State-dependent microstructural white matter changes in bipolar I depression

Abnormalities in fronto-limbic-striatal white matter (WM) have been reported in bipolar disorder (BD), but results have been inconsistent across studies. Furthermore, there have been no detailed investigations as to whether acute mood states contribute to microstructural changes in WM tracts. In order to compare fiber density and structural integrity within WM tracts between BD depression and remission, whole-brain fractional anisotropy (FA) and mean diffusivity (MD) were assessed in 37 bipolar I disorder (BD-I) patients (16 depressed and 21 remitted), and 26 healthy individuals with diffusion tensor imaging. Significantly decreased FA and increased MD in bilateral prefronto-limbic-striatal white matter and right inferior fronto-occipital, superior and inferior longitudinal fasciculi were shown in all BD-I patients versus controls, as well as in depressed BD-I patients compared to both controls and remitted BD-I patients. Depressed BD-I patients also exhibited increased FA in the ventromedial prefrontal cortex. Remitted BD-I patients did not differ from controls in FA or MD. These findings suggest that BD-I depression may be associated with acute microstructural WM changes.

Dynamic causal modeling of load-dependent modulation of effective connectivity within the verbal working memory network

Neuroimaging studies have consistently shown that working memory (WM) tasks engage a distributed neural network that primarily includes the dorsolateral prefrontal cortex, the parietal cortex, and the anterior cingulate cortex. The current challenge is to provide a mechanistic account of the changes observed in regional activity. To achieve this, we characterized neuroplastic responses in effective connectivity between these regions at increasing WM loads using dynamic causal modeling of functional magnetic resonance imaging data obtained from healthy individuals during a verbal n-back task. Our data demonstrate that increasing memory load was associated with (a) right-hemisphere dominance, (b) increasing forward (i.e., posterior to anterior) effective connectivity within the WM network, and (c) reduction in individual variability in WM network architecture resulting in the right-hemisphere forward model reaching an exceedance probability of 99% in the most demanding condition. Our results provide direct empirical support that task difficulty, in our case WM load, is a significant moderator of short-term plasticity, complementing existing theories of task-related reduction in variability in neural networks. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc.

Frontopolar cortical inefficiency may underpin reward and working memory dysfunction in bipolar disorder

Objectives. Emotional dysregulation in bipolar disorder is thought to arise from dysfunction within prefrontal cortical regions involved in cognitive control coupled with increased or aberrant activation within regions engaged in emotional processing. The aim of this study was to determine the common and distinct patterns of functional brain abnormalities during reward and working memory processing in patients with bipolar disorder. Methods. Participants were 36 euthymic bipolar disorder patients and 37 healthy comparison subjects matched for age, sex and IQ. Functional magnetic resonance imaging (fMRI) was conducted during the Iowa Gambling Task (IGT) and the n-back working memory task. Results. During both tasks, patients with bipolar disorder demonstrated a pattern of inefficient engagement within the ventral frontopolar prefrontal cortex with evidence of segregation along the medial-lateral dimension for reward and working memory processing, respectively. Moreover, patients also showed greater activation in the anterior cingulate cortex during the Iowa Gambling Task and in the insula during the n-back task. Conclusions. Our data implicate ventral frontopolar dysfunction as a core abnormality underpinning bipolar disorder and confirm that overactivation in regions involved in emotional arousal is present even in tasks that do not typically engage emotional systems. © 2012 Informa Healthcare.

Pilot investigation of the changes in cortical activation during facial affect recognition with lamotrigine monotherapy in bipolar disorder

Background: Bipolar disorder is associated with dysfunction in prefrontal and limbic areas implicated in emotional processing. Aims: To explore whether lamotrigine monotherapy may exert its action by improving the function of the neural network involved in emotional processing. Method: We used functional magnetic resonance imaging to examine changes in brain activation during a sad facial affect recognition task in 12 stable patients with bipolar disorder when medication-free compared with healthy controls and after 12 weeks of lamotrigine monotherapy. Results: At baseline, compared with controls, patients with bipolar disorder showed overactivity in temporal regions and underactivity in the dorsal medial and right ventrolateral prefrontal cortex, and the dorsal cingulate gyrus. Following lamotrigine monotherapy, patients demonstrated reduced temporal and increased prefrontal activation. Conclusions: This preliminary evidence suggests that lamotrigine may enhance the function of the neural circuitry involved in affect recognition.

Conversational interaction in the scanner:mentalizing during language processing as revealed by MEG

Humans are especially good at taking another's perspective-representing what others might be thinking or experiencing. This "mentalizing" capacity is apparent in everyday human interactions and conversations. We investigated its neural basis using magnetoencephalography. We focused on whether mentalizing was engaged spontaneously and routinely to understand an utterance's meaning or largely on-demand, to restore "common ground" when expectations were violated. Participants conversed with 1 of 2 confederate speakers and established tacit agreements about objects' names. In a subsequent "test" phase, some of these agreements were violated by either the same or a different speaker. Our analysis of the neural processing of test phase utterances revealed recruitment of neural circuits associated with language (temporal cortex), episodic memory (e.g., medial temporal lobe), and mentalizing (temporo-parietal junction and ventromedial prefrontal cortex). Theta oscillations (3-7 Hz) were modulated most prominently, and we observed phase coupling between functionally distinct neural circuits. The episodic memory and language circuits were recruited in anticipation of upcoming referring expressions, suggesting that context-sensitive predictions were spontaneously generated. In contrast, the mentalizing areas were recruited on-demand, as a means for detecting and resolving perceived pragmatic anomalies, with little evidence they were activated to make partner-specific predictions about upcoming linguistic utterances.

Are there theory of mind regions in the brain? A review of the neuroimaging literature

There have been many functional imaging studies of the brain basis of theory of mind (ToM) skills, but the findings are heterogeneous and implicate anatomical regions as far apart as orbitofrontal cortex and the inferior parietal lobe. The functional imaging studies are reviewed to determine whether the diverse findings are due to methodological factors. The studies are considered according to the paradigm employed (e.g., stories vs. cartoons and explicit vs. implicit ToM instructions), the mental state(s) investigated, and the language demands of the tasks. Methodological variability does not seem to account for the variation in findings, although this conclusion may partly reflect the relatively small number of studies. Alternatively, several distinct brain regions may be activated during ToM reasoning, forming an integrated functional "network." The imaging findings suggest that there are several "core" regions in the network-including parts of the prefrontal cortex and superior temporal sulcus-while several more "peripheral" regions may contribute to ToM reasoning in a manner contingent on relatively minor aspects of the ToM task. © 2008 Wiley-Liss, Inc.

Where do bright ideas occur in our brain? Meta-analytic evidence from neuroimaging studies of domain-specific creativity

Many studies have assessed the neural underpinnings of creativity, failing to find a clear anatomical localization. We aimed to provide evidence for a multi-componential neural system for creativity. We applied a general activation likelihood estimation (ALE) meta-analysis to 45 fMRI studies. Three individual ALE analyses were performed to assess creativity in different cognitive domains (Musical, Verbal, and Visuo-spatial). The general ALE revealed that creativity relies on clusters of activations in the bilateral occipital, parietal, frontal, and temporal lobes. The individual ALE revealed different maximal activation in different domains. Musical creativity yields activations in the bilateral medial frontal gyrus, in the left cingulate gyrus, middle frontal gyrus, and inferior parietal lobule and in the right postcentral and fusiform gyri. Verbal creativity yields activations mainly located in the left hemisphere, in the prefrontal cortex, middle and superior temporal gyri, inferior parietal lobule, postcentral and supramarginal gyri, middle occipital gyrus, and insula. The right inferior frontal gyrus and the lingual gyrus were also activated. Visuo-spatial creativity activates the right middle and inferior frontal gyri, the bilateral thalamus and the left precentral gyrus. This evidence suggests that creativity relies on multi-componential neural networks and that different creativity domains depend on different brain regions.

The special case of self-perspective inhibition in mental, but not non-mental, representation

The ventrolateral prefrontal cortex (vlPFC) has been implicated in studies of both executive and social functions. Recent meta-analyses suggest that vlPFC plays an important but little understood role in Theory of Mind (ToM). Converging neuropsychological and functional Magnetic Resonance Imaging (fMRI) evidence suggests that this may reflect inhibition of self-perspective. The present study adapted an extensively published ToM localizer to evaluate the role of vlPFC in inhibition of self-perspective. The classic false belief, false photograph vignettes that comprise the localizer were modified to generate high and low salience of self-perspective. Using a factorial design, the present study identified a behavioural and neural cost associated with having a highly salient self-perspective that was incongruent with the representational content. Importantly, vlPFC only differentiated between high versus low salience of self-perspective when representing mental state content. No difference was identified for non-mental representation. This result suggests that different control processes are required to represent competing mental and non-mental content.

Multiple roles for executive control in belief-desire reasoning:distinct neural networks are recruited for self perspective inhibition and complexity of reasoning

Belief-desire reasoning is a core component of 'Theory of Mind' (ToM), which can be used to explain and predict the behaviour of agents. Neuroimaging studies reliably identify a network of brain regions comprising a 'standard' network for ToM, including temporoparietal junction and medial prefrontal cortex. Whilst considerable experimental evidence suggests that executive control (EC) may support a functioning ToM, co-ordination of neural systems for ToM and EC is poorly understood. We report here use of a novel task in which psychologically relevant ToM parameters (true versus false belief; approach versus avoidance desire) were manipulated orthogonally. The valence of these parameters not only modulated brain activity in the 'standard' ToM network but also in EC regions. Varying the valence of both beliefs and desires recruits anterior cingulate cortex, suggesting a shared inhibitory component associated with negatively valenced mental state concepts. Varying the valence of beliefs additionally draws on ventrolateral prefrontal cortex, reflecting the need to inhibit self perspective. These data provide the first evidence that separate functional and neural systems for EC may be recruited in the service of different aspects of ToM.

On-line puzzle game based assessment & training for ADHD

Attention-deficit hyperactivity disorder (ADHD) is the most prevalent and impairing neurodevelopmental disorder, with worldwide estimates of 5.29%. ADHD is clinically characterized by hyperactivity-impulsivity and inattention, with neuropsychological deficits in executive functions, attention, working memory and inhibition. These cognitive processes rely on prefrontal cortex function; cognitive training programs enhance performance of ADHD participants supporting the idea of neuronal plasticity. Here we propose the development of an on-line puzzle game based assessment and training tool in which participants must deduce the ‘winning symbol’ out of N distracters. To increase ecological validity of assessments strategically triggered Twitter/Facebook notifications will challenge the ability to ignore distracters. In the UK, significant cost for the disorder on health, social and education services, stand at £23m a year. Thus the potential impact of neuropsychological assessment and training to improve our understanding of the pathophysiology of ADHD, and hence our treatment interventions and patient outcomes, cannot be overstated.