Differential effect of quetiapine and lithium on functional connectivity of the striatum in first episode mania

Mood disturbances seen in first-episode mania (FEM) are linked to disturbed functional connectivity of the striatum. Lithium and quetiapine are effective treatments for mania but their neurobiological effects remain largely unknown. We conducted a single-blinded randomized controlled maintenance trial in 61 FEM patients and 30 healthy controls. Patients were stabilized for a minimum of 2 weeks on lithium plus quetiapine then randomly assigned to either lithium (serum level 0.6 mmol/L) or quetiapine (dosed up to 800 mg/day) treatment for 12 months. Resting-state fMRI was acquired at baseline, 3 months (patient only) and 12 months. The effects of treatment group, time and their interaction, on striatal functional connectivity were assessed using voxel-wise general linear modelling. At baseline, FEM patients showed reduced connectivity in the dorsal (p = 0.05) and caudal (p = 0.008) cortico-striatal systems when compared to healthy controls at baseline. FEM patients also showed increased connectivity in a circuit linking the ventral striatum with the medial orbitofrontal cortex, cerebellum and thalamus (p = 0.02). Longitudinally, we found a significant interaction between time and treatment group, such that lithium was more rapid, compared to quetiapine, in normalizing abnormally increased functional connectivity, as assessed at 3-month and 12-month follow-ups. The results suggest that FEM is associated with reduced connectivity in dorsal and caudal corticostriatal systems, as well as increased functional connectivity of ventral striatal systems. Lithium appears to act more rapidly than quetiapine in normalizing hyperconnectivity of the ventral striatum with the cerebellum

Selective augmentation of striatal functional connectivity following NMDA receptor antagonism: implications for psychosis

The psychotomimetic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is thought to arise from a functional modulation of the brain's fronto-striato-thalamic (FST) circuits. Animal models suggest a pronounced effect on ventral ‘limbic' FST systems, although recent work in patients with psychosis and high-risk individuals suggests specific alterations of dorsal ‘associative' FST circuits. Here, we used functional magnetic resonance imaging to investigate the effects of a subanesthetic dose of ketamine on measures of functional connectivity as indexed by the temporal coherence of spontaneous neural activity in both dorsal and ventral FST circuits, as well as their symptom correlates. We adopted a placebo-controlled, double-blind, randomized, repeated-measures design in which 19 healthy participants received either an intravenous saline infusion or a racemic mixture of ketamine (100 ng/ml) separated by at least 1 week. Compared with placebo, ketamine increased functional connectivity between the dorsal caudate and both the thalamus and midbrain bilaterally. Ketamine additionally increased functional connectivity of the ventral striatum/nucleus accumbens and ventromedial prefrontal cortex. Both connectivity increases significantly correlated with the psychosis-like and dissociative symptoms under ketamine. Importantly, dorsal caudate connectivity with the ventrolateral thalamus and subthalamic nucleus showed inverse correlation with ketamine-induced symptomatology, pointing to a possible resilience role to disturbances in FST circuits. Although consistent with the role of FST in mediating psychosis, these findings contrast with previous research in clinical samples by suggesting that acute NMDAR antagonism may lead to psychosis-like experiences via a mechanism that is distinct from that implicated in frank psychotic illness

In vivo hippocampal subfield volumes in bipolar disorder—A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD

The role of brain fronto-striato-thalamic networks in psychosis: clinical and experimental resting-state fMRI studies

© 2014 Dr. Orwa DandashPublication included in thesis:Dandash, O., Fornito, A., Lee, J., Keefe, R. S. E., Chee, M. W. L., Adcock, R. A., Pantelis, C., Wood, S. J. & Harrison, B. J. (2014). Altered striatal functional connectivity in subjects with an at-risk mental state for psychosis. Schizophrenia Bulletin, 40(4), 904-913. DOI: 10.1093/schbul/sbt093Psychosis is a severe mental illness that blurs the boundaries between reality and illusion, confining patients to a world that is considered mostly outside of normal experience. Accumulating evidence suggests that disruption of functionally integrated brain networks—i.e., neural dysconnectivity—may underlie the pathophysiology of psychosis. The evidence further points to specific involvement of the brain’s fronto-striato-thalamic networks (FSTNs), a group of anatomically and functionally connected brain regions that work in synchrony to mediate cognitive, motor and affective processes. This thesis aimed to address a number of vital questions concerning the relevance of FSTNs to the pathophysiology of psychosis, including whether dysconnectivity in these networks pre-date psychosis onset, are under genetic control, and can be linked to specific neurochemical mechanisms. I utilized resting-state functional magnetic resonance imaging (fMRI), a validated and sensitive tool for probing the functional integrity of discrete neural networks, to address these questions. Firstly, I investigated putative disturbances in the temporal coherence of fMRI signals—so-called functional connectivity—among regions comprising the FSTNs in individuals experiencing an at-risk mental state (ARMS) for psychosis. The findings of this work indicated that disruptions in the functional connectivity of both dorsal and ventral FSTNs distinguished ARMS individuals from healthy control subjects. Moreover, the magnitude of dysconnectivity in these subjects correlated significantly with positive psychotic symptoms, such as delusional ideation and hallucination, linking these aberrations to clinical expression. This analysis was followed by an investigation into the heritability of the identified disturbances in FSTNs functional connectivity. The unique variance in FSTN functional connectivity attributable to additive genetic effects was modeled in a sample of identical monozygotic (MZ) and non-identical dizygotic (DZ) twins. Studying these disturbances in twins revealed moderately strong genetic influences, particularly with the dorsal (cognitive) network where 50% of the variance in functional connectivity between the dorsal caudate and the dorsolateral prefrontal cortex (DLPFC) was explained by genetic factors. The study additionally suggested that unique environmental effects accounted for the remaining 50% of the variance, while there was no influence of common environmental effects. Finally, the mechanistic basis of FSTN dysconnectivity was assessed. In particular, the potential impact of hypofunctional N-Methyl-D-Aspartate receptors (NMDARs), one of the primary candidate molecular pathologies proposed for schizophrenia, was determined using a pharmacological challenge. I investigated whether acute NMDAR antagonism in healthy volunteers via the intravenous infusion of the psychotomimetic agent ketamine induces FSTN connectivity changes redolent of those identified in ARMS subjects. The volunteers were assessed for psychosis-like symptoms and FSTN functional connectivity following both ketamine and placebo (saline) infusion. In contrast to the general reduction in functional connectivity identified in ARMS subjects, ketamine specifically increased functional connectivity in FSTNs. Furthermore, ketamine-induced psychotic experiences correlated significantly with these drug-related changes in FSTN functional connectivity. Together, the body of work presented in this thesis provides a number of novel and unique findings that serve to advance the current state of knowledge regarding the pathophysiology of psychosis. Specifically, the findings point to the utility of resting-state fMRI to probe changes in brain function prior to the onset of psychosis and provide direct support for the role of the FSTNs, especially the dorsal (cognitive) network, as a risk biomarker for the illness that is influenced by genetic as well as unique environmental factors. In addition, the findings challenge current pharmacological models of psychosis by demonstrating that acute administration of ketamine may not recapitulate the neurobiological disturbances evident in the psychosis prodrome

Specific functional connectivity alterations of the dorsal striatum in young people with depression

Background: Altered basal ganglia function has been implicated in the pathophysiology of youth Major Depressive Disorder (MDD). Studies have generally focused on characterizing abnormalities in ventral “affective” corticostriatal loops supporting emotional processes. Recent evidence however, has implicated alterations in functional connectivity of dorsal “cognitive” corticostriatal loops in youth MDD. The contribution of dorsal versus ventral corticostriatal alterations to the pathophysiology of youth MDD remains unclear. Methods: Twenty-one medication-free patients with moderate-to-severe MDD between the ages of 15 and 24 years old were matched with 21 healthy control participants. Using resting-state functional connectivity magnetic resonance imaging we systematically investigated connectivity of eight dorsal and ventral subdivisions of the striatum. Voxelwise statistical maps of each subregion's connectivity with other brain areas were compared between the depressed and control groups. Results: Depressed youths showed alterations in functional connectivity that were confined to the dorsal corticostriatal circuit. Compared to controls, depressed patients showed increased connectivity between the dorsal caudate nucleus and ventrolateral prefrontal cortex bilaterally. Increased depression severity correlated with the magnitude of dorsal caudate connectivity with the right dorsolateral prefrontal cortex. There were no significant between-group differences in connectivity of ventral striatal regions. Conclusions: The results provide evidence that alterations in corticostriatal connectivity are evident at the early stages of the illness and are not a result of antidepressant treatment. Increased connectivity between the dorsal caudate, which is usually associated with cognitive processes, and the more affectively related ventrolateral prefrontal cortex may reflect a compensatory mechanism for dysfunctional cognitive-emotional processing in youth depression

Quetiapine v. lithium in the maintenance phase following a first episode of mania:Randomised controlled trial

javax.xml.bind.JAXBElement@5d55dac4 Lithium and quetiapine are considered standard maintenance agents for bipolar disorder yet it is unclear how their efficacy compares with each other. javax.xml.bind.JAXBElement@17dab71d To investigate the differential effect of lithium and quetiapine on symptoms of depression, mania, general functioning, global illness severity and quality of life in patients with recently stabilised first-episode mania. javax.xml.bind.JAXBElement@7f326b9f Maintenance trial of patients with first-episode mania stabilised on a combination of lithium and quetiapine, subsequently randomised to lithium or quetiapine monotherapy (up to 800 mg/day) and followed up for 1 year. (Trial registration: Australian and New Zealand Clinical Trials Registry - ACTRN12607000639426.) javax.xml.bind.JAXBElement@4e6339d In total, 61 individuals were randomised. Within mixed-model repeated measures analyses, significant omnibus treatment × visit interactions were observed for measures of overall psychopathology, psychotic symptoms and functioning. Planned and javax.xml.bind.JAXBElement@77964a3f comparisons further demonstrated the superiority of lithium treatment over quetiapine. javax.xml.bind.JAXBElement@35b6698f In people with first-episode mania treated with a combination of lithium and quetiapine, continuation treatment with lithium rather than quetiapine is superior in terms of mean levels of symptoms during a 1-year evolution

Intracranial and subcortical volumes in adolescents with early-onset psychosis: A multisite mega-analysis from the ENIGMA consortium.

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis

In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics throughMeta-AnalysisBipolar Disorder Working Group

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen'sd = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD