Normalization of impaired emotion inhibition in bipolar disorder mediated by cholinergic neurotransmission in the cingulate cortex.

The muscarinic-cholinergic system is involved in the pathophysiology of bipolar disorder (BD), and contributes to attention and the top-down and bottom-up cognitive and affective mechanisms of emotional processing, functionally altered in BD. Emotion processing can be assessed by the ability to inhibit a response when the content of the image is emotional. Impaired regulatory capacity of cholinergic neurotransmission conferred by reduced M2-autoreceptor availability is hypothesized to play a role in elevated salience of negative emotional distractors in euthymic BD relative to individuals with no history of mood instability. Thirty-three euthymic BD type-I (DSM-V-TR) and 50 psychiatrically-healthy controls underwent functional magnetic resonance imaging (fMRI) and an emotion-inhibition paradigm before and after intravenous cholinergic challenge using the acetylcholinesterase inhibitor, physostigmine (1 mg), or placebo. Mood, accuracy, and reaction time on either recognizing or inhibiting a response associated with an image involving emotion and regional functional activation were examined for effects of cholinergic challenge physostigmine relative to placebo, prioritizing any interaction with the diagnostic group. Analyses revealed that (1) at baseline, impaired behavioral performance was associated with lower activation in the anterior cingulate cortex in BD relative to controls during emotion processing; (2) physostigmine (vs. placebo) affected behavioral performance during the inhibition of negative emotions, without altering mood, and increased activation in the posterior cingulate cortex in BD (vs. controls); (3) In BD, lower accuracy observed during emotion inhibition of negative emotions was remediated by physostigmine and was associated with cingulate cortex overactivation. Our findings implicate abnormal regulation of cholinergic neurotransmission in the cingulate cortices in BD, which may mediate exaggerated emotional salience processing, a core feature of BD.

Neuroanatomical Dysconnectivity Underlying Cognitive Deficits in Bipolar Disorder.

BACKGROUND: Graph theory applied to brain networks is an emerging approach to understanding the brain's topological associations with human cognitive ability. Despite well-documented cognitive impairments in bipolar disorder (BD) and recent reports of altered anatomical network organization, the association between connectivity and cognitive impairments in BD remains unclear. METHODS: We examined the role of anatomical network connectivity derived from T1- and diffusion-weighted magnetic resonance imaging in impaired cognitive performance in individuals with BD (n = 32) compared with healthy control individuals (n = 38). Fractional anisotropy- and number of streamlines-weighted anatomical brain networks were generated by mapping constrained spherical deconvolution-reconstructed white matter among 86 cortical/subcortical bilateral brain regions delineated in the individual's own coordinate space. Intelligence and executive function were investigated as distributed functions using measures of global, rich-club, and interhemispheric connectivity, while memory and social cognition were examined in relation to subnetwork connectivity. RESULTS: Lower executive functioning related to higher global clustering coefficient in participants with BD, and lower IQ performance may present with a differential relationship between global and interhemispheric efficiency in individuals with BD relative to control individuals. Spatial recognition memory accuracy and response times were similar between diagnostic groups and associated with basal ganglia and thalamus interconnectivity and connectivity within extended anatomical subnetworks in all participants. No anatomical subnetworks related to episodic memory, short-term memory, or social cognition generally or differently in BD. CONCLUSIONS: Results demonstrate selective influence of subnetwork patterns of connectivity in underlying cognitive performance generally and abnormal global topology underlying discrete cognitive impairments in BD.

Bipolar Disorder and Gender Are Associated with Frontolimbic and Basal Ganglia Dysconnectivity: A Study of Topological Variance Using Network Analysis.

Well-established structural abnormalities, mostly involving the limbic system, have been associated with disorders of emotion regulation. Understanding the arrangement and connections of these regions with other functionally specialized cortico-subcortical subnetworks is key to understanding how the human brain's architecture underpins abnormalities of mood and emotion. We investigated topological patterns in bipolar disorder (BD) with the anatomically improved precision conferred by combining subject-specific parcellation/segmentation with nontensor-based tractograms derived using a high-angular resolution diffusion-weighted approach. Connectivity matrices were constructed using 34 cortical and 9 subcortical bilateral nodes (Desikan-Killiany), and edges that were weighted by fractional anisotropy and streamline count derived from deterministic tractography using constrained spherical deconvolution. Whole-brain and rich-club connectivity alongside a permutation-based statistical approach was used to investigate topological variance in predominantly euthymic BD relative to healthy volunteers. BP patients (n = 40) demonstrated impairments across whole-brain topological arrangements (density, degree, and efficiency), and a dysconnected subnetwork involving limbic and basal ganglia relative to controls (n = 45). Increased rich-club connectivity was most evident in females with BD, with frontolimbic and parieto-occipital nodes not members of BD rich-club. Increased centrality in females relative to males was driven by basal ganglia and fronto-temporo-limbic nodes. Our subject-specific cortico-subcortical nontensor-based connectome map presents a neuroanatomical model of BD dysconnectivity that differentially involves communication within and between emotion-regulatory and reward-related subsystems. Moreover, the female brain positions more dependence on nodes belonging to these two differently specialized subsystems for communication relative to males, which may confer increased susceptibility to processes dependent on integration of emotion and reward-related information.

A comparative study of segmentation techniques for the quantification of brain subcortical volume.

Manual tracing of magnetic resonance imaging (MRI) represents the gold standard for segmentation in clinical neuropsychiatric research studies, however automated approaches are increasingly used due to its time limitations. The accuracy of segmentation techniques for subcortical structures has not been systematically investigated in large samples. We compared the accuracy of fully automated [(i) model-based: FSL-FIRST; (ii) patch-based: volBrain], semi-automated (FreeSurfer) and stereological (Measure®) segmentation techniques with manual tracing (ITK-SNAP) for delineating volumes of the caudate (easy-to-segment) and the hippocampus (difficult-to-segment). High resolution 1.5 T T1-weighted MR images were obtained from 177 patients with major psychiatric disorders and 104 healthy participants. The relative consistency (partial correlation), absolute agreement (intraclass correlation coefficient, ICC) and potential technique bias (Bland-Altman plots) of each technique was compared with manual segmentation. Each technique yielded high correlations (0.77-0.87, p < 0.0001) and moderate ICC's (0.28-0.49) relative to manual segmentation for the caudate. For the hippocampus, stereology yielded good consistency (0.52-0.55, p < 0.0001) and ICC (0.47-0.49), whereas automated and semi-automated techniques yielded poor ICC (0.07-0.10) and moderate consistency (0.35-0.62, p < 0.0001). Bias was least using stereology for segmentation of the hippocampus and using FreeSurfer for segmentation of the caudate. In a typical neuropsychiatric MRI dataset, automated segmentation techniques provide good accuracy for an easy-to-segment structure such as the caudate, whereas for the hippocampus, a reasonable correlation with volume but poor absolute agreement was demonstrated. This indicates manual or stereological volume estimation should be considered for studies that require high levels of precision such as those with small sample size.

Volume and shape analysis of subcortical brain structures and ventricles in euthymic bipolar I disorder.

Previous structural magnetic resonance imaging (S-MRI) studies of bipolar disorder have reported variable morphological changes in subcortical brain structures and ventricles. This study aimed to establish trait-related subcortical volumetric and shape abnormalities in a large, homogeneous sample of prospectively confirmed euthymic bipolar I disorder (BD-I) patients (n=60), compared with healthy volunteers (n=60). Participants were individually matched for age and gender. Volume and shape metrics were derived from manually segmented S-MR images for the hippocampus, amygdala, caudate nucleus, and lateral ventricles. Group differences were analysed, controlling for age, gender and intracranial volume. BD-I patients displayed significantly smaller left hippocampal volumes and significantly larger left lateral ventricle volumes compared with controls. Shape analysis revealed an area of contraction in the anterior head and medial border of the left hippocampus, as well as expansion in the right hippocampal tail medially, in patients compared with controls. There were no significant associations between volume or shape variation and lithium status or duration of use. A reduction in the head of the left hippocampus in BD-I patients is interesting, given this region's link to verbal memory. Shape analysis of lateral ventricular changes in patients indicated that these are not regionally specific.

Cortical thinning and caudate abnormalities in first episode psychosis and their association with clinical outcome.

First episode psychosis (FEP) has been associated with structural brain changes, largely identified by volumetric analyses. Advances in neuroimaging processing have made it possible to measure geometric properties that may identify subtle structural changes not appreciated by a measure of volume alone. In this study we adopt complementary methods of assessing the structural integrity of grey matter in FEP patients and assess whether these relate to patient clinical and functional outcome at 3 year follow-up. 1.5 Tesla T1-weighted Magnetic Resonance (MR) images were acquired for 46 patients experiencing their first episode of psychosis and 46 healthy controls. Cerebral cortical thickness and local gyrification index (LGI) were investigated using FreeSurfer software. Volume and shape of the hippocampus, caudate and lateral ventricles were assessed using manual tracing and spherical harmonics applied for shape description. A cluster of cortical thinning was identified in FEP compared to controls; this was located in the right superior temporal gyrus, sulcus, extended into the middle temporal gyrus (lateral temporal cortex - LTC). Bilateral caudate volumes were significantly lower in FEP relative to controls and the right caudate also displayed regions of shape deflation in the FEP group. No significant structural abnormalities were identified in cortical LGI or hippocampal or lateral ventricle volume/shape. Neither LTC nor caudate abnormalities were related to change in symptom severity or global functioning 3 years later. LTC and caudate abnormalities are present at the first episode of psychosis but do not appear to directly affect clinical or functional outcome.