthy subjects. We found a significant correlation between right hippocampal NAA and left ventrolateral prefrontal cortical grey matter (TFCE, p<0.05, FWE-corrected), as well as verbal fluency markers, and right hippocampal Glx (glutamate/glutamine) and left cerebellar volume. Our studies demonstrate a structure-function correlation that might underlie the interaction of the hippocampus with prefrontal cortex and cerebellum, which might be central to several neurological and psychiatric disorders, including schizophrenia or depression.

The effect of age on cognitive performance of frontal patients

Age is known to affect prefrontal brain structure and executive functioning in healthy older adults, patients with neurodegenerative conditions and TBI. Yet, no studies appear to have systematically investigated the effect of age on cognitive performance in patients with focal lesions. We investigated the effect of age on the cognitive performance of a large sample of tumour and stroke patients with focal unilateral, frontal (n=68), or non-frontal lesions (n=45) and healthy controls (n=52). We retrospectively reviewed their cross sectional cognitive and imaging data. In our frontal patients, age significantly predicted the magnitude of their impairment on two executive tests (Raven's Advanced Progressive Matrices, RAPM and the Stroop test) but not on nominal (Graded Naming Test, GNT) or perceptual (Incomplete Letters) task. In our non-frontal patients, age did not predict the magnitude of their impairment on the RAPM and GNT. Furthermore, the exacerbated executive impairment observed in our frontal patients manifested itself from middle age. We found that only age consistently predicted the exacerbated executive impairment. Lesions to specific frontal areas, or an increase in global brain atrophy or white matter abnormalities were not associated with this impairment. Our results are in line with the notion that the frontal cortex plays a critical role in aging to counteract cognitive and neuronal decline. We suggest that the combined effect of aging and frontal lesions impairs the frontal cortical systems by causing its computational power to fall below the threshold needed to complete executive tasks successfully.

The suppression of brain activation in post-deployment military personnel with posttraumatic stress symptoms.

Previous research using cognitive paradigms has found task-related activation that includes prefrontal brain structures and that is attenuated in association with posttraumatic stress symptoms (PTSS). The present investigation used a cognitive control paradigm, the Arrows Task, to study subjects who had not sustained a traumatic brain injury during deployment and who had a wide range of scores on the Posttraumatic Stress Disorder Checklist (PCL). During the Arrows Task there was no significant activation within the full sample of 15 subjects, but deactivation was found within areas that are likely to be involved in cognitive control, including the dorsal anterior cingulate gyrus and parietal cortex. Exploratory analyses were also conducted to compare subjects with relatively high PTSS (HIGH PTSS, n = 7) to those with lower severity or no symptoms (LOW PTSS, n = 8). LOW PTSS subjects exhibited activation in nonfrontal brain areas and their activation was greater relative to the HIGH PTSS subjects. In contrast, the HIGH PTSS group had extensive deactivation and there was a negative relationship between activation and PCL scores within subcortical structures, the cerebellum, and higher-order cortical association areas. For the HIGH PTSS group there was also a positive relationship between PCL scores and activation within basic sensory and motor areas, as well as structures thought to have a role in emotion and the regulation of internal bodily states. These findings are consistent with widespread neural dysfunction in subjects with greater PTSS, including changes similar to those reported to occur with acute stress and elevated noradrenergic activity.

Mindfulness training for adolescents: A neurodevelopmental perspective on investigating modifications in attention and emotion regulation using event-related brain potentials

Mindfulness training is increasingly being introduced in schools, yet studies examining its impact on the developing brain have been scarce. A neurodevelopmental perspective on mindfulness has been advocated as a powerful tool to enhance our understanding of underlying neurocognitive changes that have implications for developmental well-being research and the implementation of mindfulness in education. To stimulate more research in the developmental cognitive neuroscience of mindfulness, this article outlines possible indexes of mindfulness-based change in adolescence, with a focus on event-related brain potential (ERP) markers. We provide methodological recommendations for future studies and offer examples of research paradigms. We also discuss how mindfulness practice could impact on the development of prefrontal brain structures and enhance attention control and emotion regulation skills in adolescents, impacting in turn on their self-regulation and coping skills. We highlight advantages of the ERP methodology in neurodevelopmental research of mindfulness. It is proposed that research using established experimental tasks targeting ERP components such as the contingent negative variability, N200, error-related negativity and error positivity, P300, and late positive potential could elucidate developmentally salient shifts in the neural plasticity of the adolescent brain induced by mindfulness practice.

The low-frequency blood oxygenation level-dependent functional connectivity signature of the hippocampal–prefrontal network in the rat brain

Interactions between the hippocampus and the prefrontal cortex (PFC) are of major interest in the neurobiology of psychiatric and neurodegenerative disorders and are central to many experimental rodent models. Non-invasive imaging techniques offer a translatable approach to probing this system if homologous features can be identified across species. The objective of the present study was to systematically characterize the rat brain connectivity signature derived from low-frequency resting blood oxygenation level-dependent (BOLD) oscillations associated with and within the hippocampal–prefrontal network, using an array of small seed locations within the relatively large anatomical structures comprising this system. A heterogeneous structure of functional connectivity, both between and within the hippocampal–prefrontal brain structures, was observed. In the hippocampal formation, the posterior (subiculum) region correlated more strongly than the anterior dorsal hippocampus with the PFC. A homologous relationship was found in the human hippocampus, with differential functional connectivity between hippocampal locations proximal to the fornix body relative to locations more distal being localized to the medial prefrontal regions in both species. The orbitofrontal cortex correlated more strongly with sensory cortices and a heterogeneous dependence of functional coupling on seed location was observed along the midline cingulate and retrosplenial cortices. These findings are all convergent with known anatomical connectivity, with stronger BOLD correlations corresponding to known monosynaptic connections. These functional connectivity relationships may provide a useful translatable probe of the hippocampal–prefrontal system for the further study of rodent models of disease and potential treatments, and inform electrode placement in electrophysiology to yield more precise descriptors of the circuits at risk in psychiatric disease.

Amygdala responsiveness to emotional words is modulated by subclinical anxiety and depression

Several neuroimaging studies underlined the importance of the amygdala and prefrontal brain structures (e.g. dorsolateral prefrontal cortex [DLPFC]) for the processing of emotional stimuli and for emotion regulation. Many studies used visual scenes or faces as emotion-inducing material, and there is evidence that negative or positive words activate emotion-processing brain regions in the same way. However, no study so far focused on the influence of subclinical measures of anxiety or depression on the neural processing of emotional words. In this fMRI-study, we therefore investigated brain activation to emotional words in relation to subclinical measures of trait anxiety and depression in a sample of 21 healthy subjects. We also assessed effects of subclinical anxiety and depression on amygdala–prefrontal coupling during negative (versus neutral) word reading. Both negative and positive words activated the amygdala, and negative-word processing revealed a positive correlation between amygdala activity and scores of trait anxiety and subclinical depression. During negative versus neutral word reading, subjects with high trait anxiety also showed a stronger functional coupling between left amygdala and left DLPFC. These results suggest a modulation of negative-word processing by subclinical depression and anxiety, as well as possible prefrontal compensatory processes during unintentional emotion regulation in subjects with higher trait anxiety.

Differential associations between types of verbal memory and prefrontal brain structure in healthy aging and late life depression

Verbal memory deficits attributed to late life depression (LLD) may result from executive dysfunction that is more detrimental to list-learning than story-based recall when compared to healthy aging. Despite these behavioral dissociations, little work has been done investigating related neuroanatomical dissociations across types of verbal memory performance in LLD. We compared list-learning to story-based memory performance in 24 non-demented individuals with LLD (age∼66.1±7.8) and 41 non-demented/non-depressed healthy controls (HC; age∼67.6±5.3). We correlated significant results of between-group analyses across memory performance variables with brain volumes of frontal, temporal and parietal regions known to be involved with verbal learning and memory. When compared to the HC group, the LLD group showed significantly lower verbal memory performance for spontaneous recall after repeated exposure and after a long-delay but only for the list-learning task; groups did not differ on story-based memory performance. Despite equivalent brain volumes across regions, only the LLD group showed brain associations with verbal memory performance and only for the list-learning task. Specifically, frontal volumes important for subjective organization and response monitoring correlated with list-learning performance in the LLD group. This study is the first to demonstrate neuroanatomical dissociations across types of verbal memory performance in individuals with LLD. Results provide structural evidence for the behavioral dissociations between list-learning and story-based recall in LLD when compared to healthy aging. More specifically, it points toward a network of predominantly anterior brain regions that may underlie the executive contribution to list-learning in older adults with depression.

P-978 - Clinical presentation of depression comorbid to posttraumatic stress disorder

The aim of the investigation was to determine the group of symptoms which are the most prominent in depression comorbid to PTSD. The results were interpreted regarding the patterns of cerebral activity in PTSD and in depression. 120 patients were divided in experimental (depression-PTSD) and control (depression-only) group and evaluated using the following instruments: MADRS, HDRS-17 and QIDS-SR. The statistical analysis was performed by mean of Student t-test and Mann -Whitney U test. Symptoms which differed most significantly between the two groups were: On MADRS instrument inner tension, sleep disturbances trouble concentrating, lassitude, inability to feel and pessimistic thoughts (p,0,001). On HDRS-17 instrument:: early, middle and late insomnia, agitation, work and activities (p < 0,001). On QIDS instrument: early, middle and late insomnia, concentration, interest and decision-making (p < 0,001). The depression is accompanied by the increased activity of the brain centers engaged in the processing of emotional informations - the very regions that are “switched - off” in PTSD. Depressive symptoms comorbid to PTSD are not the results of the increased activation of the neural circuits by the two pathophysiological processes, but there is the case of differential engagement of neural networks in which stimulation from the lbrain structures responsible for generation of emotional input, increasingly arrives into the prefrontal brain structures, in which more intense and deeper emotional processing takes place causing more intense experience of emotional stimuli and bridging the connection from perceptual and cognitive contents up to affective and visceral centers of the organismus.

Keine Assoziation zwischen Alexithymie und dem Catechol-O-Methyltransferase Val158Met-Polymorphismus

Reduced concentrations of dopamine in prefrontal brain structures may play a role in alexithymia. Dopamine degradation in the orbitofrontal cortex is regulated by catechol-O-methyltransferase (COMT), and a functional single nucleotide polymorphism of the COMT gene, Val158Met, has been related to psychiatric illness. This study examines the association between the COMT Val158Met gene polymorphism, and alexithymia. 120 healthy students and 120 patients with mental disorders were genotyped for the COMT Val158Met polymorphism. Additionally, the Toronto Alexithymia Scale (TAS-20) was administered. COMT genotype did not show a significant correlation with the TAS-20 in either group. COMT Val158Met polymorphism alone does not seem to be a major factor in alexithymia in healthy students. This is true even if patients with mental disorders covering a broader range of alexithymia are included. Thus, other genes, possibly interacting with cultural, environmental, and developmental factors, may be implicated.

COMT genotype affects prefrontal white matter pathways in children and adolescents

Diffusion tensor imaging is widely used to evaluate the development of white matter. Information about how alterations in major neurotransmitter systems, such as the dopamine (DA) system, influence this development in healthy children, however, is lacking. Catechol-O-metyltransferase (COMT) is the major enzyme responsible for DA degradation in prefrontal brain structures, for which there is a corresponding genetic polymorphism (val158met) that confers either a more or less efficient version of this enzyme. The result of this common genetic variation is that children may have more or less available synaptic DA in prefrontal brain regions. In the present study we examined the relation between diffusion properties of frontal white matter structures and the COMT val158met polymorphism in 40 children ages 9–15. We found that the val allele was associated with significantly elevated fractional anisotropy values and reduced axial and radial diffusivities. These results indicate that the development of white matter in healthy children is related to COMT genotype and that alterations in white matter may be related to the differential availability of prefrontal DA. This investigation paves the way for further studies of how common functional variants in the genome might influence the development of brain white matter.

Feeling present in arousing virtual reality worlds: prefrontal brain regions differentially orchestrate presence experience in adults and children

Virtual reality (VR) is a powerful tool for simulating aspects of the real world. The success of VR is thought to depend on its ability to evoke a sense of “being there”, that is, the feeling of “Presence”. In view of the rapid progress in the development of increasingly more sophisticated virtual environments (VE), the importance of understanding the neural underpinnings of presence is growing. To date however, the neural correlates of this phenomenon have received very scant attention. An fMRI-based study with 52 adults and 25 children was therefore conducted using a highly immersive VE. The experience of presence in adult subjects was found to be modulated by two major strategies involving two homologous prefrontal brain structures. Whereas the right DLPFC controlled the sense of presence by down-regulating the activation in the egocentric dorsal visual processing stream, the left DLPFC up-regulated widespread areas of the medial prefrontal cortex known to be involved in self-reflective and stimulus-independent thoughts. In contrast, there was no evidence of these two strategies in children. In fact, anatomical analyses showed that these two prefrontal areas have not yet reached full maturity in children. Taken together, this study presents the first findings that show activation of a highly specific neural network orchestrating the experience of presence in adult subjects, and that the absence of activity in this neural network might contribute to the generally increased susceptibility of children for the experience of presence in VEs.

Increased NoGo-anteriorisation in first-episode schizophrenia patients during Continuous Performance Test

Objective NoGo-stimuli during a Continuous Performance Test (CPT) activate prefrontal brain structures such as the anterior cingulate gyrus and lead to an anteriorisation of the positive electrical field of the NoGo-P300 relative to the Go-P300, so-called NoGo-anteriorisation (NGA). NGA during CPT is regarded as a neurophysiological standard index for cognitive response control. While it is known that patients with chronic schizophrenia exhibit a significant reduction in NGA, it is unclear whether this also occurs in patients undergoing their first-episode. Thus, the aim of the present study was to determine NGA in a group of patients with first-episode schizophrenia by utilizing a CPT paradigm. Methods Eighteen patients with first-episode schizophrenia and 18 matched healthy subjects were investigated electrophysiologically during a cued CPT, and the parameters of the Go- and NoGo-P300 were determined using microstate analysis. Low resolution tomography analysis (LORETA) was used for source determination. Results Due to a more posterior Go- and a more anterior NoGo-centroid, NGA was greater in patients than in healthy controls. LORETA indicated the same sources for both groups after Go-stimuli, but a more anterior source in patients after NoGo-stimuli. In patients P300-amplitude responses to both Go- and NoGo-stimuli were decreased, and P300-latency to NoGo-stimuli was increased. After the Go-stimuli false reactions and reaction times were increased in patients. Conclusions Attention was reduced in patients with first-episode schizophrenia, as indicated by more false reactions, prolongation of reaction time, P300-latencies and by a decrease in P300-amplitude. Significantly however, the NGA and prefrontal LORETA-sources indicate intact prefrontal brain structures in first-episode schizophrenia patients. Previously described changes in this indicator of prefrontal function may be related to a progressive decay in chronic schizophrenia. Significance The results support the idea of a possible new biological marker of first episode psychosis, which may be a useful parameter for the longitudinal measurement of changing prefrontal brain function in a single schizophrenia patient.

Relationship of Catechol-O-Methyltransferase Variants to Brain Structure and Function in a Population at High Risk of Psychosis

There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the etiopathogenesis of schizophrenia. This study sought to clarify the effects of the COMT Val158Met polymorphism on brain structure, function, and risk of developing schizophrenia in a well-characterized cohort of individuals at high risk of schizophrenia for familial reasons. In a sample of 78 people at high genetic risk of schizophrenia, the risk of progression to schizophrenia associated with the COMT Val allele was estimated. The relationship of the Val allele to brain structure and function was investigated using structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data collected on the high-risk subjects before their disease outcome was known. The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex. In addition, there was evidence of increased activation in lateral prefrontal cortex and anterior and posterior cingulated, with increasing sentence difficulty in those with the COMT Val allele despite a similar level of performance. The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function. These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples.

Effects of Early Onset Brain Injury on the Development of Cognition and Behavior: Introduction to the Special Issue

The effects of brain injury acquired early in life on the development of cognition and behavior are not well understood. Deciphering these effects and modeling their neurodevelopmental trajectories are major concerns for clinicians and scientists. Historically, a prevailing notion has been that early-onset brain damage has a more favorable prognosis than does brain damage acquired in adulthood. However, there is growing evidence suggesting that early-onset damage to prefrontal brain structures may have devastating consequences on the emergence of adaptive behavior throughout development. Particularly prominent are disorders of personality, social behavior, and executive functions such as planning and decision making. This special issue presents a series of new empirical studies that address these issues in depth, from several different perspectives, and in both human and animal participants. The findings promise to shed further light on both the neurobiology of development, and diverse neurodevelopmental disorders. Such advances may also enhance clinical diagnosis and facilitate the design of more effective interventions to help reduce the tremendous burden that neurodevelopmental disorders place on personal well-being, family structure, educational systems, and social resources.

Effect of instructional cues on schizophrenic patients' performance on the Wisconsin Card Sorting Test.

Schizophrenic patients are particularly deficient on measures of executive functioning, notably the Wisconsin Card Sorting Test. This study was conducted to determine the efficacy of a cuing strategy in facilitating performance on this cognitive measure of the integrity of prefrontal brain structures and functioning. Twenty-four schizophrenic inpatients and 24 demographically matched inpatients with mood disorders were administered the Wisconsin Card Sorting Test either with instructional cues at the beginning of the task or with the standard administration procedure. There was a significant benefit of cues for the patients with affective disorders as well as for the schizophrenic patients. The schizophrenic subjects in the uncued condition maintained poor but stable performance throughout the course of the task. The study suggests that the deficit in executive functioning of schizophrenic patients may lie in the formation of concepts, not in their application.

An evaluation of structural and functional prefrontal deficits in schizophrenia: MRI and neuropsychological measures

Magnetic resonance imaging was used to assess prefrontal brain structure in 17 schizophrenic, 18 psychiatric control, and 19 normal control subjects of comparable age, social background, and educational status, while three neuropsychological measures were used to assess prefrontal functioning. Schizophrenic patients had significantly smaller prefrontal areas than both psychiatric control and normal control subjects in all three planes. When posterior brain area and temporal lobe were entered into statistical analysis as covariates, they did not explain the prefrontal deficits. Schizophrenic patients made more perseveration errors on the Wisconsin Card Sorting Task and had fewer correct responses on the Spatial Delayed Response Task than normal control subjects. Schizophrenic patients performed more poorly than psychiatric control subjects on the Block Design Test. No group differences were found on three other nonfrontal tasks. These data lend some support to the role of prefrontal deficits in the development of schizophrenia.