Benny Liberg

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case–control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen’s d=−0.232; P=3.50 × 10−7) and thalamus (d=−0.148; P=4.27 × 10−3) and enlarged lateral ventricles (d=−0.260; P=3.93 × 10−5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Volumetrics of the caudate nucleus: Reliability and validity of a new manual tracing protocol

Our aim was to develop a reliable and valid manual segmentation protocol for tracing the caudate nucleus in MRI for volumetric and, potentially, shape analysis of the caudate. Using the protocol, two inter- and intra-rater reliability studies were conducted using five different raters on two different image analysis platforms (ANALYZE, Mayo Biomedical Imaging Resource, Rochester MN, USA, and HERMES, Nuclear Diagnostics AB, Stockholm, Sweden). Reference images for the detailed protocol are described. Two studies were performed. In study 1, the intra-rater class correlation ICC(1,1) for an experienced rater (JCLL) using this protocol for caudate nucleus volumes was evaluated by repeating right and left caudate measurements on 10 scans (20 comparisons) and was 0.972. The inter-rater class correlation ICC(1,k) with OL was 0.922 on 5 scans (10 comparisons) and with BL was 0.960 on 5 scans (10 comparisons). In study 2, VT obtained an intra-rater class correlation of 0.9 on 5 scans (involving 10 comparisons, e.g. right and left caudate). The inter-rater class correlation ICC(1,k) was 0.988 on 5 scans (again involving 10 comparisons) with EM. We therefore developed a novel, reliable and reference image-based, method of outlining the caudate nucleus on axial MRI scans, usable in two different image analysis laboratories, across two different sets number of tracers reliably, and across software platforms. This method is therefore potentially usable for any image analysis package capable of displaying and measuring outlined voxels from MRI brain scans.

Caudate volumes in public transportation workers exposed to trauma in the Stockholm train system

The caudate nucleus is a structure implicated in the neural circuitry of psychological responses to trauma. This study aimed to quantify the volume of the caudate in persons exposed to trauma. Thirty-six subjects under 65 were recruited from transport workers in Stockholm who reported having been unintentionally responsible for a person-under-the-train accident or among employees having experienced an assault in their work (1999-2001) between 3 months and 6 years before MRI scanning. In those exposed to the trauma, a DSM-IV diagnosis of post-traumatic stress disorder (PTSD) was made by an independent psychiatrist, with subjects being classified as PTSD or no PTSD. MRI data were analyzed blindly to all clinical information by an experienced rater using a standardized manual tracing protocol to quantify the volume of the caudate. Within-group comparisons of PTSD (n=19) and no PTSD (n=17) found the right caudate nucleus to be significantly (9%) larger than the left: a right hemisphere baseline asymmetry. A multivariate analysis of covariance (MANCOVA) was conducted to assess the volume of the caudate nucleus (right and left) in relation to the diagnosis of no PTSD (n=17) or PTSD (n=19). After adjustment for the covariates (age, sex, intracranial volume, years since trauma, and number of trauma episodes), there was a significant difference in raw right caudate nucleus volume between subjects with PTSD compared with those without PTSD. Volume of the left caudate nucleus was not significantly different between the PTSD and no PTSD groups. The right caudate volume in the PTSD group was 9% greater compared with the no PTSD group. There is a larger right hemisphere volume of the caudate within those exposed to trauma with active PTSD compared with those without PTSD, superimposed upon a baseline caudate asymmetry.

Development and validation of the Affective Self Rating Scale for manic, depressive, and mixed affective states

Most rating scales for affective disorders measure either depressive or hypomanic/manic symptoms and there are few scales for hypomania/mania in a self-rating format. We wanted to develop and validate a self-rating scale for comprehensive assessment of depressive, manic/hypomanic and mixed affective states. We developed an 18-item self-rating scale starting with the DSM-IV criteria for depression and mania, with subscales for depression and mania. The scale was evaluated on 61 patients with a diagnosis of affective disorder, predominantly bipolar disorder type I, using Montgomery–Åsberg Depression Rating Scale (MADRS), Hypomania Interview Guide—Clinical version (HIGH-C) and Clinical Global Impression scale, modified for bipolar patients (CGI-BP) as reference scales. Internal consistency of the scale measured by Cronbachs alpha was 0.89 for the depression subscale and 0.91 for the mania subscale. Spearmans correlation coefficients (two-tailed) between the depression subscale and MADRS was 0.74 (P<0.01) and between mania subscale and HIGH-C 0.80 (P<0.01). A rotated factor analysis of the scale supported the separation of symptoms in the mania and depression subscale. We established that the self-rating scales sensitivity to identify mixed states, with combined cut-offs on the MADRS and HIGH-C as reference, was 0.90 with a specificity of 0.71. The study shows that the Affective Self Rating Scale is highly correlated with ratings of established interview scales for depression and mania and that it may aid the detection of mixed affective states.

Rostro-caudal and dorso-ventral gradients in medial and lateral prefrontal cortex during cognitive control of affective and cognitive interference.

Characterizing the anatomical substrates of major brain functions such as cognition and emotion is of utmost importance to the ongoing efforts of understanding the nature of psychiatric ailments and their potential treatment. The aim of our study was to investigate how the brain handles affective and cognitive interferences on cognitive processes. Functional magnetic resonance imaging investigation was performed on healthy individuals, comparing the brain oxygenation level dependent activation patterns during affective and cognitive counting Stroop tasks. The affective Stroop task activated rostral parts of medial prefrontal cortex (PFC) and rostral and ventral parts of lateral PFC, while cognitive Stroop activated caudal parts of medial PFC and caudal and dorsal parts of lateral PFC. Our findings suggest that the brain may handle affective and cognitive interference on cognitive processes differentially, with affective interference preferentially activating rostral and ventral PFC networks and cognitive interference activating caudal and dorsal PFC networks.

Vertex-based morphometry in euthymic bipolar disorder implicates striatal regions involved in psychomotor function

We hypothesized that psychomotor disturbances in patients with bipolar disorder are associated with morphometric changes in functionally specific regions of the basal ganglia and thalamus. We used structural magnetic resonance imaging and vertex-based morphometry to investigate whether psychomotor performance is associated with changes in volume and shape in euthymic subjects with bipolar disorder (n=27) compared with matched healthy controls (n=27). We saw no significant differences between age- and sex-matched groups in motor performance. We found a statistically significant group difference in the shape of the right putamen in the absence of psychomotor disturbances. There was an association between shape and motor performance in controls that was lacking in patients. We conclude that euthymic subjects with bipolar disorder without psychomotor disturbances show shape changes in regions of the right putamen that contribute to executive functions and motor function. It may be that other brain regions sustain the psychomotor functions that produce nearly identical motor performance in both groups.

Motor imagery in bipolar depression with slowed movement

Abstract We hypothesized that motor retardation in bipolar depression is mediated by disruption of the pre-executive stages of motor production. We used functional magnetic resonance imaging to investigate neural activity during motor imagery and motor execution to elucidate whether brain regions that mediate planning, preparation, and control of movement are activated differently in subjects with bipolar depression (n = 9) compared with healthy controls (n = 12). We found significant between-group differences. During motor imagery, the patients activated the posterior medial parietal cortex, the posterior cingulate cortex, the premotor cortex, the prefrontal cortex, and the frontal poles more than the controls did. Activation in the brain areas involved in motor selection, planning, and preparation was altered. In addition, limbic and prefrontal regions associated with self-reference and the default mode network were altered during motor imagery in bipolar depression with motor retardation.

Subcortical morphometry and psychomotor function in euthymic bipolar disorder with a history of psychosis

Psychomotor disturbances are prominent in bipolar disorder patients with a history of psychosis, but their neural correlates remain largely unexplored. We hypothesized that these psychomotor disturbances are associated with morphometric changes in functionally specific regions of the basal ganglia and thalamus. To test if psychomotor performance is associated with changes in volume and shape in these brain regions, we investigated 20 euthymic bipolar disorder patients with a history of psychosis and 20 healthy controls with structural magnetic resonance imaging and vertex-based morphometry. Within the patient group, the local shape of the basal ganglia was significantly associated with longer duration of illness, increased number of manic episodes, and treatment with antipsychotics. There were neither any statistically significant associations between psychomotor performance and morphometric measures in the patient group, nor any significant morphometric differences between patients and controls. We conclude that euthymic subjects with bipolar disorder and a previous history of psychosis show shape changes in regions of the basal ganglia associated to clinical variables that may predict psychomotor disturbances in bipolar disorder.

Differential effects of single-dose escitalopram on cognitive and affective interference during Stroop task

Background and objective: Our aim was to study the regulatory role of serotonin [(5-hydroxytryptamine (5-HT)] on two key nodes in the cognitive control networks – the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). We hypothesized that increasing the levels of 5-HT would preferentially modulate the activity in ACC during cognitive control during interference by negative affects compared to cognitive control during interference by a superimposed cognitive task. Methods: We performed a functional magnetic resonance imaging investigation on 11 healthy individuals, comparing the effects of the selective 5-HT reuptake inhibitor escitalopram on brain oxygenation level dependent signals in the ACC and the DLPFC using affective and cognitive counting Stroop paradigms (aStroop and cStroop). Results: Escitalopram significantly decreased the activity in rostral ACC during aStroop compared to cStroop (p < 0.05). In the absence of escitalopram, both aStroop and cStroop significantly activated ACC and DLPFC (Z ≥ 2.3, p < 0.05). Conclusion: We conclude that escitalopram in a region and task specific manner modified the cognitive control networks and preferentially decreased activity induced by affective interference in the ACC.

The neural correlates of self-paced finger tapping in bipolar depression with motor retardation

Objective Motor retardation is a characteristic feature of bipolar depression, and is also a core feature of Parkinsons disease. Within the framework of the functional deafferentiation theory in Parkinsons disease, we hypothesised that motor retardation in bipolar depression is mediated by disrupted subcortical activation, leading to decreased activation of cortical motor areas during finger tapping. Methods We used functional magnetic resonance imaging to investigate neural activity during self-paced finger tapping to elucidate whether brain regions that mediate preparation, control and execution of movement are activated differently in subjects with bipolar depression (n = 9) compared to healthy controls (n = 12). Results An uncorrected whole-brain analysis revealed significant group differences in dorsolateral and ventromedial prefrontal cortex. Corrected analyses showed non-significant differences in patients compared to controls: decreased and less widespread activation of the left putamen and left pallidum; increased activity in the left thalamus and supplementary motor area; decreased activation in the left lateral pre- and primary motor cortices; absence of activation in the pre-supplementary motor area; activation of the bilateral rostral cingulate motor area. Conclusion Both movement preparation and execution may be affected in motor retardation, and the activity in the whole left-side motor circuit is altered during self-initiated motor performance in bipolar depression.